Search Results (26)

The global impact of the COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), persists in part due to the emergence of new variants. Understanding variant-specific infection dynamics and pathogenesis in murine models is crucial for identifying phenotypic changes and guiding the development of countermeasures. To address the limitations of earlier studies that investigated only a few variants or used small sample sizes, we evaluated clinical disease, infection kinetics, viral titers, cellular localization, and histopathologic changes in the lungs and brains of transgenic B6.Cg-Tg(K18-ACE2)2Prlmn/J (“K18”) and corresponding genetic control (C57BL/6J) mice expressing human angiotensin-converting enzyme 2 (hACE2). Six SARS-CoV-2 variants were assessed: B.1 (WA1-like), alpha, beta, delta, omicron, and omicron XBB.1.5, using cohorts of ≥18 mice. Following intranasal inoculation with B.1, alpha, beta, or delta variants, K18 mice experienced rapid weight loss and reached euthanasia criteria by 5–6 days post-inoculation (dpi). In contrast, K18 mice inoculated with both omicron variants recovered to their starting weight within 4–6 dpi. Infectious SARS-CoV-2 was detected in the oropharynx at 1 and2 dpi, in the lungs at 2, 4, and 6 dpi, and in the brain at 4 and 6 dpi for all variants except omicron. SARS-CoV-2 nucleoprotein was detected, and interstitial pneumonia of varying severity was observed in K18 mice infected with all variants. Brain lesions were identified in mice infected with the B.1, beta, and delta variants 6 dpi. As K18 mice express hACE2 in the brain—a feature not present in humans—we also compared infection dynamics of three variants to those of a mouse-adapted WA1 strain in C57BL/6J mice lacking the human ACE2 gene. C57BL/6J mice did not experience lethal disease, exhibited milder pneumonia, and had no evidence of neuroinvasion despite similar infection kinetics to K18 mice. These findings demonstrate contrasting phenotypes across the two models and reduced tropism and pathology of omicron compared to earlier variants in both models. This comprehensive analysis of SARS-CoV-2 variants in two mouse models provides valuable insights for model and variant selection for future studies. Full article

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease (COVID-19), induced a global pandemic with a diverse array of clinical manifestations. While the acute phase of the pandemic may be waning, the intricacies of COVID-19′s impact on neurological health remain a crucial area of investigation. Early recognition of the spectrum of COVID-19 symptoms, ranging from mild fever and cough to life-threatening respiratory distress and multi-organ failure, underscored the significance of neurological complications, including anosmia, seizures, stroke, disorientation, encephalopathy, and paralysis. Notably, patients requiring intensive care unit (ICU) admission due to neurological challenges or due to them exhibiting neurological abnormalities in the ICU have shown increased mortality rates. COVID-19 can lead to a range of neurological complications such as anosmia, stroke, paralysis, cranial nerve deficits, encephalopathy, delirium, meningitis, seizures, etc., in affected patients. This review elucidates the burgeoning landscape of neurological sequelae associated with SARS-CoV-2 infection and explores the underlying neurobiological mechanisms driving these diverse manifestations. A meticulous examination of potential neuroinvasion routes by SARS-CoV-2 underscores the intricate interplay between the virus and the nervous system. Moreover, we dissect the diverse neurological manifestations emphasizing the necessity of a multifaceted approach to understanding the disease’s neurological footprint. In addition to elucidating the pathophysiological underpinnings, this review surveys current therapeutic modalities and delineates prospective avenues for neuro-COVID research. By integrating epidemiological, clinical, and diagnostic parameters, we endeavor to foster a comprehensive analysis of the nexus between COVID-19 and neurological health, thereby laying the groundwork for targeted therapeutic interventions and long-term management strategies. Full article

