Next Article in Journal
A Novel Combination Therapy Using Rosuvastatin and Lactobacillus Combats Dextran Sodium Sulfate-Induced Colitis in High-Fat Diet-Fed Rats by Targeting the TXNIP/NLRP3 Interaction and Influencing Gut Microbiome Composition
Next Article in Special Issue
Neuroinflammation in Sepsis: Molecular Pathways of Microglia Activation
Previous Article in Journal
N-3 PUFA Prevent Oxidative Stress in a Rat Model of Beta-Amyloid-Induced Toxicity
Previous Article in Special Issue
CCL-11 or Eotaxin-1: An Immune Marker for Ageing and Accelerated Ageing in Neuro-Psychiatric Disorders
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Pharmaceuticals
Volume 14
Issue 4
10.3390/ph14040340
pharmaceuticals-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Contribution of Pro-Inflammatory Molecules Induced by Respiratory Virus Infections to Neurological Disorders

by
Karen Bohmwald
1,
Catalina A. Andrade
1 and
Alexis M. Kalergis
1,2,*
1
Departamento de Genética Molecular y Microbiología, Millennium Institute on Immunology and Immunotherapy, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331010, Chile
2
Departamento de Endocrinología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago 8331010, Chile
*
Author to whom correspondence should be addressed.
Pharmaceuticals 2021, 14(4), 340; https://doi.org/10.3390/ph14040340
Submission received: 28 February 2021 / Revised: 30 March 2021 / Accepted: 2 April 2021 / Published: 8 April 2021
(This article belongs to the Special Issue Cerebral Production and Action of Pro-inflammatory Cytokines)
Browse Figures
Review Reports Versions Notes

Abstract

Neurobehavioral alterations and cognitive impairment are common phenomena that represent neuropsychiatric disorders and can be triggered by an exacerbated immune response against pathogens, brain injury, or autoimmune diseases. Pro-inflammatory molecules, such as cytokines and chemokines, are produced in the brain by resident cells, mainly by microglia and astrocytes. Brain infiltrating immune cells constitutes another source of these molecules, contributing to an impaired neurological synapse function, affecting typical neurobehavioral and cognitive performance. Currently, there is increasing evidence supporting the notion that behavioral alterations and cognitive impairment can be associated with respiratory viral infections, such as human respiratory syncytial virus, influenza, and SARS-COV-2, which are responsible for endemic, epidemic, or pandemic outbreak mainly in the winter season. This article will review the brain′s pro-inflammatory response due to infection by three highly contagious respiratory viruses that are the leading cause of acute respiratory illness, morbidity, and mobility in infants, immunocompromised and elderly population. How these respiratory viral pathogens induce increased secretion of pro-inflammatory molecules and their relationship with the alterations at a behavioral and cognitive level will be discussed.

1. Introduction

Pro-inflammatory molecules, such as cytokines (e.g., tumor necrosis alpha (TNF-α), interleukin (IL)-1β, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF)) [1,2] and chemokines (e.g., CCL2, CCL3, CCL4, CCL5, CCL11, CXCL-8, and CXCL10) are small signaling molecules that are mainly secreted by immune cells, as well as by brain cells, including microglia, astrocytes, and neurons [3]. These molecules play important roles both in the immune system and for the central nervous system′s normal function (CNS) [4,5]. For example, cytokines participate in the cognitive process, and it has been shown that both the overexpression and the down-regulation of these cytokines alter synaptic plasticity [6,7,8]. According to this concept, the central cytokines involved in the memory and learning processes are IL-1β, IL-6, and TNF-α [7,9,10]. Reports indicate that IL-1β is expressed in the CNS at low levels under certain physiologic conditions and is required for the consolidation of the memory and learning processes [10]. Also, it has been described that an increase or the absence of IL-1β negatively affects the cognition process [6,11].
On the other hand, IL-6 is a pro-inflammatory cytokine found in the CNS under certain physiological conditions and secreted mainly by glial cells [9,12]. It is known that both IL-1β and IL-6 levels are below the limits of detection for protein levels under certain physiological conditions [12]. Moreover, it was shown that IL-6 expression is increased during the LTP process, and the consolidation of this LTP is affected by the inhibition of IL-6 using a neutralizing antibody [9]. Meanwhile, TNF-α is also a pro-inflammatory cytokine that exerts physiological, neuroprotective, and neurodegenerative effects in the CNS [6]. Accordingly, it has been previously reported that TNF-α plays a role in the induction of LTP and LTD because either the absence or overexpression of these cytokines is detrimental to the learning and memory processes [6,13].
Additionally, IFN-γ has been associated with enhanced neurogenesis in adult mice’s’ dentate gyrus and improved spatial learning and memory [6]. Besides, chemokines such as CCL2 and CX3CL1 also contribute to synaptic plasticity in the CNS [14,15,16,17]. CCL2 is constitutively expressed in several zones of the CNS, including the hippocampus, and can modulate different neuron populations′ electrical activity (for instance, hippocampal neurons) [18,19]. Furthermore, CX3CL1 is a chemokine that is constitutively expressed in the CNS, with exceptionally high levels by hippocampal neurons, and the receptor this chemokine is expressed by microglia [17]. It has been shown that CX3CL1 can modulate the glutamatergic synapsis and exert a neuroprotective effect [17,20].
Neurobehavioral alterations and cognitive impairment are part of neuropsychiatric disorders, such as autism spectrum disorder (ASD) [21], schizophrenia (SCZ) [22], mood alterations [23], learning and memory impairment, among others. The incidence of these pathologies is about 10 to 20% worldwide [24]. The etiology of these ailments is multifactorial, where not only genetic factors are relevant, but also the environment can contribute significantly to the triggering of such neuropsychiatric disorders [25]. According to this, several studies have associated the neuroinflammation caused by pro-inflammatory molecules with these neuropsychiatric pathologies [26,27,28].
Schizophrenia (SCZ) is a neurodevelopmental and chronic psychiatric disorder with multifactorial causes, characterized by alterations at the cognitive, behavioral, and emotional levels [29]. Studies have described that reducing the gray matter takes place, mainly in the hippocampus, prefrontal, and temporal cortex [30,31,32]. SCZ has four stages; risk stage, the prodrome of SCZ, the onset of psychosis, and chronic disability stage [33]. A pro-inflammatory component has been shown for this mental disease, with an abnormal serum pattern of cytokines characterized by high levels of IL-2, IL-6, and CXCL8 (also known as IL-8) [34,35,36]. It has been suggested that exposure to increased levels of pro-inflammatory molecules during pregnancy can alter neurodevelopment [37]. Elevated levels of CXCL8 during the second or third trimester of pregnancy can have an impact on the development of the fetus brain, which might lead to an alteration of the synaptic density, neuronal migration, and/or survival of these cells in the cortex. These neurological alterations can contribute to explaining the memory impairment observed in schizophrenia [37].
Meanwhile, the altered secretion of IL-6 and TNF-α during the last trimester of pregnancy has been related to the inhibition of proper synaptic formation and glial cell development [37]. The SCZ is manifested in puberty or early adulthood, where serum IL-1β, IL-6, and TNF-α increase in patients with the first episode of psychosis (FEP) with or without drug treatment [38]. CXCL8 and IFN-γ also have been found elevated in sera from patients with FEP with drug treatment and stable chronic patients [38]. However, these data are controversial due to depending on the experimental design and sample collection of the study.
Another neuropsychiatric illness is autism spectrum disorder (ASD), a behavioral alteration mainly in communication and social interaction, besides the stereotyped behavior with restricted interest [39,40]. The etiology of this disease is heterogeneous, but it is thought that maternal pro-inflammatory molecules′ contribution may contribute to the neurodevelopment of the fetus brain [41,42,43]. Pro-inflammatory cytokines, such as GM-CSF, IL1-α, IL-6, and IFN-γ increase in the serum during the mid-gestational maternal, correlates with a higher risk of ASD and intellectual disability [41]. Furthermore, cytokines that include IL-1β, IL-5, and IL-13, among others, have also been implicated in the severity of ASD after birth [44]. During the first ten years of age, studies have been shown that ASD children have increased level of pro-inflammatory molecules anti-inflammatory molecules such as IL-4 and IL-13 [45,46,47].
In the past few years, the hypothesis that viral infections can be, in part, responsible for the development of neurological illnesses has been explored [25,48]. Consistently, some viruses invade and cause damage to the central nervous system (CNS) directly by infecting the resident cells or by a local inflammation induced for the host immune response [25,49]. Most of the viruses infecting the CNS can spread from the infection site to the peripheral nervous system and travel via axon fibers to the CNS areas, through olfactory nerves and the epithelium [25,50,51]. Viruses can also enter the CNS via a ‘Trojan horse’ mechanism, in which infected leukocytes can carry pathogens from the blood across the blood–brain barrier (BBB) [50,51]. The BBB is a multicellular structure that is part of the neurovascular unit (NVU) and is composed of endothelial cells, pericytes, astrocytes, neurons, and the basement membrane located near the cerebral vasculature [52]. The BBB function is maintenance homeostasis by controlling the passage of macromolecules, cells, and foreign substances, mediating the communication between the periphery and the CNS [52,53]. The endothelial cells are attached to each other through the tight junction that allows forming a monolayer that acts as the first line of defense against circulating molecules and foreign cells [53]. The endothelial cells are attached to each other through the tight junction that allows forming a monolayer that acts as the first line of defense against circulating molecules and foreign cells [53].
On the other hand, astrocytes are the most abundant cell type of the CNS, which has multiple functions, such as pH maintenance, homeostasis of ion concentrations, participates in blood flow regulation, and participates in neurotransmission, the local immune response, among others [53,54]. The pericytes are located in the abluminal surface of the endothelial cells and the vascular basement membrane. These cells are connected with the endothelial cells through gap junctions and are necessary to develop tight junctions even in the uterus′ BBB function [53]. Furthermore, pericytes participate in the BBB integrity, angiogenesis, and microvasculature stability, among others [55].
As was mentioned above, the BBB controls the passage of cells into the CNS. The peripheral immune surveillance is performed by specialized innate immune cells such as macrophages located in the meninges, perivascular spaces, and choroid plexus [56]. Moreover, it is known that monocytes, dendritic cells, and T lymphocytes are present in the cerebrospinal fluid (CSF) of healthy individuals, where the most abundant subset found are activated central memory T cells which monitoring the subarachnoid space [57,58,59,60]. Additionally, these T cells maintain the ability to initiate a local immune response, or in the absence of an injury, these cells can return to a secondary lymphoid organ [59].
The CNS local immune response is commanded by microglia that are the only immune cells found in the brain parenchyma [58,61]. Microglia patrol the healthy CNS and when they found strange signals, increased HLA-DR expression in humans (MHC-II in mouse) due to the antigen presentation capacity [58]. Moreover, microglia can be activated and, depending on the stimuli, polarize to an M1 or M2 phenotype, which secretes pro-inflammatory and anti-inflammatory molecules, respectively [62]. On the other hand, astrocytes also contribute to the CNS immune response, which can detect dangerous signals and respond to secreting pro-inflammatory molecules at the same as microglia. Astrocytes have a cytoskeletal protein named glial fibrillary acid protein (GFAP) that not only allows identifying these cells but also its expression increased where astrocytes are activated [63]. It was established that both glial cells respond quickly to a CNS insult and that the interaction between astrocytes and microglia is crucial for the microglial immune response [64].
It is known that some viruses, such as influenza, hRSV, coronaviruses, among others, can complete their viral cycle in CNS cells and further cause alterations in normal function [25,65,66,67]. However, viral infections can also cause CNS inflammation without brain invasion and lead to alterations in this tissue′s function that could cause neurological damage.

2. Neuroinflammation Induced by Respiratory Viruses

As described above, neuroinflammation can contribute to several behavioral and cognitive disorders [26,27]. Among the most relevant respiratory viruses leading to inflammation in the CNS are the influenza virus, the human respiratory syncytial virus (hRSV), and SARS-CoV2 [68,69,70]. The influenza virus′s relevance is its capability to infect people of a wide range of ages during the winter season and can cause neurological alteration from pregnancy [71,72]. As for the case of hRSV, studies have shown that it is a highly contagious virus that affects mainly infants, which can affect neurological development [73]. Although SARS-CoV2 is an emerging virus that mainly infects young adults and the elderly, it has been shown to affect the CNS [74,75,76]. In this section, we will discuss how the infection by these viruses can promote neuroinflammation and the consequences for the host.

