Search Results (24)

While viral pathogens are often subdivided into neurotropic and non-neurotropic categories, systemic inflammation caused by non-neurotropic viruses still possesses the ability to alter the central nervous system (CNS). Studies of CNS disease induced by viral infection, whether neurotropic or not, are presented with a unique set of challenges. First, because brain biopsies are rarely necessary to diagnose viral-associated neurological disorders, antemortem tissue samples are not readily available for study and human pathological studies must rely on end-stage, postmortem evaluations. Second, in vitro models fail to fully capture the nuances of an intact immune system, necessitating the use of animal models to fully characterize pathogenesis and identify potential therapeutic approaches. Non-human primates (NHP) represent a particularly attractive animal model in that they overcome many of the limits posed by more distant species and most closely mirror human disease pathogenesis and susceptibility. Here, we review NHP infection models of viruses known to infect and/or replicate within cells of the CNS, including West Nile virus, the equine encephalitis viruses, Zika virus, and herpesviruses, as well as those known to alter the immune status of the brain in the absence of significant CNS penetrance, including human immunodeficiency virus (HIV) in the current era of combination antiretroviral therapy (cART) and the coronavirus of severe acute respiratory syndrome (SARS)-CoV−2. This review focuses on viruses with an established role in causing CNS disease, including encephalitis, meningitis, and myelitis and NHP models of viral infection that are directly translatable to the human condition through relevant routes of infection, comparable disease pathogenesis, and responses to therapeutic intervention. Full article

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is known to affect multiple organ systems, including the respiratory tract and nervous and ocular systems. This retrospective study aimed to characterize the spatiotemporal distribution of viral antigen and associated pathological changes in the nose, lungs, brain, and eyes of K18-hACE2 mice intranasally infected with SARS-CoV-2. Using histology and immunohistochemistry, tissues were examined at 3, 6, and 7/8 days post-infection (dpi). In addition, lung and brain tissues were analyzed by means of RT-qPCR to determine viral RNA titers. Viral antigen was most pronounced in the nose, brain, and lung at 3, 6, and 7/8 dpi, respectively, whereas viral antigen was detected at 6 and 7/8 dpi in the retina. Quantitative PCR confirmed increasing viral RNA levels in both lung and brain, peaking at 7/8 dpi. Nasal and lung inflammation mirrored viral antigen distribution and localization. In the brain, the predominantly basal viral spread correlated with lymphohistiocytic meningoencephalitis, neuronal vacuolation, and altered neurofilament immunoreactivity. Retinal ganglion cells showed viral antigen expression without associated lesions. Microglial activation was evident in both the optic chiasm and the brain. These findings highlight the K18-hACE2 model’s utility for studying extrapulmonary SARS-CoV-2 pathogenesis. Understanding the temporal and spatial dynamics of viral spread enhances insights into SARS-CoV-2 neurotropism and its clinical manifestations. Full article

Alzheimer’s Disease (AD), a progressive and debilitating condition, is reported to be the most common type of dementia, with at least 55 million people believed to be currently affected. Many causation hypotheses of AD exist, yet the intriguing link between viral infection and its possible contribution to the known etiology of AD has become an attractive focal point of research for the field and a challenging study task. In this review, we will explore the historical perspective and milestones that led the field to investigate the viral connection to AD. Specifically, several viruses such as Herpes Simplex Virus 1 (HSV-1), Zika virus (ZIKV), and severe cute respiratory syndrome coronavirus 2 (SARS-CoV-2), along with several others mentioned, include the various viruses presently considered within the field. We delve into the strong evidence implicating these viruses in the development of AD such as the lytic replication and axonal transport of HSV-1, the various mechanisms of ZIKV neurotropism through the human protein Musashi-1 (MSI1), and the spread of SARS-CoV-2 through the transfer of the virus through the BBB endothelial cells to glial cells and then to neurons via transsynaptic transfer. We will also explore beyond these mere associations by carefully analyzing the potential mechanisms by which these viruses may contribute to AD pathology. This includes but is not limited to direct neuronal infections, the dysregulation of immune responses, and the impact on protein processing (Aβ42 and hyperphosphorylated tau). Controversies and challenges of the virus–AD relationship emerge as we tease out these potential mechanisms. Looking forward, we emphasize future directions, such as distinct questions and proposed experimentations to explore, that the field should take to tackle the remaining unanswered questions and the glaring research gaps that persist. Overall, this review aims to provide a comprehensive survey of the past, present, and future of the potential link between viral infections and their association with AD development while encouraging further discussion. Full article