Neurological manifestations are a significant complication of coronavirus disease 2019 (COVID-19), but the underlying mechanisms are yet to be understood. Recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced neuroinvasion and encephalitis were observed in K18-hACE2 mice, leading to mortality. Our goal in this study was to gain insights into the molecular pathogenesis of neurological manifestations in this mouse model. To analyze differentially expressed genes (DEGs) in the brains of mice following SARS-CoV-2 infection, we performed NanoString gene expression analysis using three individual animal samples at 1, 3, and 6 days post-infection. We identified the DEGs by comparing them to animals that were not infected with the virus. We found that genes upregulated at day 6 post-infection were mainly associated with Toll-like receptor (TLR) signaling, RIG-I-like receptor (RLR) signaling, and cell death pathways. However, downregulated genes were associated with neurodegeneration and synaptic signaling pathways. In correlation with gene expression profiles, a multiplexed immunoassay showed the upregulation of multiple cytokines and chemokines involved in inflammation and cell death in SARS-CoV-2-infected brains. Furthermore, the pathway analysis of DEGs indicated a possible link between TLR2-mediated signaling pathways and neuroinflammation, as well as pyroptosis and necroptosis in the brain. In conclusion, our work demonstrates neuroinflammation-associated gene expression profiles, which can provide key insight into the severe disease observed in COVID-19 patients. Full article

A growing body of evidence indicates that a neuropathological cross-talk takes place between the coronavirus disease 2019 (COVID-19) -the pandemic severe pneumonia that has had a tremendous impact on the global economy and health since three years after its outbreak in December 2019- and Alzheimer’s Disease (AD), the leading cause of dementia among human beings, reaching 139 million by the year 2050. Even though COVID-19 is a primary respiratory disease, its causative agent, the so-called Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), is also endowed with high neuro-invasive potential (Neurocovid). The neurological complications of COVID-19, resulting from the direct viral entry into the Central Nervous System (CNS) and/or indirect systemic inflammation and dysregulated activation of immune response, encompass memory decline and anosmia which are typically associated with AD symptomatology. In addition, patients diagnosed with AD are more vulnerable to SARS-CoV-2 infection and are inclined to more severe clinical outcomes. In the present review, we better elucidate the intimate connection between COVID-19 and AD by summarizing the involved risk factors/targets and the underlying biological mechanisms shared by these two disorders with a particular focus on the Angiotensin-Converting Enzyme 2 (ACE2) receptor, APOlipoprotein E (APOE), aging, neuroinflammation and cellular pathways associated with the Amyloid Precursor Protein (APP)/Amyloid beta (Aβ) and tau neuropathologies. Finally, the involvement of ophthalmological manifestations, including vitreo-retinal abnormalities and visual deficits, in both COVID-19 and AD are also discussed. Understanding the common physiopathological aspects linking COVID-19 and AD will pave the way to novel management and diagnostic/therapeutic approaches to cope with them in the post-pandemic future. Full article

SARS-CoV-2, a single-stranded RNA coronavirus, causes an illness known as coronavirus disease 2019 (COVID-19). Long-term complications are an increasing issue in patients who have been infected with COVID-19 and may be a result of viral-associated systemic and central nervous system inflammation or may arise from a virus-induced hypercoagulable state. COVID-19 may incite changes in brain function with a wide range of lingering symptoms. Patients often experience fatigue and may note brain fog, sensorimotor symptoms, and sleep disturbances. Prolonged neurological and neuropsychiatric symptoms are prevalent and can interfere substantially in everyday life, leading to a massive public health concern. The mechanistic pathways by which SARS-CoV-2 infection causes neurological sequelae are an important subject of ongoing research. Inflammation- induced blood-brain barrier permeability or viral neuro-invasion and direct nerve damage may be involved. Though the mechanisms are uncertain, the resulting symptoms have been documented from numerous patient reports and studies. This review examines the constellation and spectrum of nervous system symptoms seen in long COVID and incorporates information on the prevalence of these symptoms, contributing factors, and typical course. Although treatment options are generally lacking, potential therapeutic approaches for alleviating symptoms and improving quality of life are explored. Full article