2.1. Influenza Virus

Influenza virus is the most important viral agents causing acute respiratory tract infections in a wide range of ages, which affects between 2% to 10% of the global population [77]. Every year influenza viruses causes around 500,000 death worldwide [77]. Influenza viruses belong to the Orthomyxoviridae family, which includes at least four members; Influenza A (IAV), B (IBV), C (ICV), and D (IDV) [78,79,80]. Only IAV and IBV are responsible for seasonal epidemics annually [79]. The Influenza virus′s viral structure is composed of a segmented single-strand RNA with negative-sense, which has an envelope [79]. The genomes of IAV and IBV consist of eight segments, while ICV has seven segments [80]. The classification of IAV subtypes is based on two structural proteins, hemagglutinin (HA) and neuraminidase (NA), which can be found in eighteen different HA subtypes (H1-H18) and eleven NA subtypes (N1–N11) [67,79]. The H1, H2 and H3, subtypes are relevant for human health because they can be transmitted between individuals and cause neurological symptoms [81,82].
An influenza virus infection can cause severe manifestations, such as pneumonia and acute respiratory distress syndrome [83,84]. The immune response against influenza virus is initiated by the airways epithelial cells, which secrete pro-inflammatory molecules such as IFNα/β, IL-6, TNF-α CCL2, CCL3, CCL5, and CXCL8, allowing the recruitment of natural killer (NK) cells, monocytes, macrophages, dendritic cells (DCs), and neutrophils [85,86,87,88,89]. Upon influenza infection, activated CD4+ T cells polarized to both Th1 and Th2 phenotypes, but Th1 cells are associated with survival after the infection [88]. Also, CD8+ cells are responsible for the viral clearance and bring protection to the host during Influenza infection [87]. Furthermore, the Th17 cells suppress the regulatory T cells (Tregs) function through the secretion of IL-6; meanwhile, Tregs control both the CD4+ and CD8+ T cell responses after infection [88].
The clinical neurological symptoms associated with the influenza virus respiratory infection that has been described consist of encephalitis [90,91,92,93], myelitis [84,94], meningitis [95,96,97], seizures [93,96] and Guillain-Barré syndrome [97,98]. Moreover, influenza virus infection has been related to chronic manifestations, such as SCZ [99,100], ASD [101], and mood disorders. All the evidence about the influenza virus and neurological pathologies suggests direct or indirect effects on the occurrence of neuroinflammation. Despite the neurological symptoms shown by several patients in different studies, the detection of influenza viruses in CSF has been only infrequently reported [102,103,104,105,106]. Furthermore, increased levels of pro-inflammatory molecules, such as IL-1β, IL-6, CXCL8, CCL2, CXCL10, CXCL9, and TNF-α, have been detected in the CSF of patients showing neurological alterations due to influenza virus infection, such as acute encephalitis and encephalopathy [103,107,108]. Further, increased serum levels for IL-6, IL-10, TNF-α, IFN-γ [107,108] have been shown for these patients (Figure 1).
Neuroinflammation has been described during the acute phase of the influenza virus infection [91]. As was mentioned above, besides the neurological symptoms observed in patients, not always the viral RNA can be detected. For this reason, studies performed in mice show that both neurotropic and non-neurotropic strains of the influenza virus can cause CNS alterations [111,112,113,114,115]. Mice intranasally challenged with H5N1 (Vietnam/1203/04) showed viral RNA in the CNS at three days post-infection, demonstrating the neurotropic potential of this strain [115,116]. First, the H5N1 (Vietnam/1203/04) was related to developing a parkinsonian phenotype in mice that is a neurodegenerative pathology characterized by protein aggregation, a phenomenon observed in Influenza virus-infected mice [115]. Furthermore, Influenza virus not only can reach the brain but also can infect resident cells, such as neurons and microglia. Besides, the influenza virus infection promotes microglial apoptosis [116]. Moreover, the profile of pro-inflammatory cytokines, chemokines, and growth factors was evaluated in four brain zones (brainstem, substantia nigra, striatum, and cortex) and different points post-infection (p.i.). In the brainstem, it was observed an increase of pro-inflammatory cytokines, such as IL-1β, IL-12(p70), IL-13, and TNF-α; chemokines, such as CCL2, CCL3, CCL4, CCL11, CXCL10, and CXCL1; growth factors, such as G-CSF, GM-CSF, M-CSF, and anti-inflammatory IL-10 at ten days post-infection (Table 1) [116]. Interestingly, increased levels of IL-1β, IL-2, and VEGF were found 60–90 days p.i. in the substantia nigra, elevated levels of IL-1β, IL-2, IL-6, CCL2, G-CSF, and M-CSF were found during the acute phase of influenza virus infection, whereas CCL4 and GM-CSF increased at 60 days p.i. and then decrease at 90 days p.i. [116]. On the other hand, CCL11 and G-CSF were increased at ten days p.i. and then returned to the baseline levels, whereas that IL-2 showed a biphasic increase (peak at three days p.i. and 60–90 days p.i.) and IL-10 was increased at 60 days p.i. in the striatum [116]. Finally, in the cortex, the levels of IL-1β, IL-9, CCL2, CCL11, CXCL1, CXCL10, and M-CSF have increased only the acute phase of the Influenza virus infection, whereas IL-2 and IL-10 presented a biphasic increase (peak at three days p.i. and 60–90 days p.i.) [116]. On the contrary, VEGF only was increased at 60–90 days p.i. [116]. The results obtained in this study suggest that the neurotropic strain H5N1 can induce a local innate immune response that involves the microglia. The neuroinflammation found in the acute phase of the influenza virus infection may be responsible for the encephalitis or encephalopathies observed in patients [116]. Moreover, the elevated levels of pro-inflammatory molecules after the infection underscore their role in developing neurodegenerative diseases [116]. Another neurotropic strain studied was H7N7 (rSC35M), which can cause long-term neuroinflammation. The data showed that infection with H7N7 promoted cognitive impairment at 30 days p.i. and caused an increase of IFN-γ and TNF-α in both sera and brains at eight days p.i. (Table 1) [113]. Moreover, H7N7 infection also altered the BBB permeability, promoting a strong local immune response that could be involved in the LTP impairment observed in the infected mice, suggesting that the pro-inflammatory molecules could play an important role in the normal function of these brain process [113]. Mouse cortical neurons were infected in culture with two strains of H1N1 (A/PR/8/34 and A/Shantou/169/2006) to evaluate the effects of influenza virus infection on CNS local cells, showing that both can infect neurons, but the replication was abortive [117]. However, the two strains of Influenza virus-induced a differential increase in the levels of IL-6, TNF-α, and CXCL-10 (Table 1) [117]. Furthermore, similar results were found in human neurons and astrocytes cell lines infected with H5N1 (A/Hong Kong/483/97), in which increased levels of IL-6 and TNF-α were found (Table 1) [118]. The avian H7N9 (H7/SH2/13) also can infect human neurons and astrocytes cell lines, and thus the infection results in the increase of IL-6, IL-8, TNF-α, IFN-β, and CCL2 (Table 1) [119]. These results suggest that neurons and astrocytes may contribute to the neuroinflammation caused by Influenza virus infection.
A study in a neonatal model evaluated whether influenza virus infection might influence brain function [120]. Mice were intraperitoneally infected with the mouse-adapted H1N1 (NWS/33) strain, detecting viral RNA in different brain zones, including the hippocampus, midbrain, the cerebellum, and the cerebral cortex, of neonatal mice as well in the CSF from adult mice [120]. Furthermore, increased mRNA levels of TNF-α, IL-1β, and IL-6 were found at five days p.i. simultaneously with the viral load peak. Interestingly, TNF-α mRNA levels decreased under the baseline at 15 days p.i. as compared to control mice, whereas IL-6 was decreased at 15 and 21 days p.i. as compared to control mice [120]. On the contrary, IL-1β mRNA levels were increased at 21 days p.i. (Table 1) [120]. These data suggest that the neuroinflammation directly caused by influenza virus infection may occur at different ages [120]. More information about the implication of neonatal infection and the possible neurological alteration in adulthood needs to be investigated.
Not only the neuroinflammation caused by influenza virus infection can be a result of neuroinvasion, but also by a systemic effect. H1N1 A/PR/8/34 is not a neurotropic virus but can induce a spatial learning impairment in the acute phase of infection, which may be caused by increased mRNA levels of pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6 in the hippocampus, where the cognitive process takes place (Table 1) [114]. Additionally, the viral infection induces a decrease in the mRNA levels of neurotrophic factors, such as BDNF and NGF, which are essential to the neurons′ function and survival. The microglial activation may lead to the neuroinflammation observed that is consistent with the decreased mRNA levels CD200 and CX3CL1, which maintain the resting state of these cells and the increased microglia reactivity in the hippocampus of Influenza virus-infected mice [114]. H1N1 cannot cause long-term CNS alterations [113]. The non-neurotropic strain H3N2 (maHK68) also can cause an impairment of spatial learning and also alter the LTP [114]. This influenza virus strain has the ability to disrupt the BBB permeability and showed increased levels of TNF-α in the hippocampus at eight days p.i. [114]. The fact that non-neurotropic viruses can cause neurological alterations in animals can provide insights about potentially equivalent effects on patients.
According to the association between Influenza virus infection and SCZ disorder, several studies have evaluated how maternal infection with Influenza virus can be a risk factor for developing SCZ in the offspring [121,122,123]. A study suggested a higher risk of developing SCZ in the offspring when the mother was exposed to Influenza virus during the second trimester of pregnancy [124], but not with direct evidence [124]. Later, serological evidence associated the maternal exposure to Influenza virus during the first trimester of gestation with a higher risk of suffering SCZ by the offspring [125]. However, this association is still controversial in humans due to the study′s limitations [125]. According to the knowledge about the effects of the maternal immune activation (MIA), which induces systemic increased levels of pro-inflammatory molecules that may be triggered by the infection with influenza virus, can impair the brain development of the fetus [42,109]. However, the Influenza virus has not been detected in the brain of fetuses in an animal model, suggesting that the damage is an indirect effect of the infection [72,126]. H1N1 (A/WSN/33) infection during mid-pregnancy promotes an impairment in the locomotor activity in the offspring of mice and also affects the expression of 5-HT2A and mGlu2 in the frontal cortex, which are implicated in behavioral alteration [71,72]. Indeed, infection with this strain of the Influenza virus also promoted pyramidal neuron atrophy [71,72]. Additionally, maternal infection with H1N1 (A/NC-L/99) and H1N1 (A/WSN/33) promotes the loss of dopaminergic neurons in the offspring as well as behavioral alterations [110]. However, there is little evidence for an association between maternal infection with influenza virus, and the relationship with the development of SCZ, the influence of pro-inflammatory molecules was not addressed [110].
The potential association between maternal infection with influenza virus and an increased risk of developing ASD in the offspring remains unclear [102,127,128,129,130]. Abnormalities were found in the development of the brains of fetuses from influenza virus-infected mothers in animal models [71,123]. Similar findings were made for SCZ and influenza virus infection. There is no data about the pro-inflammatory molecule′s role triggered after maternal Influenza virus infection and ASD in the offspring.