Recognition of viruses invading the central nervous system (CNS) by pattern recognition receptors (PRRs) is crucial to elicit early innate responses that stem dissemination. These innate responses comprise both type I interferon (IFN-I)-mediated defenses as well as signals recruiting leukocytes to control the infection. Focusing on insights from the neurotropic mouse CoV model, this review discusses how early IFN-I, fibroblast, and myeloid signals can influence protective anti-viral adaptive responses. Emphasis is placed on three main areas: the importance of coordinating the distinct capacities of resident CNS cells to induce and respond to IFN-I, the effects of select IFN-stimulated genes (ISGs) on host immune responses versus viral control, and the contribution of fibroblast activation and myeloid cells in aiding the access of T cells to the parenchyma. By unraveling how the dysregulation of early innate components influences adaptive immunity and viral control, this review illustrates the combined effort of resident CNS cells to achieve viral control. Full article

The virus SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) is capable of attacking the nervous system in several ways and leading to neurological diseases such as GBS (Guillain–Barré syndrome) through the resulting neurotropism and immune response. The aim of this study is to show the relationship between Coronavirus disease (COVID-19) and GBS and to better understand the clinical symptoms to prevent poor outcomes. Data from 15 patients were extracted from the Department of Neurology, University Hospital of Split, Croatia, for the year 2021. The age of the patients ranged from 26 to 89 years, of whom 27% were women. Sixty seven percent of all GBS patients recovered from COVID-19 infection, whereas post-vaccinal polyradiculoneuritis was detected in 6%. Forty four percent of the patients who developed GBS had a severe form of COVID-19 infection. Forty percent of patients were treated with intravenous immunoglobulins (IVIG), followed by therapeutic plasma exchange (PLEX) in 27%. After the therapy, improvement was observed in 13 patients, while two patients died. The results suggest that SARS-CoV-2 triggers GBS because it follows a similar pattern of infection as the other viral and bacterial agents that contribute to the onset of GBS. There is no evidence that prior infection with COVID-19 worsens the clinical presentation of GBS. Full article

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative pathogen of the coronavirus disease 2019 (COVID-19) pandemic, a fatal respiratory illness. The associated risk factors for COVID-19 are old age and medical comorbidities. In the current combined antiretroviral therapy (cART) era, a significant portion of people living with HIV-1 (PLWH) with controlled viremia is older and with comorbidities, making these people vulnerable to SARS-CoV-2 infection and COVID-19-associated severe outcomes. Additionally, SARS-CoV-2 is neurotropic and causes neurological complications, resulting in a health burden and an adverse impact on PLWH and exacerbating HIV-1-associated neurocognitive disorder (HAND). The impact of SARS-CoV-2 infection and COVID-19 severity on neuroinflammation, the development of HAND and preexisting HAND is poorly explored. In the present review, we compiled the current knowledge of differences and similarities between SARS-CoV-2 and HIV-1, the conditions of the SARS-CoV-2/COVID-19 and HIV-1/AIDS syndemic and their impact on the central nervous system (CNS). Risk factors of COVID-19 on PLWH and neurological manifestations, inflammatory mechanisms leading to the neurological syndrome, the development of HAND, and its influence on preexisting HAND are also discussed. Finally, we have reviewed the challenges of the present syndemic on the world population, with a particular emphasis on PLWH. Full article

The severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19, possesses an unusually large positive-sense, single-stranded viral RNA (ssvRNA) genome of about ~29,903 nucleotides (nt). In many respects, this ssvRNA resembles a very large, polycistronic messenger RNA (mRNA) possessing a 5′-methyl cap (m⁷GpppN), a 3′- and 5′-untranslated region (3′-UTR, 5′-UTR), and a poly-adenylated (poly-A+) tail. As such, the SARS-CoV-2 ssvRNA is susceptible to targeting by small non-coding RNA (sncRNA) and/or microRNA (miRNA), as well as neutralization and/or inhibition of its infectivity via the human body’s natural complement of about ~2650 miRNA species. Depending on host cell and tissue type, in silico analysis, RNA sequencing, and molecular-genetic investigations indicate that, remarkably, almost every single human miRNA has the potential to interact with the primary sequence of SARS-CoV-2 ssvRNA. Individual human variation in host miRNA abundance, speciation, and complexity among different human populations and additional variability in the cell and tissue distribution of the SARS-CoV-2 angiotensin converting enzyme-2 (ACE2) receptor (ACE2R) appear to further contribute to the molecular-genetic basis for the wide variation in individual host cell and tissue susceptibility to COVID-19 infection. In this paper, we review recently described aspects of the miRNA and ssvRNA ribonucleotide sequence structure in this highly evolved miRNA–ssvRNA recognition and signaling system and, for the first time, report the most abundant miRNAs in the control superior temporal lobe neocortex (STLN), an anatomical area involved in cognition and targeted by both SARS-CoV-2 invasion and Alzheimer’s disease (AD). We further evaluate important factors involving the neurotropic nature of SARS-CoV-2 and miRNAs and ACE2R distribution in the STLN that modulate significant functional deficits in the brain and CNS associated with SARS-CoV-2 infection and COVID-19’s long-term neurological effects. Full article

Billions of years of co-evolution has made mitochondria central to the eukaryotic cell and organism life playing the role of cellular power plants, as indeed they are involved in most, if not all, important regulatory pathways. Neurological disorders depending on impaired mitochondrial function or homeostasis can be caused by the misregulation of “endogenous players”, such as nuclear or cytoplasmic regulators, which have been treated elsewhere. In this review, we focus on how exogenous agents, i.e., viral pathogens, or unbalanced microbiota in the gut-brain axis can also endanger mitochondrial dynamics in the central nervous system (CNS). Neurotropic viruses such as Herpes, Rabies, West-Nile, and Polioviruses seem to hijack neuronal transport networks, commandeering the proteins that mitochondria typically use to move along neurites. However, several neurological complications are also associated to infections by pandemic viruses, such as Influenza A virus and SARS-CoV-2 coronavirus, representing a relevant risk associated to seasonal flu, coronavirus disease-19 (COVID-19) and “Long-COVID”. Emerging evidence is depicting the gut microbiota as a source of signals, transmitted via sensory neurons innervating the gut, able to influence brain structure and function, including cognitive functions. Therefore, the direct connection between intestinal microbiota and mitochondrial functions might concur with the onset, progression, and severity of CNS diseases. Full article

Background and Objectives: Recent findings demonstrate that the transmigration of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) to the nervous system implicates severe neurotropic pathologies, including the onset of the rare disease called Guillain–Barré syndrome (GBS) which is characterized by immune-mediated polyneuropathy. This study aimed to identify the predisposing factors and the clinical features of coronavirus disease 2019 (COVID-19)-induced GBS. Materials and Methods: We have performed an analysis of 147 cases. A systematic review of the published research work was performed per the PRISMA statement to obtain individual participant data (IPD) for the meta-analysis. The search was conducted through PubMed, using the combined search terms “Guillain–Barré syndrome” and “COVID-19”. All case reports and series in the English language with accessed full text were included in the search. Results: A systematic database search led to the retrieval of 112 peer-reviewed articles published between 1 April 2020, and 8 February 2022. The articles comprised 16 case series and 96 case reports containing IPD for 147 patients. Our findings showed that 77.6% of all cases were 40 years or older. Males comprised most of the cases (65.3%; n = 96). The intensive care unit (ICU) admission was 44.9%, and the need for mechanical ventilation (MV) was 38.1%. The patients presented with hyporeflexia or areflexia (84.4%; n = 124), lower limb strength and sensation impairment (93.2%; n = 138), upper limb strength and sensation impairment (85.7; n = 126), and somatic sensation impairment (72.8%; n = 107). The patients presented with increased cerebral spinal fluid (CSF) protein levels (92%; n = 92) and the presence of CSF albuminocytological dissociation (83.5%; n = 71). The most common variant of GBS observed was acute inflammatory demyelinating polyneuropathy (AIDP). We found that predisposing factors concomitant with COVID-19 and GBS were male gender and older age. Among the cases, patient mortality was 10.9%. Conclusions: A gap of knowledge exists regarding the complete spectrum of clinical characteristics of COVID-19-related GBS. Recent findings suggest that SARS-CoV-2 triggers GBS, as it follows a similar para-infectious pattern as the other viral agents contributing to the onset of GBS. Full article