Coronavirus infections are neuroinvasive and can provoke injury to the central nervous system (CNS) and long-term illness consequences. They may be associated with inflammatory processes due to cellular oxidative stress and an imbalanced antioxidant system. The ability of phytochemicals with antioxidant and anti-inflammatory activities, such as Ginkgo biloba, to alleviate neurological complications and brain tissue damage has attracted strong ongoing interest in the neurotherapeutic management of long COVID. Ginkgo biloba leaf extract (EGb) contains several bioactive ingredients, e.g., bilobalide, quercetin, ginkgolides A–C, kaempferol, isorhamnetin, and luteolin. They have various pharmacological and medicinal effects, including memory and cognitive improvement. Ginkgo biloba, through its anti-apoptotic, antioxidant, and anti-inflammatory activities, impacts cognitive function and other illness conditions like those in long COVID. While preclinical research on the antioxidant therapies for neuroprotection has shown promising results, clinical translation remains slow due to several challenges (e.g., low drug bioavailability, limited half-life, instability, restricted delivery to target tissues, and poor antioxidant capacity). This review emphasizes the advantages of nanotherapies using nanoparticle drug delivery approaches to overcome these challenges. Various experimental techniques shed light on the molecular mechanisms underlying the oxidative stress response in the nervous system and help comprehend the pathophysiology of the neurological sequelae of SARS-CoV-2 infection. To develop novel therapeutic agents and drug delivery systems, several methods for mimicking oxidative stress conditions have been used (e.g., lipid peroxidation products, mitochondrial respiratory chain inhibitors, and models of ischemic brain damage). We hypothesize the beneficial effects of EGb in the neurotherapeutic management of long-term COVID-19 symptoms, evaluated using either in vitro cellular or in vivo animal models of oxidative stress. Full article

The development of long-term symptoms of coronavirus disease 2019 (COVID-19) more than four weeks after primary infection, termed “long COVID” or post-acute sequela of COVID-19 (PASC), can implicate persistent neurological complications in up to one third of patients and present as fatigue, “brain fog”, headaches, cognitive impairment, dysautonomia, neuropsychiatric symptoms, anosmia, hypogeusia, and peripheral neuropathy. Pathogenic mechanisms of these symptoms of long COVID remain largely unclear; however, several hypotheses implicate both nervous system and systemic pathogenic mechanisms such as SARS-CoV2 viral persistence and neuroinvasion, abnormal immunological response, autoimmunity, coagulopathies, and endotheliopathy. Outside of the CNS, SARS-CoV-2 can invade the support and stem cells of the olfactory epithelium leading to persistent alterations to olfactory function. SARS-CoV-2 infection may induce abnormalities in innate and adaptive immunity including monocyte expansion, T-cell exhaustion, and prolonged cytokine release, which may cause neuroinflammatory responses and microglia activation, white matter abnormalities, and microvascular changes. Additionally, microvascular clot formation can occlude capillaries and endotheliopathy, due to SARS-CoV-2 protease activity and complement activation, can contribute to hypoxic neuronal injury and blood–brain barrier dysfunction, respectively. Current therapeutics target pathological mechanisms by employing antivirals, decreasing inflammation, and promoting olfactory epithelium regeneration. Thus, from laboratory evidence and clinical trials in the literature, we sought to synthesize the pathophysiological pathways underlying neurological symptoms of long COVID and potential therapeutics. Full article

Introduction: SARS-CoV-2 is the newest beta coronavirus family member to demonstrate neuroinvasive capability in severe cases of infection. Despite much research activity in the SARS-CoV-2/COVID-19 space, the gene-level biology of this phenomenon remains poorly understood. In the present analysis, we leveraged spatial transcriptomics methodologies to examine relevant gene heterogeneity in tissue retrieved from the human prefrontal cortex. Methods: Expression profiles of genes with established relations to the SARS-CoV-2 neuroinvasion process were spatially resolved in dorsolateral prefrontal cortex tissue (N = 4). Spotplots were generated with mapping to six (6) previously defined gray matter layers. Results: Docking gene BSG, processing gene CTSB, and viral defense gene LY6E demonstrated similar spatial enrichment. Docking gene ACE2 and transmembrane series proteases involved in spike protein processing were lowly expressed across DLPFC samples. Numerous other findings were obtained. Conclusion: Efforts to spatially represent expression levels of key SARS-CoV-2 brain infiltration genes remain paltry to date. Understanding the sobering history of beta coronavirus neuroinvasion represents a weak point in viral research. Here we provide the first efforts to characterize a motley of such genes in the dorsolateral prefrontal cortex. Full article

COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global pandemic that might lead to very serious consequences. Notably, mental status change, brain confusion, and smell and taste disorders along with neurological complaints have been reported in patients infected with SARS-CoV-2. Furthermore, human brain tissue autopsies from COVID-19 patients show the presence of SARS-CoV-2 neuroinvasion, which correlates with the manifestation of meningitis, encephalitis, leukocyte infiltration, and neuronal damage. The olfactory mucosa has been suggested as a way of entry into the brain. SARS-CoV-2 infection is also known to provoke a hyper-inflammatory reaction with an exponential increase in the production of pro-inflammatory cytokines leading to systemic responses, even in the absence of direct infection of brain cells. Angiotensin-converting enzyme 2 (ACE2), the entry receptor of SARS-CoV-2, has been extensively demonstrated to be present in the periphery, neurons, and glial cells in different brain regions. To dissect the details of neurological complications and develop therapies helping COVID-19 survivors regain pre-infection quality of life, the development of robust clinical models is highly warranted. Several human angiotensin-converting enzyme 2 (hACE2) transgenic mouse models have been developed and used for antiviral drug screening and vaccine development, as well as for better understanding of the molecular pathogenetic mechanisms of SARS-CoV-2 infection. In this review, we summarize recent results from the studies involving two such mouse models, namely K18- and CAG-hACE2 transgenics, to evaluate the direct and indirect impact of SARS-CoV-2 infection on the central nervous system. Full article

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), may lead to acute and chronic neurological symptoms (NeuroCOVID-19). SARS-CoV-2 may spread from the respiratory tract to the central nervous system as the central nervous system (CNS) of certain patients dying from COVID-19 shows virus-related neuropathological changes. Moreover, a syndrome found in many patients having passed a SARS-CoV-2 infection, which is termed long COVID and characterized by lasting fatigue and other diverse clinical features, may well have some of its pathological correlates inside the CNS. Although knowledge on the routes of SARS-CoV-2 neuroinvasion and the pathophysiology of NeuroCOVID have increased, the molecular mechanisms are not yet fully understood. This includes the key question: to understand if observed CNS damage is a direct cause of viral damage or indirectly mediated by an overshooting neuroimmune response. Full article

Transgenic mice expressing human angiotensin-converting enzyme 2 under the cytokeratin 18 promoter (K18-hACE2) have been extensively used to investigate the pathogenesis and tissue tropism of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Neuroinvasion and the replication of SARS-CoV-2 within the central nervous system (CNS) of K18-hACE2 mice is associated with increased mortality; although, the mechanisms by which this occurs remain unclear. In this study, we generated primary neuronal cultures from K18-hACE2 mice to investigate the effects of a SARS-CoV-2 infection. We also evaluated the immunological response to SARS-CoV-2 infection in the CNS of K18-hACE2 mice and mouse neuronal cultures. Our data show that neuronal cultures obtained from K18-hACE2 mice are permissive to SARS-CoV-2 infection and support productive virus replication. Furthermore, SARS-CoV-2 infection upregulated the expression of genes involved in innate immunity and inflammation, including IFN-α, ISG-15, CXCL10, CCL2, IL-6 and TNF-α, in the neurons and mouse brains. In addition, we found that SARS-CoV-2 infection of neurons and mouse brains activates the ZBP1/pMLKL-regulated necroptosis pathway. Together, our data provide insights into the neuropathogenesis of SARS-CoV-2 infection in K18-hACE2 mice. Full article