2.2. Human Respiratory Syncytial Virus

Infants under two years old are the main targets of the human respiratory syncytial virus (hRSV) as well as the elderly and immunocompromised individuals, causing acute lower respiratory tract infection (ALTRI) [131,132,133]. The hRSV, recently renamed as human orthopneumovirus, is an enveloped, negative-sense singled stranded RNA virus [134]. The more severe clinical pathologies caused by the infection with hRSV are bronchiolitis and pneumonia [135]. hRSV infection leads to a strong inflammatory response in the airways, which is thought to establish a hyper-reactive immunological environment that fails to clear the virus [136]. Following virus entry into the respiratory tract, hRSV reaches alveoli and infects airway epithelial cells leading to the secretion of several pro-inflammatory molecules by epithelial cells, such as IL-1β, IL-6, CXCL8, IFNα/β, and TNF-α [136,137].
Moreover, the innate immune system’s activation can lead to massive infiltration of inflammatory cells into the lung parenchyma and alveoli [137]. The host response to the hRSV infection involves alveolar infiltration of neutrophils, eosinophils, NK cells, mDCs, plasmacytoid dendritic cells (pDCs), macrophages, B lymphocytes, CD4+ and CD8+ T cells [136,138]. Besides, lung pathology of hRSV infection is associated with a strong T helper 2 (Th2)-polarized T cell immunity against the virus [139] characterized by the production of cytokines such as IL-4, IL-5, and IL-13 [140]. These cytokines increase the recruitment of inflammatory cells, such as eosinophils, neutrophils, and monocytes, to the lungs and impair cytotoxic CD8+ T cells [141]. Several studies have suggested that hRSV could modulate the host adaptive immune response’s polarization to promote a detrimental Th2-biased T cell response. Moreover, the virus blocks the priming, expansion, and function of the Th1 and cytotoxic T cells needed for viral clearance [141,142,143]. Infection with this virus can also cause neurological alterations, such as seizures, encephalitis, and encephalopathy [144,145,146,147,148]. The detection of hRSV RNA in CSF has been reported in some cases, supporting the notion of neuroinvasion by this pathogen during the acute phase of the infection [147,149]. Besides, an elevated amount of IL-6 was found in CSF from patients with neurological signs and decreased levels of TNF-α, which correlates negatively with hRSV detection in CSF (Table 2) [150]. Furthermore, the detection of high levels of IL-8, CCL2, and CCL4 in CSF, also has been documented, which has no relation with the hRSV detection in CSF (Table 2) [150]. These findings suggest that not only hRSV can infect the CNS but also induce local inflammation directly or indirectly (Figure 2).
To better understand the neurological alterations caused by hRSV, studies in animals infected intranasally with strain 13018–8 of hRSV (a clinical isolate) showed that viral RNA and proteins were detected in several zones of the brain, such as the cortex and hippocampus, at three days p.i. [65]. The possible consequences of what may have caused the infection in the CNS were further evaluated by testing processes such as spatial learning and behavior 30 days p.i. The results showed impairment in both processes, demonstrating that the hRSV infection can have a long-term detrimental effect in these cognitive events [65]. Later, the ability of hRSV to infect CNS cells, including neurons was evaluated in vitro using the N2a cell line [151]. These cells not only were susceptible to the hRSV infection but also increased levels of IL-6 and TNF-α were detected in the supernatant of N2a hRSV-infected cells [151]. According to the fact that hRSV infection promotes learning and behavioral impairment and possibly infects neurons, new data showed that hRSV could disrupt the BBB, promoting immune cell infiltration [66]. Moreover, the behavioral alteration reporter previously in hRSV infected mice can be observed up to 60 days p.i. and also increased levels of anti-inflammatory molecules, such as IL-4 and IL-10, and pro-inflammatory molecules including CCL2 were found in the brain of these mice [66]. Moreover, GFAP was found elevated in hRSV-infected mice′s brains, suggesting that which suggest that are active and possibly causing chronic inflammation [66]. Besides infecting neurons, hRSV was able to infect endothelial cells, microglia, and astrocytes, being these last cells infected in a higher percentage [66]. Primary cultures of astrocytes infected with hRSV showed elevated amounts of anti-inflammatory molecules, such as IL-4, IL-10, and pro-inflammatory molecules including TNF-α during the first 12h p.i. whereas IL-6 was increased until 72h p.i. [66]. These results suggest that hRSV infection in the CNS promotes a local immune response leading to the production of pro-inflammatory molecules that may be important for the impairment of cognitive and behavioral processes. Besides, contrary to the knowledge about the pulmonary pathology caused by hRSV infection, the CNS alteration has been poorly studied.
As compared to other viruses such as influenza, no studies that can associate the hRSV with any neuropsychiatric disorder have been published yet. A recent study reported neurological effects even after the hRSV infection has been resolved [73]. This study evaluated in infants whether a severe episode of hRSV infection before six months of age could lead to long-term learning difficulties [73]. The acquisition of the native phoneme repertoire during the first year of age was evaluated. The data showed that infants who suffer a severe disease caused by hRSV infection presented poor distinction of native and nonnative phonetic contrasts at six months of age [73]. This poor distinction remained atypically sensitive to nonnative contrasts even after 12 months of infection, suggesting weak communicative abilities (Table 2 and Figure 2) [73]. This case is the first report about the long-term effect of hRSV infections in humans, showing possible neurological consequences of a viral respiratory infection. However, the mechanisms of cognitive impairment still need to be elucidated, as well as a potential association between the secretion of pro-inflammatory molecules and the cognitive and behavioral impairment observed in humans.

2.3. Severe Acute Respiratory Syndrome Coronavirus 2

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new respiratory virus first identified in December 2019, during an outbreak of pneumonia in Wuhan, China [152,153]. SARS-CoV-2 was quickly disseminated to the entire planet, leading to a global pandemic that, up to date, remains uncontrolled. This virus belongs to the family Coronavirus and the genre betacoronavirus and has a non-segmented, single-stranded, and positive-sense viral RNA [154]. Since the identification of SARS-CoV-2, the virus has mutated and created several new variants (B.1.1.7., B.1.351, P.1 and B.1.526.) [155,156]. Up to the time this article was written, over 100 million positive cases and more than 2 million fatalities had been reported [157]. This virus severely affects the elderly and people with co-morbidities, such as hypertension, cardiovascular and respiratory diseases [158]. The most common symptoms are fever, myalgia, headache, and cough, and in severe cases, the patients can display respiratory distress and pneumonia [158]. Furthermore, the infection with SARS-CoV-2 has been associated with neurologic symptoms [158]. Several cases reported showing that patients with the infection displayed symptoms including encephalitis, anosmia, ageusia, and Guillain-Barré syndrome, among others [75,159,160]. Besides these cases, neuropsychiatric cases associated with the infection of SARS-CoV-2 have been reported, such as psychosis, delirium, neurocognitive syndrome, and mood disorders (Figure 3) [76,161].
Infection with SARS-CoV-2 can cause neurologic symptoms through direct contact—reaching the brain via olfactory nerves or hematogenous routes—or indirectly through the cytokine inflammatory storm [76]. Although none of these possibilities have been conclusively demonstrated, the genetic material of SARS-CoV-2 has been found in the CSF of patients with neurologic manifestation (demyelinating disease) [162]. The presence of the virus in the CSF suggests that SARS-CoV-2 can reach the CNS [162]. Post-mortem studies on patients infected with SARS-CoV-2 have revealed astrocyte activation, gliosis, microglial nodules, loss of myelin and axon degeneration, among other features [162,163,164,165]. Additionally, these studies revealed that various parts of the brain are affected due to the lung infection with SARS-CoV-2.
Pharmaceuticals 14 00340 g003
Figure 3. Infection with SARS-CoV-2 could cause neurologic consequences in patients. The respiratory infection with SARS-CoV-2 might lead to neuroinflammation as a consequence of a cytokine storm, which might increase the pro-inflammatory cytokines in the brain [74]. This increase might promote the development of neurologic disorders such as ageusia, anosmia, delirium, psychosis, encephalitis, mood disorders, Guillain-Barré Syndrome, and neurocognitive syndrome [75,76,159,164,165].
Figure 3. Infection with SARS-CoV-2 could cause neurologic consequences in patients. The respiratory infection with SARS-CoV-2 might lead to neuroinflammation as a consequence of a cytokine storm, which might increase the pro-inflammatory cytokines in the brain [74]. This increase might promote the development of neurologic disorders such as ageusia, anosmia, delirium, psychosis, encephalitis, mood disorders, Guillain-Barré Syndrome, and neurocognitive syndrome [75,76,159,164,165].
Pharmaceuticals 14 00340 g003
As mentioned above, patients infected with SARS-CoV-2 can develop neurological disorders through an inflammatory cytokine storm [74]. The cytokine storm is a term used when the immune system overacts due to the presence of an infection and leads to an increase in the secretion of inflammatory molecules systemically and to the bloodstream [166]. It has been reported that the infection with SARS-CoV-2 can cause a cytokine storm in patients with symptoms severe or critical, consisting of an increase of IL-1β, IL-4, IL-6, IL-10, IL-17, TNF-α, G-CSF, GM-CSF, IFN-γ, CCL2, CXCL8, and CXCL10 [167]. The increase in the inflammatory molecules has been related to cases of depression and anxiety in patients infected with SARS-CoV-2 [168]. In these cases, IL-6 was elevated when the symptoms appeared, and after the treatment -which decreased the inflammation- the neurologic symptoms were less notorious [168]. These cases suggest that the presence of specific inflammatory molecules can cause neurologic disorders. Unlike the previously described viruses, SARS-CoV-2 is a newly identified virus, and studies in animals analyzing this aspect have not been performed yet.

3. Potential Treatments to Decrease Neurologic Symptoms Caused by Infections

Patients infected by any of the previously mentioned viruses and show neurological symptoms are usually treated with antivirals and anti-inflammatory drugs (Figure 4). When an adult patient infected by influenza virus develops neurological symptoms, antiviral treatment has often been used [169,170,171]. Oseltamivir phosphate is an antiviral from the neuraminidase inhibitors drug used in treating patients infected with Influenza virus since this antiviral inhibits the reproduction of the virus [170]. During a study performed in 2009, 61.2% of the infants infected with influenza virus and with neurologic symptoms were treated with oseltamivir phosphate upon admission to the hospital, and because of this treatment, most of them have recovered without sequels [172]. Another antiviral drug that has been used is amantadine, which has the characteristic to penetrate the CSF [170]. In one case, infants infected with IAV received the antiviral treatment, and at the same time, were treated with methylprednisolone and ulinastatin -which are anti-cytokines drugs- and decreasing the temperature of the forehead [171]. Both patients were able to recover and did not present any sequels [171]. Other pro-inflammatory inhibitors that might be useful to reduce neuroinflammation are against TNF-α, IL-1β, and IL-6 [173]. It has been suggested that the use of therapies that suppress the pro-inflammatory molecules might be beneficial against SCZ as a complement of the regular treatment used in this disease [173]. The use of vaccines to protect against the complications developed due to the infection with influenza virus has been controversial. Some reports have indicated that certain vaccines against the influenza virus might be related to the development of neurologic disorders, while other reports have suggested possible protection against the development of symptoms like BGS [174,175]. If the vaccination against the Influenza virus protects from neurologic disorders, then the mother′s immunization during the pregnancy might prevent the neurologic symptoms in the offspring [176].
In the case of hRSV, there are no current treatments that have been tested in the population [67]. However, studies in animal models have suggested a possible way to prevent neurologic symptoms. In the study made in 2013, it was demonstrated that the vaccination of mice previous to the infection with hRSV could decrease the neurologic symptoms due to the infection with this virus [65].
For patients infected with SARS-CoV-2 that developed neurologic symptoms have been treated with antivirals. In the case of a patient positive to SARS-CoV-2 that presented acute myelitis, it was treated with several antivirals -such as ganciclovir and loponavir- along with antibiotics, such as moxifloxacin and meropenem [177]. Since this virus appeared over a year ago, not much has been advance in this area. However, probably suppressing the neuroinflammation might decrease the neurological symptoms. The evaluation as to how vaccines affect these symptoms remains unknown.

4. Conclusions

Pro-inflammatory molecules, such as cytokines and chemokines, play an essential role in the immune response and the immune and central nervous system′s proper function. IL-1β, IL-6, and TNF-α are the cytokines that have been constantly involved in the cognitive process. The pro-inflammatory molecules have been related to causing neuroinflammation, which might lead to neuropsychiatric disorders, including neurobehavioral alterations and cognitive impairment. Interestingly, viral infections have been thought to develop these alterations through direct infection of the CNS or increased local inflammation. Respiratory viruses are no exception to this; the influenza virus, hRSV, and SARS-CoV-2 have been associated with neuropsychiatric disorders. The Influenza virus infection can lead to neurologic symptoms by directly reaching the brain or increasing the brain′s inflammatory response. The pro-inflammatory molecules commonly increased during the infection with influenza virus are the IL-6, TNF-α, and IL-1β.
Additionally, the infection of pregnant women might result in neurologic alterations in the offspring due to the increase of pro-inflammatory cytokines in the mother. The hRSV infection can cause neurologic symptoms due to the virus′s possible neurotropic effect or the increase of inflammation in the brain. The pro-inflammatory molecules that increased in the CNS during the infection are most commonly IL-6 and CCL2. The infection with SARS-CoV-2 might cause neurologic symptoms since cases with neuropsychiatric symptoms have been related to an increase of pro-inflammatory cytokine IL-6. Whether this virus can reach the brain, or its effects are based on the pro-inflammatory response remains unclear. Notably, the symptoms developed due to these viral infections can be treated through the use of antivirals o preventing the pro-inflammatory response. It needs to be further evaluated the possibility of the prevention of these symptoms through the use of vaccines.

Author Contributions

All authors listed have made substantial, direct, and intellectual contribution to the work and approved it for publication. K.B. conceptualization, writing original draft, review, editing and revision; C.A.A. writing original draft, figure design, review, editing and revision; A.M.K. revision of original draft, editing and revision of final version. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by FONDECYT grants N° 3180570, CONICYT scholarship 21210662 and the Millennium Institute on Immunology and Immunotherapy (P09/016-F). COPEC-UC2019.R.1169. COPEC-UC2020.E.1. Biomedical Research Consortium Chile (13CTI-21526/P4).

Conflicts of Interest

The authors declare no conflict of interest regarding this manuscript.