Several reports have shown that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has the potential to also be neurotropic. However, the mechanisms by which SARS-CoV-2 induces neurologic injury, including neurological and/or psychological symptoms, remain unclear. In this review, the available knowledge on the neurobiological mechanisms underlying COVID-19 was organized using the AOP framework. Four AOPs leading to neurological adverse outcomes (AO), anosmia, encephalitis, stroke, and seizure, were developed. Biological key events (KEs) identified to induce these AOs included binding to ACE2, blood–brain barrier (BBB) disruption, hypoxia, neuroinflammation, and oxidative stress. The modularity of AOPs allows the construction of AOP networks to visualize core pathways and recognize neuroinflammation and BBB disruption as shared mechanisms. Furthermore, the impact on the neurological AOPs of COVID-19 by modulating and multiscale factors such as age, psychological stress, nutrition, poverty, and food insecurity was discussed. Organizing the existing knowledge along an AOP framework can represent a valuable tool to understand disease mechanisms and identify data gaps and potentially contribute to treatment, and prevention. This AOP-aligned approach also facilitates synergy between experts from different backgrounds, while the fast-evolving and disruptive nature of COVID-19 emphasizes the need for interdisciplinarity and cross-community research. Full article

Flavonoids are a group of natural compounds that have been described in the literature as having anti-inflammatory, antioxidant, and neuroprotective compounds. Although they are considered versatile molecules, little has been discussed about their antiviral activities for neurotropic viruses. Hence, the present study aimed to investigate the pharmacological potential of flavonoids in the face of viruses that can affect the central nervous system (CNS). We carried out research from 2011 to 2021 using the Pubmed platform. The following were excluded: articles not in the English language, letters to editors, review articles and papers that did not include any experimental or clinical tests, and papers that showed antiviral activities against viruses that do not infect human beings. The inclusion criteria were in silico predictions and preclinical pharmacological studies, in vitro, in vivo and ex vivo, and clinical studies with flavonoids, flavonoid fractions and extracts that were active against neurotropic viruses. The search resulted in 205 articles that were sorted per virus type and discussed, considering the most cited antiviral activities. Our investigation shows the latest relevant data about flavonoids that have presented a wide range of actions against viruses that affect the CNS, mainly influenza, hepatitis C and others, such as the coronavirus, enterovirus, and arbovirus. Considering that these molecules present well-known anti-inflammatory and neuroprotective activities, using flavonoids that have demonstrated both neuroprotective and antiviral effects could be viewed as an alternative for therapy in the course of CNS infections. Full article

The recent outbreak of the novel Coronavirus (SARS-CoV-2 or CoV-2) pandemic in 2019 and the risk of CoV-2 infection during pregnancy led the scientific community to investigate the potential negative effects of Coronavirus infection on pregnancy outcomes and fetal development. In particular, as CoV-2 neurotropism has been demonstrated in adults, recent studies suggested a possible risk of fetal brain damage and fetal brain development impairment, with consequent psychiatric manifestations in offspring of mothers affected by COronaVIrus Disease (COVID) during pregnancy. Through the understanding of CoV-2’s pathogenesis and the pathways responsible for cell damage, along with the available data about neurotropic virus attitudes, different strategies have been suggested to lower the risk of neurologic disease in newborns. In this regard, the role of nutrition in mitigating fetal damages related to oxidative stress and the inflammatory environment during viral infection has been investigated, and arginine, n3PUFA, vitamins B1 and B9, choline, and flavonoids were found to be promising in and out of pregnancy. The aim of this review is to provide an overview of the current knowledge on the mechanism of fetal brain damage and the impact of nutrition in reducing inflammation related to worse neurological outcomes in the context of CoV-2 infections during pregnancy. Full article