Since the outbreak of the global pandemic caused by severe acute respiratory coronavirus 2 (SARS-CoV-2), several clinical aspects of the disease have come into attention. Besides its primary route of infection through the respiratory system, SARS-CoV-2 is known to have neuroinvasive capacity, causing multiple neurological symptoms with increased neuroinflammation and blood–brain barrier (BBB) damage. The viral spike protein disseminates via circulation during infection, and when reaching the brain could possibly cross the BBB, which was demonstrated in mice. Therefore, its medical relevance is of high importance. The aim of this study was to evaluate the barrier penetration of the S1 subunit of spike protein in model systems of human organs highly exposed to the infection. For this purpose, in vitro human BBB and intestinal barrier cell–culture systems were investigated by an optical biosensing method. We found that spike protein crossed the human brain endothelial cell barrier effectively. Additionally, spike protein passage was found in a lower amount for the intestinal barrier cell layer. These observations were corroborated with parallel specific ELISAs. The findings on the BBB model could provide a further basis for studies focusing on the mechanism and consequences of spike protein penetration across the BBB to the brain. Full article

Coronavirus 2019 (COVID-19) is an infectious respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that mainly affects the lungs. COVID-19 symptoms include the presence of fevers, dry coughs, fatigue, sore throat, headaches, diarrhea, and a loss of taste or smell. However, it is understood that SARS-CoV-2 is neurotoxic and neuro-invasive and could enter the central nervous system (CNS) via the hematogenous route or via the peripheral nerve route and causes encephalitis, encephalopathy, and acute disseminated encephalomyelitis (ADEM) in COVID-19 patients. This review discusses the possibility of SARS-CoV-2-mediated Multiple Sclerosis (MS) development in the future, comparable to the surge in Parkinson’s disease cases following the Spanish Flu in 1918. Moreover, the SARS-CoV-2 infection is associated with a cytokine storm. This review highlights the impact of these modulated cytokines on glial cell interactions within the CNS and their role in potentially prompting MS development as a secondary disease by SARS-CoV-2. SARS-CoV-2 is neurotropic and could interfere with various functions of neurons leading to MS development. The influence of neuroinflammation, microglia phagocytotic capabilities, as well as hypoxia-mediated mitochondrial dysfunction and neurodegeneration, are mechanisms that may ultimately trigger MS development. Full article

The dysfunctional effects of the coronavirus disease 2019 (COVID-19) infection on the nervous system are established. The manifestation of neuropsychiatric symptoms during and after infection is influenced by the neuroinvasive and neurotrophic properties of SARS-CoV-2 as well as strong inflammation characterised by a specific “cytokine storm”. Research suggests that a strong immune response to a SARS-CoV-2 infection and psychological stressors related to the pandemic may cause chronic inflammatory processes in the body with elevated levels of inflammatory markers contributing to the intensification of neurodegenerative processes. It is suggested that neuroinflammation and associated central nervous system changes may significantly contribute to the etiopathogenesis of depressive disorders. In addition, symptoms after a COVID-19 infection may persist for up to several weeks after an acute infection as a post-COVID-19 syndrome. Moreover, previous knowledge indicates that among SSRI (selective serotonin reuptake inhibitor) group antidepressants, fluoxetine is a promising drug against COVID-19. In conclusion, further research, observation and broadening of the knowledge of the pathomechanism of a SARS-CoV-2 infection and the impact on potential complications are necessary. It is essential to continue research in order to assess the long-term neuropsychiatric effects in COVID-19 patients and to find new therapeutic strategies. Full article

The coronavirus disease of 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome 2 (SARS-CoV-2). In addition to pneumonia, individuals affected by the disease have neurological symptoms. Indeed, SARS-CoV-2 has a neuroinvasive capacity. It is known that the infection caused by SARS-CoV-2 leads to a cytokine storm. An exacerbated inflammatory state can lead to the blood–brain barrier (BBB) damage as well as to intestinal dysbiosis. These changes, in turn, are associated with microglial activation and reactivity of astrocytes that can promote the degeneration of neurons and be associated with the development of psychiatric disorders and neurodegenerative diseases. Studies also have been shown that SARS-CoV-2 alters the composition and functional activity of the gut microbiota. The microbiota-gut-brain axis provides a bidirectional homeostatic communication pathway. Thus, this review focuses on studies that show the relationship between inflammation and the gut microbiota–brain axis in SARS-CoV-2 infection. Full article