References

  1. Cavaillon, J.M. Pro- versus anti-inflammatory cytokines: Myth or reality. Cell. Mol. Biol. 2001, 47, 695–702. [Google Scholar] [PubMed]
  2. Chi, H.; Barry, S.P.; Roth, R.J.; Wu, J.J.; Jones, E.A.; Bennett, A.M.; Flavell, R.A. Dynamic regulation of pro- and anti-inflammatory cytokines by MAPK phosphatase 1 (MKP-1) in innate immune responses. Proc. Natl. Acad. Sci. USA 2006, 103, 2274–2279. [Google Scholar] [CrossRef]
  3. Galic, M.A.; Riazi, K.; Pittman, Q.J. Cytokines and brain excitability. Front. Neuroendocrinol. 2012, 33, 116–125. [Google Scholar] [CrossRef] [PubMed]
  4. Kronfol, Z.; Remick, D.G. Cytokines and the brain: Implications for clinical psychiatry. Am. J. Psychiatry 2000, 157, 683–694. [Google Scholar] [CrossRef]
  5. Donzis, E.J.; Tronson, N.C. Modulation of learning and memory by cytokines: Signaling mechanisms and long term consequences. Neurobiol. Learn. Mem. 2014, 115, 68–77. [Google Scholar] [CrossRef] [PubMed]
  6. McAfoose, J.; Baune, B.T. Evidence for a cytokine model of cognitive function. Neurosci. Biobehav. Rev. 2009, 33, 355–366. [Google Scholar] [CrossRef]
  7. Yirmiya, R.; Goshen, I. Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain. Behav. Immun. 2011, 25, 181–213. [Google Scholar] [CrossRef] [PubMed]
  8. Beattie, E.C.; Stellwagen, D.; Morishita, W.; Bresnahan, J.C.; Byeong, K.H.; Von Zastrow, M.; Beattie, M.S.; Malenka, R.C. Control of synaptic strength by glial TNFα. Science 2002, 295, 2282–2285. [Google Scholar] [CrossRef] [PubMed]
  9. Balschun, D.; Wetzel, W.; Rey, A.; Pitossi, F.; Schneider, H.; Zuschratter, W.; Besedovsky, H.O. Interleukin-6: A cytokine to forget. FASEB J. 2004, 18, 1788–1790. [Google Scholar] [CrossRef]
  10. Goshen, I.; Kreisel, T.; Ounallah-Saad, H.; Renbaum, P.; Zalzstein, Y.; Ben-Hur, T.; Levy-Lahad, E.; Yirmiya, R. A dual role for interleukin-1 in hippocampal-dependent memory processes. Psychoneuroendocrinology 2007, 32, 1106–1115. [Google Scholar] [CrossRef] [PubMed]
  11. Lynch, A.M.; Walsh, C.; Delaney, A.; Nolan, Y.; Campbell, V.A.; Lynch, M.A. Lipopolysaccharide-induced increase in signalling in hippocampus is abrogated by IL-10—A role for IL-1β? J. Neurochem. 2004, 88, 635–646. [Google Scholar] [CrossRef]
  12. Wilson, C.J.; Finch, C.E.; Cohen, H.J. Cytokines and cognition—The case for a head-to-toe inflammatory paradigm. J. Am. Geriatr. Soc. 2002, 50, 2041–2056. [Google Scholar] [CrossRef] [PubMed]
  13. Stellwagen, D.; Malenka, R.C. Synaptic scaling mediated by glial TNF-α. Nature 2006, 440, 1054–1059. [Google Scholar] [CrossRef] [PubMed]
  14. Hansen, R.; Sauder, C.; Czub, S.; Bachmann, E.; Schimmer, S.; Hegyi, A.; Czub, M. Activation of microglia cells is dispensable for the induction of rat retroviral spongiform encephalopathy. J. Neurovirol. 2001, 7, 501–510. [Google Scholar] [CrossRef] [PubMed]
  15. Nelson, T.E.; Hao, C.; Manos, J.; Ransohoff, R.M.; Gruol, D.L. Altered hippocampal synaptic transmission in transgenic mice with astrocyte-targeted enhanced CCL2 expression. Brain Behav. Immun. 2011, 25, S106–S119. [Google Scholar] [CrossRef] [PubMed]
  16. Rogers, J.T.; Morganti, J.M.; Bachstetter, A.D.; Hudson, C.E.; Peters, M.M.; Grimmig, B.A.; Weeber, E.J.; Bickford, P.C.; Gemma, C. CX3CR1 deficiency leads to impairment of hippocampal cognitive function and synaptic plasticity. J. Neurosci. 2011, 31, 16241–16250. [Google Scholar] [CrossRef] [PubMed]
  17. Sheridan, G.K.; Wdowicz, A.; Pickering, M.; Watters, O.; Halley, P.; O’Sullivan, N.C.; Mooney, C.; O’Connell, D.J.; O’Connor, J.J.; Murphy, K.J. CX3CL1 is up-regulated in the rat hippocampus during memory-associated synaptic plasticity. Front. Cell. Neurosci. 2014, 8, 233. [Google Scholar] [CrossRef]
  18. Rostène, W.; Dansereau, M.A.; Godefroy, D.; Van Steenwinckel, J.; Goazigo, A.R.L.; Mélik-Parsadaniantz, S.; Apartis, E.; Hunot, S.; Beaudet, N.; Sarret, P. Neurochemokines: A menage a trois providing new insights on the functions of chemokines in the central nervous system. J. Neurochem. 2011, 118, 680–694. [Google Scholar] [CrossRef] [PubMed]
  19. Zhou, Y.; Tang, H.; Liu, J.; Dong, J.; Xiong, H. Chemokine CCL2 modulation of neuronal excitability and synaptic transmission in rat hippocampal slices. J. Neurochem. 2011, 116, 406–414. [Google Scholar] [CrossRef] [PubMed]
  20. Lauro, C.; Catalano, M.; Trettel, F.; Limatola, C. Fractalkine in the nervous system: Neuroprotective or neurotoxic molecule? Ann. N. Y. Acad. Sci. 2015, 1351, 141–148. [Google Scholar] [CrossRef] [PubMed]
  21. Homberg, J.R.; Kyzar, E.J.; Nguyen, M.; Norton, W.H.; Pittman, J.; Poudel, M.K.; Gaikwad, S.; Nakamura, S.; Koshiba, M.; Yamanouchi, H.; et al. Understanding autism and other neurodevelopmental disorders through experimental translational neurobehavioral models. Neurosci. Biobehav. Rev. 2016, 65, 292–312. [Google Scholar] [CrossRef] [PubMed]
  22. Sullivan, P.F.; Posthuma, D. Biological pathways and networks implicated in psychiatric disorders. Curr. Opin. Behav. Sci. 2015. [Google Scholar] [CrossRef]
  23. Okusaga, O.; Yolken, R.H.; Langenberg, P.; Lapidus, M.; Arling, T.A.; Dickerson, F.B.; Scrandis, D.A.; Severance, E.; Cabassa, J.A.; Balis, T.; et al. Association of seropositivity for influenza and coronaviruses with history of mood disorders and suicide attempts. J. Affect. Disord. 2011, 130, 220–225. [Google Scholar] [CrossRef]
  24. Kieling, C.; Baker-Henningham, H.; Belfer, M.; Conti, G.; Ertem, I.; Omigbodun, O.; Rohde, L.A.; Srinath, S.; Ulkuer, N.; Rahman, A. Child and adolescent mental health worldwide: Evidence for action. Lancet 2011, 378, 1515–1525. [Google Scholar] [CrossRef]
  25. Tomonaga, K. Virus-induced neurobehavioral disorders: Mechanisms and implications. Trends Mol. Med. 2004, 10, 71–77. [Google Scholar] [CrossRef] [PubMed]
  26. Fineberg, A.M.; Ellman, L.M. Inflammatory cytokines and neurological and neurocognitive alterations in the course of schizophrenia. Biol. Psychiatry 2013, 73, 951–966. [Google Scholar] [CrossRef]
  27. Rizzo, F.R.; Musella, A.; De Vito, F.; Fresegna, D.; Bullitta, S.; Vanni, V.; Guadalupi, L.; Stampanoni Bassi, M.; Buttari, F.; Mandolesi, G.; et al. Tumor Necrosis Factor and Interleukin-1β Modulate Synaptic Plasticity during Neuroinflammation. Neural Plast. 2018, 2018, 8430123. [Google Scholar] [CrossRef] [PubMed]
  28. Tanaka, M.; Toldi, J.; Vécsei, L. Exploring the etiological links behind neurodegenerative diseases: Inflammatory cytokines and bioactive kynurenines. Int. J. Mol. Sci. 2020, 21, 2431. [Google Scholar] [CrossRef]
  29. Wu, Y.; Kang, R.; Yan, Y.; Gao, K.; Li, Z.; Jiang, J.; Chi, X.; Xia, L. Epidemiology of schizophrenia and risk factors of schizophrenia-associated aggression from 2011 to 2015. J. Int. Med. Res. 2018, 46, 4039–4049. [Google Scholar] [CrossRef]
  30. Cannon, T.D. How Schizophrenia Develops: Cognitive and Brain Mechanisms Underlying Onset of Psychosis. Trends Cogn. Sci. 2015, 19, 744–756. [Google Scholar] [CrossRef]
  31. Vita, A.; De Peri, L.; Deste, G.; Sacchetti, E. Progressive loss of cortical gray matter in schizophrenia: A meta-analysis and meta-regression of longitudinal MRI studies. Transl. Psychiatry 2012, 2, e190. [Google Scholar] [CrossRef] [PubMed]
  32. Gur, R.E.; Turetsky, B.I.; Bilker, W.B.; Gur, R.C. Reduced gray matter volume in schizophrenia. Arch. Gen. Psychiatry 1999, 56, 905–911. [Google Scholar] [CrossRef] [PubMed]
  33. Nadira, K. First episode schizophrenia: Review. South Afr. Fam. Pract. 2015, 57, 29–33. [Google Scholar] [CrossRef]
  34. Fond, G.; Lançon, C.; Korchia, T.; Auquier, P.; Boyer, L. The Role of Inflammation in the Treatment of Schizophrenia. Front. Psychiatry 2020, 11, 160. [Google Scholar] [CrossRef] [PubMed]
  35. Zhang, X.Y.; Zhou, D.F.; Cao, L.Y.; Zhang, P.Y.; Wu, G.Y.; Shen, Y.C. Changes in serum interleukin-2, -6, and -8 levels before and during treatment with risperidone and haloperidol: Relationship to outcome in schizophrenia. J. Clin. Psychiatry 2004, 65, 940–947. [Google Scholar] [CrossRef] [PubMed]
  36. Lin, A.; Kenis, G.; Bignotti, S.; Tura, G.J.B.; De Jong, R.; Bosmans, E.; Pioli, R.; Altamura, C.; Scharpé, S.; Maes, M. The inflammatory response system in treatment-resistant schizophrenia: Increased serum interleukin-6. Schizophr. Res. 1998, 32, 9–15. [Google Scholar] [CrossRef]
  37. Allswede, D.M.; Cannon, T.D. Prenatal inflammation and risk for schizophrenia: A role for immune proteins in neurodevelopment. Dev. Psychopathol. 2018, 30, 1157–1178. [Google Scholar] [CrossRef]
  38. Momtazmanesh, S.; Zare-Shahabadi, A.; Rezaei, N.; Garcia-Gutierrez, M.S.; Schiavone, S.; Arsenijevic, N.N. Cytokine Alterations in Schizophrenia: An Updated Review. Front. Psychiatry 2019, 10, 892. [Google Scholar] [CrossRef]
  39. Won, H.; Mah, W.; Kim, E. Autism spectrum disorder causes, mechanisms, and treatments: Focus on neuronal synapses. Front. Mol. Neurosci. 2013, 6, 19. [Google Scholar] [CrossRef]
  40. Libbey, J.E.; Sweeten, T.L.; McMahon, W.M.; Fujinami, R.S. Autistic disorder and viral infections. J. Neurovirol. 2005, 11, 1–10. [Google Scholar] [CrossRef]
  41. Jones, K.L.; Croen, L.A.; Yoshida, C.K.; Heuer, L.; Hansen, R.; Zerbo, O.; Delorenze, G.N.; Kharrazi, M.; Yolken, R.; Ashwood, P.; et al. Autism with intellectual disability is associated with increased levels of maternal cytokines and chemokines during gestation. Mol. Psychiatry 2017, 22, 273–279. [Google Scholar] [CrossRef] [PubMed]
  42. Paraschivescu, C.; Barbosa, S.; Lorivel, T.; Glaichenhaus, N.; Davidovicid, L.; Davidovic, L. Cytokine changes associated with the maternal immune activation (mia) model of autism: A penalized regression approach. PLoS ONE 2020, 15, e0231609. [Google Scholar] [CrossRef] [PubMed]
  43. Masi, A.; Breen, E.J.; Alvares, G.A.; Glozier, N.; Hickie, I.B.; Hunt, A.; Hui, J.; Beilby, J.; Ravine, D.; Wray, J.; et al. Cytokine levels and associations with symptom severity in male and female children with autism spectrum disorder. Mol. Autism 2017, 8, 63. [Google Scholar] [CrossRef] [PubMed]