Using new and original nineteenth-century sources, we analysed the epidemiology, clinical features and virology of the 1889 pandemic, which was referred to at the time as ‘Russian flu’ or ‘Asiatic flu’. However, we rejected this identification of the disease as an ‘influenza’, which we believe to have been based on insufficient knowledge of the causative agent and instead posit that the pandemic was caused by a coronavirus. We provide a new account of the 1889–1893 pandemic, with a more detailed chronology that included at least four epidemiological waves. At the end of 1889, a new virus appeared in Europe, which could be identified as the coronavirus HCoV-OC43, causing crude death rates of 1.3 per 1000 population in St Petersburg; 2.1 per 1000 in Paris; 2.8 per 1000 in Bilbao and on the French–Spanish border; between 2.9 and 5.2 per 1000 in small towns in the Basque Country; and 5.8 deaths per 1000 in Madrid, which had the highest death rate. The clinical features of the disease differed from classical influenza pandemics in terms of the latency phase, duration, symptomatology, convalescence, immunity, age and death rates. Another factor to be considered was the neurotropic capacity of the disease. The most frequent form of the 1889 pandemic was the ‘nervous form’, with specific symptoms such as ‘heavy headache’ (céphalalgie gravative), tiredness, fever and delirium. There are strong parallels between the 1889–1894 pandemic and the COVID-19 pandemic, and a better understanding of the former may therefore help us to better manage the latter. Full article

The knowledge of the COVID-19 symptomatology has increased since the beginning of the SARS-CoV-2 pandemic. The symptoms of nervous system involvement have been observed across the spectrum of COVID-19 severity. Reports describing difficulties of nerve roots are rare; the affection of brain and spinal cord by SARS-CoV-2 is of leading interest. Our aim therefore is to describe the radicular pain deterioration in the group of nine chronic lumbosacral radicular syndrome sufferers in acute COVID-19. The intensity of radicular pain was evaluated by the Visual Analogue Scale (VAS). The VAS score in acute infection increased from 5.6 ± 1.1 to 8.0 ± 1.3 (Cohen’s d = 1.99) over the course of COVID-19, indicating dramatic aggravation of pain intensity. However, the VAS score decreased spontaneously to pre-infection levels after 4 weeks of COVID-19 recovery (5.8 ± 1.1). The acute SARS-CoV-2 infection worsened the pre-existing neural root irritation symptomatology, which may be ascribed to SARS-CoV-2 radiculitis of neural roots already compressed by the previous disc herniation. These findings based on clinical observations indicate that the neurotropism of novel coronavirus infection can play an important role in the neural root irritation symptomatology deterioration in patients with chronic pre-existing lumbosacral radicular syndrome. Full article

Pathogenesis of viral infections of the central nervous system (CNS) is poorly understood, and this is partly due to the limitations of currently used preclinical models. Brain organoid models can overcome some of these limitations, as they are generated from human derived stem cells, differentiated in three dimensions (3D), and can mimic human neurodevelopmental characteristics. Therefore, brain organoids have been increasingly used as brain models in research on various viruses, such as Zika virus, severe acute respiratory syndrome coronavirus 2, human cytomegalovirus, and herpes simplex virus. Brain organoids allow for the study of viral tropism, the effect of infection on organoid function, size, and cytoarchitecture, as well as innate immune response; therefore, they provide valuable insight into the pathogenesis of neurotropic viral infections and testing of antivirals in a physiological model. In this review, we summarize the results of studies on viral CNS infection in brain organoids, and we demonstrate the broad application and benefits of using a human 3D model in virology research. At the same time, we describe the limitations of the studies in brain organoids, such as the heterogeneity in organoid generation protocols and age at infection, which result in differences in results between studies, as well as the lack of microglia and a blood brain barrier. Full article