  44. Masi, A.; Glozier, N.; Dale, R.; Guastella, A.J. The Immune System, Cytokines, and Biomarkers in Autism Spectrum Disorder. Neurosci. Bull. 2017, 33, 194–204. [Google Scholar] [CrossRef]
  45. Kordulewska, N.K.; Kostyra, E.; Piskorz-Ogórek, K.; Moszyńska, M.; Cieślińska, A.; Fiedorowicz, E.; Jarmołowska, B. Serum cytokine levels in children with spectrum autism disorder: Differences in pro- and anti-inflammatory balance. J. Neuroimmunol. 2019, 337, 577066. [Google Scholar] [CrossRef]
  46. Jyonouchi, H.; Sun, S.; Le, H. Proinflammatory and regulatory cytokine production associated with innate and adaptive immune responses in children with autism spectrum disorders and developmental regression. J. Neuroimmunol. 2001, 120, 170–179. [Google Scholar] [CrossRef]
  47. Theoharides, T.C.; Tsilioni, I.; Patel, A.B.; Doyle, R. Atopic diseases and inflammation of the brain in the pathogenesis of autism spectrum disorders. Transl. Psychiatry 2016, 6, 844. [Google Scholar] [CrossRef] [PubMed]
  48. Atluri, V.S.R.; Hidalgo, M.; Samikkannu, T.; Kurapati, K.R.V.; Nair, M. Synaptic Plasticity and Neurological Disorders in Neurotropic Viral Infections. Neural Plast. 2015, 2015, 1–14. [Google Scholar] [CrossRef] [PubMed]
  49. Benros, M.E.; Sørensen, H.J.; Nielsen, P.R.; Nordentoft, M.; Mortensen, P.B.; Petersen, L. The association between infections and general cognitive ability in young men—A nationwide study. PLoS ONE 2015, 10, e0124005. [Google Scholar] [CrossRef]
  50. Koyuncu, O.O.; Hogue, I.B.; Enquist, L.W. Virus infections in the nervous system. Cell Host Microbe 2013, 13, 379–393. [Google Scholar] [CrossRef]
  51. Mori, I.; Nishiyama, Y.; Yokochi, T.; Kimura, Y. Olfactory transmission of neurotropic viruses. J. Neurovirol. 2005, 11, 129–137. [Google Scholar] [CrossRef]
  52. Obermeier, B.; Verma, A.; Ransohoff, R.M. The blood-brain barrier. In Handbook of Clinical Neurology; Elsevier: Amsterdam, The Netherlands, 2016; Volume 133, pp. 39–59. ISBN 9780444634320. [Google Scholar]
  53. Rhea, E.M.; Banks, W.A. Role of the Blood-Brain Barrier in Central Nervous System Insulin Resistance. Front. Neurosci. 2019, 13, 521. [Google Scholar] [CrossRef]
  54. Profaci, C.P.; Munji, R.N.; Pulido, R.S.; Daneman, R. The blood–brain barrier in health and disease: Important unanswered questions. J. Exp. Med. 2020, 217, 217. [Google Scholar] [CrossRef]
  55. Kadry, H.; Noorani, B.; Cucullo, L. A blood–brain barrier overview on structure, function, impairment, and biomarkers of integrity. Fluids Barriers CNS 2020, 17, 69. [Google Scholar] [CrossRef]
  56. Russo, M.V.; McGavern, D.B. Immune Surveillance of the CNS following Infection and Injury. Trends Immunol. 2015, 36, 637–650. [Google Scholar] [CrossRef]
  57. Negi, N.; Das, B.K. CNS: Not an immunoprivilaged site anymore but a virtual secondary lymphoid organ. Int. Rev. Immunol. 2018, 37, 57–68. [Google Scholar] [CrossRef]
  58. Ousman, S.S.; Kubes, P. Immune surveillance in the central nervous system. Nat. Neurosci. 2012, 15, 1096–1101. [Google Scholar] [CrossRef] [PubMed]
  59. Kivisäkk, P.; Mahad, D.J.; Callahan, M.K.; Trebst, C.; Tucky, B.; Wei, T.; Wu, L.; Baekkevold, E.S.; Lassmann, H.; Staugaitis, S.M.; et al. Human cerebrospinal fluid central memory CD4+ T cells: Evidence for trafficking through choroid plexus and meninges via P-selectin. Proc. Natl. Acad. Sci. USA 2003, 100, 8389–8394. [Google Scholar] [CrossRef] [PubMed]
  60. Hatterer, E.; Davoust, N.; Didier-Bazes, M.; Vuaillat, C.; Malcus, C.; Belin, M.F.; Nataf, S. How to drain without lymphatics? Dendritic cells migrate from the cerebrospinal fluid to the B-cell follicles of cervical lymph nodes. Blood 2006, 107, 806–812. [Google Scholar] [CrossRef] [PubMed]
  61. Morimoto, K.; Nakajima, K. Role of the Immune System in the Development of the Central Nervous System. Front. Neurosci. 2019, 13, 916. [Google Scholar] [CrossRef] [PubMed]
  62. Yao, K.; Zu, H. bing Microglial polarization: Novel therapeutic mechanism against Alzheimer’s disease. Inflammopharmacology 2020, 28, 95–110. [Google Scholar] [CrossRef]
  63. Colombo, E.; Farina, C. Astrocytes: Key Regulators of Neuroinflammation. Trends Immunol. 2016, 37, 608–620. [Google Scholar] [CrossRef]
  64. Sochocka, M.; Diniz, B.S.; Leszek, J. Inflammatory Response in the CNS: Friend or Foe? Mol. Neurobiol. 2017, 54, 8071–8089. [Google Scholar] [CrossRef] [PubMed]
  65. Espinoza, J.A.; Bohmwald, K.; Cespedes, P.F.; Gomez, R.S.; Riquelme, S.A.; Cortes, C.M.; Valenzuela, J.A.; Sandoval, R.A.; Pancetti, F.C.; Bueno, S.M.; et al. Impaired learning resulting from Respiratory Syncytial Virus infection. Proc. Natl. Acad. Sci. USA 2013, 110, 9112–9117. [Google Scholar] [CrossRef]
  66. Bohmwald, K.; Soto, J.A.; Andrade-Parra, C.; Fernández-Fierro, A.; Espinoza, J.A.; Ríos, M.; Eugenin, E.A.; González, P.A.; Opazo, M.C.; Riedel, C.A.; et al. Lung pathology due to hRSV infection impairs blood–brain barrier permeability enabling astrocyte infection and a long-lasting inflammation in the CNS. Brain Behav. Immun. 2021, 91, 159–171. [Google Scholar] [CrossRef] [PubMed]
  67. Bohmwald, K.; Gálvez, N.M.S.; Ríos, M.; Kalergis, A.M. Neurologic Alterations Due to Respiratory Virus Infections. Front. Cell. Neurosci. 2018, 12, 386. [Google Scholar] [CrossRef] [PubMed]
  68. Baselga-Moreno, V.; Trushakova, S.; McNeil, S.; Sominina, A.; Nunes, M.C.; Draganescu, A.; Unal, S.; Koul, P.; Kyncl, J.; Zhang, T.; et al. Influenza epidemiology and influenza vaccine effectiveness during the 2016-2017 season in the Global Influenza Hospital Surveillance Network (GIHSN). BMC Public Health 2019, 19, 487. [Google Scholar] [CrossRef]
  69. Barbati, F.; Moriondo, M.; Pisano, L.; Calistri, E.; Lodi, L.; Ricci, S.; Giovannini, M.; Canessa, C.; Indolfi, G.; Azzari, C. Epidemiology of respiratory syncytial virus-related hospitalization over a 5-year period in Italy: Evaluation of seasonality and age distribution before vaccine introduction. Vaccines 2020, 8, 15. [Google Scholar] [CrossRef] [PubMed]
  70. Rothan, H.A.; Byrareddy, S.N. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. J. Autoimmun. 2020, 109, 102433. [Google Scholar] [CrossRef] [PubMed]
  71. Fatemi, S.H.; Earle, J.; Kanodia, R.; Kist, D.; Emamian, E.S.; Patterson, P.H.; Shi, L.; Sidwell, R. Prenatal viral infection leads to pyramidal cell atrophy and macrocephaly in adulthood: Implications for genesis of autism and schizophrenia. Cell. Mol. Neurobiol. 2002, 22, 25–33. [Google Scholar] [CrossRef]
  72. Moreno, J.L.; Kurita, M.; Holloway, T.; López, J.; Cadagan, R.; Martínez-Sobrido, L.; García-Sastre, A.; González-Maeso, J. Maternal influenza viral infection causes schizophrenia-like alterations of 5-HT2Aand mGlu2 receptors in the adult offspring. J. Neurosci. 2011, 31, 1863–1872. [Google Scholar] [CrossRef] [PubMed]
  73. Peña, M.; Jara, C.; Flores, J.C.; Hoyos-Bachiloglu, R.; Iturriaga, C.; Medina, M.; Carcey, J.; Espinoza, J.; Bohmwald, K.; Kalergis, A.M.; et al. Severe respiratory disease caused by human respiratory syncytial virus impairs language learning during early infancy. Sci. Rep. 2020, 10, 22356. [Google Scholar] [CrossRef]
  74. Guadarrama-Ortiz, P.; Choreño-Parra, J.A.; Sánchez-Martínez, C.M.; Pacheco-Sánchez, F.J.; Rodríguez-Nava, A.I.; García-Quintero, G. Neurological Aspects of SARS-CoV-2 Infection: Mechanisms and Manifestations. Front. Neurol. 2020, 11, 1–14. [Google Scholar] [CrossRef] [PubMed]
  75. Kilinc, D.; van de Pasch, S.; Doets, A.Y.; Jacobs, B.C.; van Vliet, J.; Garssen, M.P.J. Guillain–Barré syndrome after SARS-CoV-2 infection. Eur. J. Neurol. 2020, 27, 1757–1758. [Google Scholar] [CrossRef] [PubMed]
  76. Szcześniak, D.; Gładka, A.; Misiak, B.; Cyran, A.; Rymaszewska, J. The SARS-CoV-2 and mental health: From biological mechanisms to social consequences. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2021, 28, 110046. [Google Scholar] [CrossRef] [PubMed]
  77. El Ramahi, R.; Freifeld, A. Epidemiology, diagnosis, treatment, and prevention of influenza infection in oncology patients. J. Oncol. Pract. 2019, 15, 177–184. [Google Scholar] [CrossRef]
  78. Resa-Infante, P.; Recuero-Checa, M.Á.; Zamarreño, N.; Llorca, Ó.; Ortín, J. Structural and Functional Characterization of an Influenza Virus RNA Polymerase-Genomic RNA Complex. J. Virol. 2010, 84, 10477–10487. [Google Scholar] [CrossRef] [PubMed]
  79. Asha, K.; Kumar, B. Emerging Influenza D Virus Threat: What We Know so Far! J. Clin. Med. 2019, 8, 192. [Google Scholar] [CrossRef] [PubMed]
  80. Bouvier, N.M.; Palese, P. The biology of influenza viruses. Vaccine 2008, 26, D49. [Google Scholar] [CrossRef] [PubMed]
  81. Louten, J. Influenza Viruses. In Essential Human Virology; Elsevier: Amsterdam, The Netherlands, 2016; pp. 171–191. [Google Scholar]
  82. Uyeki, T.M.; Peiris, M. Novel Avian Influenza A Virus Infections of Humans. Infect. Dis. Clin. N. A. 2019, 33, 907–932. [Google Scholar] [CrossRef] [PubMed]
  83. Gounder, A.P.; Boon, A.C.M. Influenza Pathogenesis: The Effect of Host Factors on Severity of Disease. J. Immunol. 2019, 202, 341–350. [Google Scholar] [CrossRef] [PubMed]
  84. Kalil, A.C.; Thomas, P.G. Influenza virus-related critical illness: Pathophysiology and epidemiology. Crit. Care 2019, 23, 258. [Google Scholar] [CrossRef] [PubMed]
  85. Tavares, L.P.; Teixeira, M.M.; Garcia, C.C. The inflammatory response triggered by Influenza virus: A two edged sword. Inflamm. Res. 2017, 66, 283–302. [Google Scholar] [CrossRef]
  86. Chen, X.; Liu, S.; Goraya, M.U.; Maarouf, M.; Huang, S.; Chen, J.L. Host immune response to influenza A virus infection. Front. Immunol. 2018, 9, 320. [Google Scholar] [CrossRef] [PubMed]
  87. Jung, H.E.; Lee, H.K. Host protective immune Responses against influenza a virus infection. Viruses 2020, 12, 504. [Google Scholar] [CrossRef] [PubMed]
  88. Bahadoran, A.; Lee, S.H.; Wang, S.M.; Manikam, R.; Rajarajeswaran, J.; Raju, C.S.; Sekaran, S.D. Immune responses to influenza virus and its correlation to age and inherited factors. Front. Microbiol. 2016, 7, 1841. [Google Scholar] [CrossRef] [PubMed]
  89. Schmolke, M.; García-Sastre, A. Evasion of innate and adaptive immune responses by influenza A virus. Cell. Microbiol. 2010, 12, 873–880. [Google Scholar] [CrossRef]
  90. Wang, G.F.; Li, W.; Li, K. Acute encephalopathy and encephalitis caused by influenza virus infection. Curr. Opin. Neurol. 2010, 23, 305–311. [Google Scholar] [CrossRef] [PubMed]
  91. Goenka, A.; Michael, B.D.; Ledger, E.; Hart, I.J.; Absoud, M.; Chow, G.; Lilleker, J.; Lunn, M.; Mckee, D.; Peake, D.; et al. Neurological Manifestations of Influenza Infection in Children and Adults: Results of a National British Surveillance Study. J. Neurol. Neurosurg. Psychiatry 2013, 84, e2. [Google Scholar] [CrossRef]
  92. Amin, R.; Ford-Jones, E.; Richardson, S.E.; Macgregor, D.; Tellier, R.; Heurter, H.; Fearon, M.; Bitnun, A. Acute childhood encephalitis and encephalopathy associated with influenza: A prospective 11-year review. Pediatric Infect. Dis. J. 2008, 27, 390–395. [Google Scholar] [CrossRef] [PubMed]
  93. Paksu, M.S.; Aslan, K.; Kendirli, T.; Akyildiz, B.N.; Yener, N.; Yildizdas, R.D.; Davutoglu, M.; Yaman, A.; Isikay, S.; Sensoy, G.; et al. Neuroinfluenza: Evaluation of seasonal influenza associated severe neurological complications in children (a multicenter study). Child’s Nerv. Syst. 2018, 34, 335–347. [Google Scholar] [CrossRef] [PubMed]
  94. Xia, J.B.; Zhu, J.; Hu, J.; Wang, L.M.; Zhang, H. H7N9 influenza A-induced pneumonia associated with acute myelitis in an adult. Intern. Med. 2014, 53, 1093–1095. [Google Scholar] [CrossRef] [PubMed]
  95. Yong, C.H.; Vallat, W.; Norton, G.; Chen, D.; Yong, H. Influenza B-related meningoencephalitis in adults Unusual association of diseases/symptoms. BMJ Case Rep. 2018, 2018. [Google Scholar] [CrossRef]
  96. Radzišauskienė, D.; Vitkauskaitė, M.; Žvinytė, K.; Mameniškienė, R. Neurological complications of pandemic A(H1N1)2009pdm, postpandemic A(H1N1)v, and seasonal influenza A. Brain Behav. 2021, 11, e01916. [Google Scholar] [CrossRef] [PubMed]
  97. Blackburn, K.M.; Wang, C. Post-infectious neurological disorders. Ther. Adv. Neurol. Disord. 2020, 13. [Google Scholar] [CrossRef] [PubMed]
  98. Lehmann, H.C.; Hartung, H.P.; Kieseier, B.C.; Hughes, R.A.C. Guillain-Barré syndrome after exposure to influenza virus. Lancet Infect. Dis. 2010, 10, 643–651. [Google Scholar] [CrossRef]
  99. Flinkkilä, E.; Keski-Rahkonen, A.; Marttunen, M.; Raevuori, A. Prenatal inflammation, infections and mental disorders. Psychopathology 2016, 49, 317–333. [Google Scholar] [CrossRef] [PubMed]
  100. Manjunatha, N.; Math, S.; Kulkarni, G.; Chaturvedi, S. The neuropsychiatric aspects of influenza/swine flu: A selective review. Ind. Psychiatry J. 2011, 20, 83. [Google Scholar] [CrossRef] [PubMed]
  101. Atladóttir, H.Ó.; Henriksen, T.B.; Schendel, D.E.; Parner, E.T. Autism after infection, febrile episodes, and antibiotic use during pregnancy: An exploratory study. Pediatrics 2012, 130, e1447–e1454. [Google Scholar] [CrossRef] [PubMed]
  102. Lee, N.; Wong, C.K.; Chan, P.K.S.; Lindegardh, N.; White, N.J.; Hayden, F.G.; Wong, E.H.C.; Wong, K.S.; Cockram, C.S.; Sung, J.J.Y.; et al. Acute Encephalopathy Associated with Influenza A Infection in Adults. Emerg. Infect. Dis. 2010, 16, 139–142. [Google Scholar] [CrossRef] [PubMed]
  103. Paiva, T.M.; Theotonio, G.; Paulino, R.S.; Benega, M.A.; Silva, D.B.B.; Borborema, S.E.T.; Ikeda, T.I.; Kisielius, J.J.; Ueda, M.; Oliveira, M.I.; et al. Influenza virus A(H3N2) strain isolated from cerebrospinal fluid from a patient presenting myelopathy post infectious. J. Clin. Virol. 2013, 58, 283–285. [Google Scholar] [CrossRef] [PubMed][Green Version]
  104. Steininger, C.; Popow-Kraupp, T.; Laferl, H.; Seiser, A.; Gödl, I.; Djamshidian, S.; Puchhammer-Stöckl, E. Acute encephalopathy associated with influenza A virus infection. Clin. Infect. Dis. 2003, 36, 567–574. [Google Scholar] [CrossRef] [PubMed]
  105. Fujimoto, S.; Kobayashi, M.; Uemura, O.; Iwasa, M.; Ando, T.; Katoh, T.; Nakamura, C.; Maki, N.; Togari, H.; Wada, Y. PCR on cerebrospinal fluid to show influenza-associated acute encephalopathy or encephalitis. Lancet 1998, 352, 873–875. [Google Scholar] [CrossRef]
  106. Ito, Y.; Ichiyama, T.; Kimura, H.; Shibata, M.; Ishiwada, N.; Kuroki, H.; Furukawa, S.; Morishima, T. Detection of influenza virus RNA by reverse transcription-PCR and proinflammatory cytokines in influenza-virus-associated encephalopathy. J. Med. Virol. 1999, 58, 420–425. [Google Scholar] [CrossRef]
  107. Ichiyama, T.; Nishikawa, M.; Yoshitomi, T.; Hayashi, T.; Furukawa, S. Tumor necrosis factor-α, interleukin-1β and interleukin-6 in cerebrospinal fluid from children with prolonged febrile seizures: Comparison with acute encephalitis/encephalopathy. Neurology 1998, 50, 407–411. [Google Scholar] [CrossRef] [PubMed]
  108. Hasegawa, S.; Matsushige, T.; Inoue, H.; Shirabe, K.; Fukano, R.; Ichiyama, T. Serum and cerebrospinal fluid cytokine profile of patients with 2009 pandemic H1N1 influenza virus-associated encephalopathy. Cytokine 2011, 54, 167–172. [Google Scholar] [CrossRef] [PubMed]
  109. Sun, G.; Ota, C.; Kitaoka, S.; Chiba, Y.; Takayanagi, M.; Kitamura, T.; Yamamoto, K.; Fujie, H.; Mikami, H.; Uematsu, M.; et al. Elevated serum levels of neutrophil elastase in patients with influenza virus-associated encephalopathy. J. Neurol. Sci. 2015, 349, 190–195. [Google Scholar] [CrossRef] [PubMed]
  110. Landreau, F.; Galeano, P.; Caltana, L.R.; Masciotra, L.; Chertcoff, A.; Pontoriero, A.; Baumeister, E.; Amoroso, M.; Brusco, H.A.; Tous, M.I.; et al. Effects of Two Commonly Found Strains of Influenza A Virus on Developing Dopaminergic Neurons, in Relation to the Pathophysiology of Schizophrenia. PLoS ONE 2012, 7, e51068. [Google Scholar] [CrossRef] [PubMed]
  111. Shinya, K.; Silvano, F.D.; Morita, T.; Shimada, A.; Nakajima, M.; Ito, T.; Otsuki, K.; Umemura, T. Encephalitis in Mice Inoculated Intranasally with an Influenza Virus Strain Originated from a Water Bird. J. Vet. Med. Sci. 1998, 60, 627–629. [Google Scholar] [CrossRef]
  112. Shinya, K.; Shimada, A.; Ito, T.; Otsuki, K.; Morita, T.; Tanaka, H.; Takada, A.; Kida, H.; Umemura, T. Avian influenza virus intranasally inoculated infects the central nervous system of mice through the general visceral afferent nerve. Arch. Virol. 2000, 145, 187–195. [Google Scholar] [CrossRef] [PubMed]
  113. Hosseini, S.; Wilk, E.; Michaelsen-Preusse, K.; Gerhauser, I.; Baumgärtner, W.; Geffers, R.; Schughart, K.; Korte, M. Long-term neuroinflammation induced by influenza a virus infection and the impact on hippocampal neuron morphology and function. J. Neurosci. 2018, 38, 3060–3080. [Google Scholar] [CrossRef]
  114. Jurgens, H.A.; Amancherla, K.; Johnson, R.W. Influenza Infection Induces Neuroinflammation, Alters Hippocampal Neuron Morphology, and Impairs Cognition in Adult Mice. J. Neurosci. 2012, 32, 3958–3968. [Google Scholar] [CrossRef]
  115. Jang, H.; Boltz, D.; Sturm-Ramirez, K.; Shepherd, K.R.; Jiao, Y.; Webster, R.; Smeyne, R.J. Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration. Proc. Natl. Acad. Sci. USA 2009, 106, 14063–14068. [Google Scholar] [CrossRef]
  116. Jang, H.; Boltz, D.; McClaren, J.; Pani, A.K.; Smeyne, M.; Korff, A.; Webster, R.; Smeyne, R.J. Inflammatory effects of highly pathogenic H5N1 influenza virus infection in the CNS of mice. J. Neurosci. 2012, 32, 1545–1559. [Google Scholar] [CrossRef] [PubMed]
  117. Wang, G.; Li, R.; Jiang, Z.; Gu, L.; Chen, Y.; Dai, J.; Li, K. Influenza Virus Induces Inflammatory Response in Mouse Primary Cortical Neurons with Limited Viral Replication. BioMed Res. Int. 2016, 2016, 1–7. [Google Scholar] [CrossRef] [PubMed]
  118. Ng, Y.P.; Lee, S.M.Y.; Cheung, T.K.W.; Nicholls, J.M.; Peiris, J.S.M.; Ip, N.Y. Avian influenza H5N1 virus induces cytopathy and proinflammatory cytokine responses in human astrocytic and neuronal cell lines. Neuroscience 2010, 168, 613–623. [Google Scholar] [CrossRef]
  119. Ng, Y.P.; Yip, T.F.; Peiris, J.S.M.; Ip, N.Y.; Lee, S.M.Y. Avian influenza A H7N9 virus infects human astrocytes and neuronal cells and induces inflammatory immune responses. J. Neurovirol. 2018, 24, 752–760. [Google Scholar] [CrossRef] [PubMed]
  120. Yu, J.E.; Kim, M.; Lee, J.H.; Chang, B.J.; Song, C.S.; Nahm, S.S. Neonatal influenza infection causes pathological changes in the mouse brain. Vet. Res. 2014, 45, 63. [Google Scholar] [CrossRef] [PubMed]
  121. Meyer, U.; Feldon, J.; Dammann, O. Schizophrenia and autism: Both shared and disorder-specific pathogenesis via perinatal inflammation? Pediatric Res. 2011, 69, 26R–33R. [Google Scholar] [CrossRef] [PubMed]
  122. Kępińska, A.P.; Iyegbe, C.O.; Vernon, A.C.; Yolken, R.; Murray, R.M.; Pollak, T.A. Schizophrenia and Influenza at the Centenary of the 1918-1919 Spanish Influenza Pandemic: Mechanisms of Psychosis Risk. Front. Psychiatry 2020, 11, 72. [Google Scholar] [CrossRef]
  123. Brown, A.S. Epidemiologic studies of exposure to prenatal infection and risk of schizophrenia and autism. Dev. Neurobiol. 2012, 72, 1272–1276. [Google Scholar] [CrossRef] [PubMed]
  124. Mednick, S.A.; Machon, R.A.; Huttunen, M.O.; Bonett, D. Adult Schizophrenia Following Prenatal Exposure to an Influenza Epidemic. Arch. Gen. Psychiatry 1988, 45, 189–192. [Google Scholar] [CrossRef] [PubMed]
  125. Brown, A.S.; Begg, M.D.; Gravenstein, S.; Schaefer, C.A.; Wyatt, R.J.; Bresnahan, M.; Babulas, V.P.; Susser, E.S. Serologic evidence of prenatal influenza in the etiology of schizophrenia. Arch. Gen. Psychiatry 2004, 61, 774–780. [Google Scholar] [CrossRef] [PubMed]
  126. Shi, L.; Fatemi, S.H.; Sidwell, R.W.; Patterson, P.H. Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring. J. Neurosci. 2003, 23, 297–302. [Google Scholar] [CrossRef]
  127. Fang, S.Y.; Wang, S.; Huang, N.; Yeh, H.H.; Chen, C.Y. Prenatal infection and autism spectrum disorders in childhood: A population-based case-control study in Taiwan. Paediatr. Perinat. Epidemiol. 2015, 29, 307–316. [Google Scholar] [CrossRef]
  128. Atladóttir, H.O.´; Thorsen, P.; Østergaard, L.; Schendel, D.E.; Lemcke, S.; Abdallah, M.; Parner, E.T. Maternal Infection Requiring Hospitalization during Pregnancy and Autism Spectrum Disorders. J. Autism Dev. Disord. 2010, 40, 1423–1430. [Google Scholar] [CrossRef]
  129. Malkova, N.V.; Yu, C.Z.; Hsiao, E.Y.; Moore, M.J.; Patterson, P.H. Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism. Brain. Behav. Immun. 2012, 26, 607–616. [Google Scholar] [CrossRef] [PubMed]
  130. Mahic, M.; Che, X.; Susser, E.; Levin, B.; Reichborn-Kjennerud, T.; Magnus, P.; Stoltenberg, C.; Chauhan, L.; Briese, T.; Bresnahan, M.; et al. Epidemiological and Serological Investigation into the Role of Gestational Maternal Influenza Virus Infection and Autism Spectrum Disorders. mSphere 2017, 2, 2020. [Google Scholar] [CrossRef] [PubMed]
  131. Calvo, C.; García-García, M.L.; Blanco, C.; Vázquez, M.C.; Frías, M.E.; Pérez-Breña, P.; Casas, I. Multiple simultaneous viral infections in infants with acute respiratory tract infections in Spain. J. Clin. Virol. 2008, 42, 268–272. [Google Scholar] [CrossRef] [PubMed]
  132. Bohmwald, K.; Espinoza, J.A.; Rey-Jurado, E.; Gómez, R.S.; González, P.A.; Bueno, S.M.; Riedel, C.A.; Kalergis, A.M. Human Respiratory Syncytial Virus: Infection and Pathology. Semin. Respir. Crit. Care Med. 2016, 37, 522–537. [Google Scholar] [CrossRef] [PubMed]
  133. Avendaño, L.F.; Palomino, M.A.; Larrañaga, C. Surveillance for respiratory syncytial virus in infants hospitalized for acute lower respiratory infection in Chile (1989 to 2000). J. Clin. Microbiol. 2003, 41, 4879–4882. [Google Scholar] [CrossRef] [PubMed]
  134. Afonso, C.L.; Amarasinghe, G.K.; Bányai, K.; Bào, Y.; Basler, C.F.; Bavari, S.; Bejerman, N.; Blasdell, K.R.; Briand, F.-X.; Briese, T.; et al. Taxonomy of the order Mononegavirales: Update 2016. Arch. Virol. 2016, 161, 2351–2360. [Google Scholar] [CrossRef] [PubMed]
  135. Antonucci, R.; Chiappe, S.; Porcella, A.; Rosatelli, D.; Fanos, V. Bronchiolitis-associated encephalopathy in critically-ill infants: An underestimated complication? J. Matern. Neonatal Med. 2010, 23, 431–436. [Google Scholar] [CrossRef]
  136. Bueno, S.M.; González, P.A.; Cautivo, K.M.; Mora, J.E.; Leiva, E.D.; Tobar, H.E.; Fennelly, G.J.; Eugenin, E.A.; Jacobs, W.R.; Riedel, C.A.; et al. Protective T cell immunity against respiratory syncytial virus is efficiently induced by recombinant BCG. Proc. Natl. Acad. Sci. USA 2008, 105, 20822–20827. [Google Scholar] [CrossRef] [PubMed]
  137. Lay, M.K.; González, P.A.; León, M.A.; Céspedes, P.F.; Bueno, S.M.; Riedel, C.A.; Kalergis, A.M. Advances in understanding respiratory syncytial virus infection in airway epithelial cells and consequential effects on the immune response. Microbes Infect. 2013, 15, 230–242. [Google Scholar] [CrossRef]
  138. Varga, S.; Schwarze, J.; De Giovanni, M.; González, P.A.; Tognarelli, E.I.; Bueno, S.M. Immune-Modulation by the Human Respiratory Syncytial Virus: Focus on Dendritic Cells. Front. Immunol. 2019, 1, 810. Available online: www.frontiersin.org (accessed on 19 March 2021). [CrossRef]
  139. Wan, Y.Y.; Flavell, R.A. How diverse-CD4 effector T cells and their functions. J. Mol. Cell Biol. 2009, 1, 20–36. [Google Scholar] [CrossRef]
  140. Olson, M.R.; Hartwig, S.M.; Varga, S.M. The Number of Respiratory Syncytial Virus (RSV)-Specific Memory CD8 T Cells in the Lung Is Critical for Their Ability to Inhibit RSV Vaccine-Enhanced Pulmonary Eosinophilia. J. Immunol. 2008, 181, 7958–7968. [Google Scholar] [CrossRef] [PubMed]
  141. Gonzalez, P.; Carreno, L.; Bueno, S.; Riedel, C.; Kalergis, A. Understanding Respiratory Syncytial Virus Infection to Improve Treatment and Immunity. Curr. Mol. Med. 2013, 13, 1122–1139. [Google Scholar] [CrossRef]
  142. Vallbracht, S.; Unsöld, H.; Ehl, S. Functional impairment of cytotoxic T cells in the lung airways following respiratory virus infections. Eur. J. Immunol. 2006, 36, 1434–1442. [Google Scholar] [CrossRef]
  143. Bueno, S.M.; González, P.A.; Pacheco, R.; Leiva, E.D.; Cautivo, K.M.; Tobar, H.E.; Mora, J.E.; Prado, C.E.; Zúñiga, J.P.; Jiménez, J.; et al. Host immunity during RSV pathogenesis. Int. Immunopharmacol. 2008, 8, 1320–1329. [Google Scholar] [CrossRef] [PubMed]
  144. Sweetman, L.L.; Ng, Y.T.Y.T.; Butler, I.J.I.J.; Bodensteiner, J.B.; Wright, R.B.; Pomerantz, W.J.; Luria, J.W.; Church, N.R.; Anas, N.G.; Hall, C.B.; et al. Neurologic complications associated with respiratory syncytial virus. Pediatric Neurol. 2005, 32, 307–310. [Google Scholar] [CrossRef]
  145. Ng, Y.; Cox, C.; Atkins, J.; Butler, I.J. Encephalopathy Associated With Respiratory Syncytial Virus Bronchiolitis. J. Child Neurol. 2001, 16, 105–108. [Google Scholar] [CrossRef] [PubMed]
  146. Cappel, R.; Thiry, L.; Clinet, G. Viral Antibodies in the CSF After Acute CNS Infections. Arch. Neurol. 1975, 32, 629–631. [Google Scholar] [CrossRef] [PubMed]
  147. Kawashima, H.; Ioi, H.; Ushio, M.; Yamanaka, G.; Matsumoto, S.; Nakayama, T. Cerebrospinal fluid analysis in children with seizures from respiratory syncytial virus infection. Scand. J. Infect. Dis. 2009, 41, 228–231. [Google Scholar] [CrossRef] [PubMed]
  148. Kho, N.; Kerrigan, J.F.; Tong, T.; Browne, R.; Knilans, J. Respiratory Syncytial Virus Infection and Neurologic Abnormalities: Retrospective Cohort Study. J. Child Neurol. 2004, 19, 859–864. [Google Scholar] [CrossRef] [PubMed]
  149. Zlateva, K.T.; Van Ranst, M. Detection of subgroup B respiratory syncytial virus in the cerebrospinal fluid of a patient with respiratory syncytial virus pneumonia. Pediatric Infect. Dis. J. 2004, 23, 1065–1066. [Google Scholar] [CrossRef] [PubMed]
  150. Kawashima, H.; Kashiwagi, Y.; Ioi, H.; Morichi, S.; Oana, S.; Yamanaka, G.; Takekuma, K.; Hoshika, A.; Sawai, J.; Kato, Y. Production of chemokines in respiratory syncytial virus infection with central nervous system manifestations. J. Infect. Chemother. 2012, 18, 827–831. [Google Scholar] [CrossRef]
  151. Yuan, X.; Hu, T.; He, H.; Qiu, H.; Wu, X.; Chen, J.; Wang, M.; Chen, C.; Huang, S. Respiratory syncytial virus prolifically infects N2a neuronal cells, leading to TLR4 and nucleolin protein modulations and RSV F protein co-localization with TLR4 and nucleolin. J. Biomed. Sci. 2018, 25, 13. [Google Scholar] [CrossRef]
  152. Zhu, N.; Zhang, D.; Wang, W.; Li, X.; Yang, B.; Song, J.; Zhao, X.; Huang, B.; Shi, W.; Lu, R.; et al. A novel coronavirus from patients with pneumonia in China, 2019. N. Engl. J. Med. 2020, 382, 727–733. [Google Scholar] [CrossRef] [PubMed]
  153. Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. The species Severe acute respiratory syndrome-related coronavirus: Classifying 2019-nCoV and naming it SARS-CoV-2. Nat. Microbiol. 2020, 5, 536–544. [Google Scholar] [CrossRef] [PubMed]
  154. Hasöksüz, M.; Kiliç, S.; Saraç, F. Coronaviruses and sars-cov-2. Turkish J. Med. Sci. 2020, 50, 549–556. [Google Scholar] [CrossRef] [PubMed]
  155. Burki, T. Understanding Variants of SARS-CoV-2. Lancet 2021, 397, 462. [Google Scholar] [CrossRef]
  156. Soucheray, S. New COVID-19 Variants Found in New York, California. Available online: https://www.cidrap.umn.edu/news-perspective/2021/02/new-covid-19-variants-found-new-york-california (accessed on 19 March 2021).
  157. World Health Organization. Weekly Epidemiological Update—2 February 2021. Available online: https://www.who.int/publications/m/item/weekly-epidemiological-update---2-february-2021 (accessed on 19 March 2021).
  158. Canedo-Marroquín, G.; Saavedra, F.; Andrade, C.A.; Berrios, R.V.; Rodríguez-Guilarte, L.; Opazo, M.C.; Riedel, C.A.; Kalergis, A.M. SARS-CoV-2: Immune Response Elicited by Infection and Development of Vaccines and Treatments. Front. Immunol. 2020, 11, 569760. [Google Scholar] [CrossRef]
  159. Moriguchi, T.; Harii, N.; Goto, J.; Harada, D.; Sugawara, H.; Takamino, J.; Ueno, M.; Sakata, H.; Kondo, K.; Myose, N.; et al. A first Case of Meningitis/Encephalitis associated with SARS-Coronavirus-2. Int. J. Infect. Dis. 2020, 94, 55–58. [Google Scholar] [CrossRef] [PubMed]
  160. Carignan, A.; Valiquette, L.; Grenier, C.; Musonera, J.B.; Nkengurutse, D.; Marcil-Héguy, A.; Vettese, K.; Marcoux, D.; Valiquette, C.; Xiong, W.T.; et al. Anosmia and dysgeusia associated with SARS-CoV-2 infection: An age-matched case−control study. CMAJ 2020, 192, E702–E707. [Google Scholar] [CrossRef] [PubMed]
  161. Ellul, M.A.; Benjamin, L.; Singh, B.; Lant, S.; Michael, B.D.; Easton, A.; Kneen, R.; Defres, S.; Sejvar, J.; Solomon, T. Neurological associations of COVID-19. Lancet Neurol. 2020, 19, 767–783. [Google Scholar] [CrossRef]
  162. Domingues, R.B.; Mendes-Correa, M.C.; de Moura Leite, F.B.V.; Sabino, E.C.; Salarini, D.Z.; Claro, I.; Santos, D.W.; de Jesus, J.G.; Ferreira, N.E.; Romano, C.M.; et al. First case of SARS-COV-2 sequencing in cerebrospinal fluid of a patient with suspected demyelinating disease. J. Neurol. 2020, 267, 1–3. [Google Scholar] [CrossRef] [PubMed]
  163. Reichard, R.R.; Kashani, K.B.; Boire, N.A.; Constantopoulos, E.; Guo, Y.; Lucchinetti, C.F. Neuropathology of COVID-19: A spectrum of vascular and acute disseminated encephalomyelitis (ADEM)-like pathology. Acta Neuropathol. 2020, 140, 1–6. [Google Scholar] [CrossRef]
  164. Duarte-Neto, A.N.; Monteiro, R.A.A.; da Silva, L.F.F.; Malheiros, D.M.A.C.; de Oliveira, E.P.; Theodoro-Filho, J.; Pinho, J.R.R.; Gomes-Gouvêa, M.S.; Salles, A.P.M.; de Oliveira, I.R.S.; et al. Pulmonary and systemic involvement in COVID-19 patients assessed with ultrasound-guided minimally invasive autopsy. Histopathology 2020, 77, 186–197. [Google Scholar] [CrossRef]
  165. Generoso, J.S.; Barichello de Quevedo, J.L.; Cattani, M.; Lodetti, B.F.; Sousa, L.; Collodel, A.; Diaz, A.P.; Felipe, D.-P. Neurobiology of COVID-19: How can the virus affect the brain? Braz. J. Psychiatry 2021. [Google Scholar] [CrossRef] [PubMed]
  166. Tisoncik, J.R.; Korth, M.J.; Simmons, C.P.; Farrar, J.; Martin, T.R.; Katze, M.G. Into the Eye of the Cytokine Storm. Microbiol. Mol. Biol. Rev. 2012, 76, 16–32. [Google Scholar] [CrossRef] [PubMed]
  167. Wang, J.; Jiang, M.; Chen, X.; Montaner, L.J. Cytokine storm and leukocyte changes in mild versus severe SARS-CoV-2 infection: Review of 3939 COVID-19 patients in China and emerging pathogenesis and therapy concepts. J. Leukoc. Biol. 2020, 108, 17–41. [Google Scholar] [CrossRef] [PubMed]
  168. Alpert, O.; Begun, L.; Garren, P.; Solhkhah, R. Cytokine storm induced new onset depression in patients with COVID-19. A new look into the association between depression and cytokines -two case reports. Brain Behav. Immun. Health 2020, 9, 100173. [Google Scholar] [CrossRef] [PubMed]
  169. Jefferson, T.; Jones, M.; Doshi, P.; Spencer, E.A.; Onakpoya, I.; Heneghan, C.J. Oseltamivir for influenza in adults and children: Systematic review of clinical study reports and summary of regulatory comments. BMJ 2014, 348, g2545. [Google Scholar] [CrossRef]
  170. Studahl, M. Influenza virus and CNS manifestations. J. Clin. Virol. 2003, 28, 225–232. [Google Scholar] [CrossRef]
  171. Munakata, M.; Kato, R.; Yokoyama, H.; Haginoya, K.; Tanaka, Y.; Kayaba, J.; Kato, T.; Takayanagi, R.; Endo, H.; Hasegawa, R.; et al. Combined therapy with hypothermia and anticytokine agents in influenza A encephalopathy. Brain Dev. 2000, 22, 373–377. [Google Scholar] [CrossRef]
  172. Khandaker, G.; Zurynski, Y.; Buttery, J.; Marshall, H.; Richmond, P.C.; Dale, R.C.; Royle, J.; Gold, M.; Snelling, T.; Whitehead, B.; et al. Neurologic complications of influenza A(H1N1)pdm09 surveillance in 6 pediatric hospitals. Neurology 2012, 79, 1474–1481. [Google Scholar] [CrossRef]
  173. Lurie, D.I. An integrative approach to neuroinflammation in psychiatric disorders and neuropathic pain. J. Exp. Neurosci. 2018, 12, 1–11. [Google Scholar] [CrossRef] [PubMed]
  174. Bardage, C.; Persson, I.; Ortqvist, A.; Bergman, U.; Ludvigsson, J.F.; Granath, F. Neurological and autoimmune disorders after vaccination against pandemic influenza A (H1N1) with a monovalent adjuvanted vaccine: Population based cohort study in Stockholm, Sweden. BMJ 2011, 343, d5956. [Google Scholar] [CrossRef]
  175. Chang, K.-H.; Lyu, R.-K.; Lin, W.-T.; Huang, Y.-T.; Lin, H.-S.; Chang, S.-H. Gulllain-Barre Syndrome After Trivalent Influenza Vaccination in Adults. Front. Neurol. 2019, 10, 768. [Google Scholar] [CrossRef] [PubMed]
  176. Nunes, M.C.; Cutland, C.L.; Jones, S.; Hugo, A.; Madimabe, R.; Simões, E.A.F.; Weinberg, A.; Madhi, S.A. Duration of infant protection against influenza illness conferred by maternal immunization secondary analysis of a randomized clinical trial. JAMA Pediatrics 2016, 170, 840–847. [Google Scholar] [CrossRef] [PubMed]
  177. Zhao, K.; Huang, J.; Dai, D.; Feng, Y.; Liu, L.; Nie, S. Acute myelitis after SARS-CoV-2 infection: A case report. medRxiv 2020. [Google Scholar] [CrossRef]
Pharmaceuticals 14 00340 g001
Figure 1. Infections with the influenza virus can cause neurologic consequences directly and indirectly. The respiratory infection with the Influenza virus can lead to neuroinflammation as a consequence of the elevated pro-inflammatory molecules, such as IL-6, TNF-α, IL-1β, CXCL8, CCL2, CXCL10 and CXCL9 [103,107,108]. An increase of these molecules can directly promote the development of neurologic symptoms such as schizophrenia (SCZ), autism spectrum disorder (ASD), myelitis, seizures, meningitis, encephalitis, mood disorders and Guillain-Barré syndrome. On the other hand, the respiratory infection with Influenza virus in pregnant women can increase maternal immune activation (MIA), which increases the secretion of pro-inflammatory cytokines, such as IL-6, TNF-α and IL-1β. An increase expression of these molecules might indirectly promote brain inflammation of the offspring in the uterus, impairing brain development [42,109]. A possible result of brain inflammation is SCZ and ASD [110].
Figure 1. Infections with the influenza virus can cause neurologic consequences directly and indirectly. The respiratory infection with the Influenza virus can lead to neuroinflammation as a consequence of the elevated pro-inflammatory molecules, such as IL-6, TNF-α, IL-1β, CXCL8, CCL2, CXCL10 and CXCL9 [103,107,108]. An increase of these molecules can directly promote the development of neurologic symptoms such as schizophrenia (SCZ), autism spectrum disorder (ASD), myelitis, seizures, meningitis, encephalitis, mood disorders and Guillain-Barré syndrome. On the other hand, the respiratory infection with Influenza virus in pregnant women can increase maternal immune activation (MIA), which increases the secretion of pro-inflammatory cytokines, such as IL-6, TNF-α and IL-1β. An increase expression of these molecules might indirectly promote brain inflammation of the offspring in the uterus, impairing brain development [42,109]. A possible result of brain inflammation is SCZ and ASD [110].
Pharmaceuticals 14 00340 g001
Pharmaceuticals 14 00340 g002
Figure 2. Human respiratory syncytial virus infection can cause neurologic consequences in patients. The respiratory infection with the respiratory syncytial virus can lead to neuroinflammation as a consequence of the elevated pro-inflammatory molecules such as IL-6, IL-8, CCL2, and CCL4 [150]. This increase can promote the development of neurologic symptoms such as encephalitis and encephalopathies [144,145,146].
Figure 2. Human respiratory syncytial virus infection can cause neurologic consequences in patients. The respiratory infection with the respiratory syncytial virus can lead to neuroinflammation as a consequence of the elevated pro-inflammatory molecules such as IL-6, IL-8, CCL2, and CCL4 [150]. This increase can promote the development of neurologic symptoms such as encephalitis and encephalopathies [144,145,146].
Pharmaceuticals 14 00340 g002
Pharmaceuticals 14 00340 g004
Figure 4. Possible treatments to prevent neurologic consequences in patients infected by respiratory viruses. Adults and infants that present diverse neuropsychiatric disorders can be decreased using antivirals drugs, which will prevent the brain′s local infection and therefore protect from further consequences. Additionally, the use of inhibitors of pro-inflammatory molecules and mild hypothermia can decrease the secretion of pro-inflammatory molecules, and as a result, decrease neuroinflammation. The use of vaccines might protect from developing neuropsychiatric disorders in adults, infants, and offspring due to the maternal vaccination.
Figure 4. Possible treatments to prevent neurologic consequences in patients infected by respiratory viruses. Adults and infants that present diverse neuropsychiatric disorders can be decreased using antivirals drugs, which will prevent the brain′s local infection and therefore protect from further consequences. Additionally, the use of inhibitors of pro-inflammatory molecules and mild hypothermia can decrease the secretion of pro-inflammatory molecules, and as a result, decrease neuroinflammation. The use of vaccines might protect from developing neuropsychiatric disorders in adults, infants, and offspring due to the maternal vaccination.
Pharmaceuticals 14 00340 g004
Table 1. Cytokine profile elicited by the influenza virus strains.
Table 1. Cytokine profile elicited by the influenza virus strains.
StrainH5N1 (Vietnam/1203/04)H7N7 (rSC35M)H1N1 (A/PR/8/34 and A/Shantou/169/2006)H5N1 (A/Hong Kong/483/97)H7N9 (H7/SH2/13)H1N1 (A/PR/8/34)H3N2 (maHK68)
Neurotropic effectYesYesYesYesYesNoNo
Infection of cellsNeurons and microgliaNo informationNeuronsAstrocytesNeurons and astrocytesNo informationNo information
Pro-inflammatory CytokinesIncrease of IL-1β, IL-12(p70), IL-2, IL-13, and TNF-αIncrease of IFN-γ and TNF-αIncrease of IL-6 and TNF-αIncrease of IL-6 and TNF-αIncrease of IL-6, IL-8, TNF-α and IFN-βIncrease of TNF-α, IL-1β, and IL-6Increase of TNF-α
ChemokinesIncrease of CCL2, CCL3, CCL4, CCL11, CXCL10, and CXCL1No informationIncrease of CXCL-10No informationIncrease of CCL2No informationNo information
Grown factorsIncrease of G-CSF, GM-CSF, M-CSF and VEGFNo informationNo informationNo informationNo informationDecrease of BDNF and NGFNo information
Anti-inflammatory CytokinesIncrease of IL-10No informationNo informationNo informationNo informationNo informationNo information
Table 2. Cytokines elicited by hRSV infection in CNS and the associated consequences.
Table 2. Cytokines elicited by hRSV infection in CNS and the associated consequences.
Clinical FindingsPro-Inflammatory MoleculesConsequences
hRSV genetic material in cerebrospinal fluidElevated levels of IL-6, IL-8, CCL2, and CCL4 and low levels of TNF-α in cerebrospinal fluidEncephalitis
Encephalopathies
Learning difficulties To be definedLanguage difficulties
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Bohmwald, K.; Andrade, C.A.; Kalergis, A.M. Contribution of Pro-Inflammatory Molecules Induced by Respiratory Virus Infections to Neurological Disorders. Pharmaceuticals 2021, 14, 340. https://doi.org/10.3390/ph14040340

AMA Style

Bohmwald K, Andrade CA, Kalergis AM. Contribution of Pro-Inflammatory Molecules Induced by Respiratory Virus Infections to Neurological Disorders. Pharmaceuticals. 2021; 14(4):340. https://doi.org/10.3390/ph14040340

Chicago/Turabian Style

Bohmwald, Karen, Catalina A. Andrade, and Alexis M. Kalergis. 2021. "Contribution of Pro-Inflammatory Molecules Induced by Respiratory Virus Infections to Neurological Disorders" Pharmaceuticals 14, no. 4: 340. https://doi.org/10.3390/ph14040340

APA Style

Bohmwald, K., Andrade, C. A., & Kalergis, A. M. (2021). Contribution of Pro-Inflammatory Molecules Induced by Respiratory Virus Infections to Neurological Disorders. Pharmaceuticals, 14(4), 340. https://doi.org/10.3390/ph14040340

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop