Data analysis evidence beyond correlation of a possible causal impact of weather on the COVID-19 spread, mediated by human mobility.

Previous correlative and modeling approaches indicate influences of environmental factors on COVID-19 spread through atmospheric conditions' impact on virus survival and transmission or host susceptibility. However, causal connections from environmental factors to the pandemic, mediated by human mobility, received less attention. We use the technique of Convergent Cross Mapping to identify the causal connections, beyond correlation at the country level, between pairs of variables associated with weather conditions, human mobility, and the number of COVID-19 cases for 32 European states. Here, we present data-based evidence that the relatively reduced number of cases registered in Northern Europe is related to the causal impact of precipitation on people's decision to spend more time at home and that the relatively large number of cases observed in Southern Europe is linked to people's choice to spend time outdoors during warm days. We also emphasize the channels of the significant impact of the pandemic on human mobility. The weather-human mobility connections inferred here are relevant not only for COVID-19 spread but also for any other virus transmitted through human interactions. These results may help authorities and public health experts contain possible future waves of the COVID-19 pandemic or limit the threats of similar human-to-human transmitted viruses.

Molecular mimicry in multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C) is a severe, post-infectious sequela of SARS-CoV-2 infection1,2, yet the pathophysiological mechanism connecting the infection to the broad inflammatory syndrome remains unknown. Here we leveraged a large set of samples from patients with MIS-C to identify a distinct set of host proteins targeted by patient autoantibodies including a particular autoreactive epitope within SNX8, a protein involved in regulating an antiviral pathway associated with MIS-C pathogenesis. In parallel, we also probed antibody responses from patients with MIS-C to the complete SARS-CoV-2 proteome and found enriched reactivity against a distinct domain of the SARS-CoV-2 nucleocapsid protein. The immunogenic regions of the viral nucleocapsid and host SNX8 proteins bear remarkable sequence similarity. Consequently, we found that many children with anti-SNX8 autoantibodies also have cross-reactive T cells engaging both the SNX8 and the SARS-CoV-2 nucleocapsid protein epitopes. Together, these findings suggest that patients with MIS-C develop a characteristic immune response to the SARS-CoV-2 nucleocapsid protein that is associated with cross-reactivity to the self-protein SNX8, demonstrating a mechanistic link between the infection and the inflammatory syndrome, with implications for better understanding a range of post-infectious autoinflammatory diseases.

SARS-CoV-2 Rapidly Infects Peripheral Sensory and Autonomic Neurons, Contributing to Central Nervous System Neuroinvasion before Viremia.

Neurological symptoms associated with COVID-19, acute and long term, suggest SARS-CoV-2 affects both the peripheral and central nervous systems (PNS/CNS). Although studies have shown olfactory and hematogenous invasion into the CNS, coinciding with neuroinflammation, little attention has been paid to susceptibility of the PNS to infection or to its contribution to CNS invasion. Here we show that sensory and autonomic neurons in the PNS are susceptible to productive infection with SARS-CoV-2 and outline physiological and molecular mechanisms mediating neuroinvasion. Our infection of K18-hACE2 mice, wild-type mice, and golden Syrian hamsters, as well as primary peripheral sensory and autonomic neuronal cultures, show viral RNA, proteins, and infectious virus in PNS neurons, satellite glial cells, and functionally connected CNS tissues. Additionally, we demonstrate, in vitro, that neuropilin-1 facilitates SARS-CoV-2 neuronal entry. SARS-CoV-2 rapidly invades the PNS prior to viremia, establishes a productive infection in peripheral neurons, and results in sensory symptoms often reported by COVID-19 patients.

Adenosine A2AR in viral immune evasion and therapy: unveiling new avenues for treating COVID-19 and AIDS.

Adenosine is a neuro- and immunomodulator that functions via G protein-coupled cell surface receptors. Several microbes, including viruses, use the adenosine signaling pathway to escape from host defense systems. Since the recent research developments in its role in health and disease, adenosine and its signaling pathway have attracted attention for targeting to treat many diseases. The therapeutic role of adenosine has been extensively studied for neurological, cardiovascular, and inflammatory disorders and bacterial pathophysiology, but published data on the role of adenosine in viral infections are lacking. Therefore, the purpose of this review article was to explain in detail the therapeutic role of adenosine signaling against viral infections, particularly COVID-19 and HIV. Several therapeutic approaches targeting A2AR-mediated pathways are in development and have shown encouraging results in decreasing the intensity of inflammatory reaction. The hypoxia-adenosinergic mechanism provides protection from inflammation-mediated tissue injury during COVID-19. A2AR expression increased remarkably in CD39 + and CD8 + T cells harvested from HIV patients in comparison to healthy subjects. A combined in vitro treatment performed by blocking PD-1 and CD39/adenosine signaling produced a synergistic outcome in restoring the CD8 + T cells funstion in HIV patients. We suggest that A2AR is an ideal target for pharmacological interventions against viral infections because it reduces inflammation, prevents disease progression, and ultimately improves patient survival.

Epitranscriptomic m5C methylation of SARS-CoV-2 RNA regulates viral replication and the virulence of progeny viruses in the new infection.

While the significance of N6-methyladenosine (m6A) in viral regulation has been extensively studied, the functions of 5-methylcytosine (m5C) modification in viral biology remain largely unexplored. In this study, we demonstrate that m5C is more abundant than m6A in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and provide a comprehensive profile of the m5C landscape of SARS-CoV-2 RNA. Knockout of NSUN2 reduces m5C levels in SARS-CoV-2 virion RNA and enhances viral replication. Nsun2 deficiency mice exhibited higher viral burden and more severe lung tissue damages. Combined RNA-Bis-seq and m5C-MeRIP-seq identified the NSUN2-dependent m5C-methylated cytosines across the positive-sense genomic RNA of SARS-CoV-2, and the mutations of these cytosines enhance RNA stability. The progeny SARS-CoV-2 virions from Nsun2 deficiency mice with low levels of m5C modification exhibited a stronger replication ability. Overall, our findings uncover the vital role played by NSUN2-mediated m5C modification during SARS-CoV-2 replication and propose a host antiviral strategy via epitranscriptomic addition of m5C methylation to SARS-CoV-2 RNA.

Introduction.

The coronavirus disease 2019 (COVID-19) pandemic emerged just months after the publication of the first ever textbook devoted to cytokine storm syndromes (CSSs). The severe disease caused by COVID-19 and the intersection between immune responses and their pathologies played out before the world in media reports, in scientific publications, and through the personal narratives of millions of people's experiences. An entirely new immune-mediated disease, multisystem inflammatory disease in children (MISC), was described. Cytokines played a role in all of these areas, bringing the idea of a cytokine storm squarely to the front and center of the public eye. At the same time, science continued to progress in the lab and in the clinic, thus illuminating our understanding of CSSs both old and new since the publication of the first edition of this book. It was clear that a new edition was needed to keep up with these changes.

COVID-19-Related Multi-systemic Inflammatory Syndrome in Children (MIS-C).

Multisystem inflammatory syndrome in children (MIS-C) is a severe complication of SARS-CoV-2 infections in children. This syndrome manifests about a month after the initial viral infection and is characterized by fever, multiorgan dysfunction, and systemic inflammation. This chapter will review the emergence, epidemiology, clinical characteristics, diagnosis, pathophysiology, immunomodulatory treatment, prognosis, outcomes, and prevention of MIS-C. While the pathophysiology of MIS-C remains to be defined, it is a post-infection, hyperinflammatory syndrome of childhood with elevated inflammatory cytokines.

Long COVID-19 and Suicide.

Suicide is a significant public health problem around the world. More than 90% of individuals who die by suicide have a diagnosable psychiatric disorder, and most persons who attempt suicide also have a psychiatric illness. Depression, anxiety, posttraumatic symptoms, sleep disturbances, decreased energy, and cognitive abnormalities are the most frequently reported psychiatric symptoms of long COVID. All these conditions are associated with suicidal ideation and behavior. Therefore, individuals with long COVID may be at increased risk of suicide. Recent studies of patients with long COVID confirm that individuals with long COVID are at increased suicide risk. It is vital to educate clinicians taking care of long COVID individuals that patients with long COVID may be suicidal, that it is essential to screen patients with long COVID for suicidality, and if needed, suicide prevention interventions should be employed.

COVID-19 Pandemic: From Population Need to Professional Nursing Competence.

Nursing has proven to be an essential healthcare profession, especially in the face of the COVID-19 pandemic crisis. In this chapter, it shows the essential aspects of the discipline of care and its application in the face of the pandemic from an Informatics Nursing approach. The conceptual bases include the conception of care and its historical evolution. Thus, the Personal Care Knowledge Model, the clinical care sequence and its standardized languages allow Taxonomic Triangulation to be developed. Taxonomic Triangulation is a technique created by nurses that allows managing information and that served to extract knowledge from documents and clinical experiences. The application of this vision of care and its knowledge management models have been tested in different situations: from the identification of care diagnoses in a World Health Organization clinical guide to the design of a care plan manual in a hospital. On the other hand, a secondary result is the resilience shown by the nurses. A resilience based on theoretical models centered on the person and on a language that can represent life from care. In addition, nursing includes a comprehensive perspective that addresses the emotional and spiritual area. In conclusion, nurses and their specialization with skills in knowledge management allow giving visibility to care. A professional care whose purpose is to improve health systems through solutions based on care so that people can achieve their best health situation.

Climate Changes and COVID-19.

Climatic change, which influences population growth and land usage, has been theorized to be linked to the emergence and spread of new viruses like the currently unfolding COVID-19 pandemic. In this chapter, we explain how climate change may have altered the beginning, transmission, and maybe even the sickness consequences of the COVID-19 pandemic. Where possible, we also provide mechanistic explanations for how this may have occurred. We have presented evidence that suggests climate change may have had a role in the establishment and transmission of SARS-CoV-2 infection, and most possibly even in some of its clinical effects. Human activities bringing people into closer contact with bats and animals like pangolins that potentially represent the intermediate hosts, and evidence that climate-induced changes in vegetation are the main reservoir source of coronaviruses for human infection, are among the explanations. Although there are still unsubstantiated indications that the first viral pathogen may have escaped from a laboratory, it is possible that this encounter took place in the field or in marketplaces in the instance of COVID-19. We also present the argument that climate change is working to enhance transmission between diseased and uninfected humans, and this is true regardless of the source of the original development of the disease. Changes in temperature and humidity make it easier for viruses to survive, and the impacts of industrial pollution induce people to cough and sneeze, which releases highly infectious aerosols into the air. These three factors combine to make this a more likely scenario than it would otherwise be. We suggest that changes in climate are contributing to create conditions that are favorable for the development of more severe symptoms of illness. It is more difficult to build the argument for this circumstance, and much of it is indirect. However, climate change has caused some communities to adjust their nutritional habits, both in terms of the quantity of food they eat and the quality of the foods they consume. The effects frequently become apparent as a result of alterations that are imposed on the microbiome of the gut, which, in turn, influence the types of immune responses that are produced. The incidence of comorbidities like diabetes and animal vectors like bats that transmit other illnesses that modify vulnerability to SARS-CoV-2 are also two examples of the factors that have been affected by climate change. In order to curb the development of infectious illnesses caused by new viruses, it is necessary to understand the connection between environmental dynamics and the emergence of new coronaviruses. This knowledge should lead to initiatives aimed at reducing global greenhouse gas emissions.

Histopathological impact of SARS-CoV-2 on the liver: Cellular damage and long-term complications.

Coronavirus disease 2019 (COVID-19), caused by the highly pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), primarily impacts the respiratory tract and can lead to severe outcomes such as acute respiratory distress syndrome, multiple organ failure, and death. Despite extensive studies on the pathogenicity of SARS-CoV-2, its impact on the hepatobiliary system remains unclear. While liver injury is commonly indicated by reduced albumin and elevated bilirubin and transaminase levels, the exact source of this damage is not fully understood. Proposed mechanisms for injury include direct cytotoxicity, collateral damage from inflammation, drug-induced liver injury, and ischemia/hypoxia. However, evidence often relies on blood tests with liver enzyme abnormalities. In this comprehensive review, we focused solely on the different histopathological manifestations of liver injury in COVID-19 patients, drawing from liver biopsies, complete autopsies, and in vitro liver analyses. We present evidence of the direct impact of SARS-CoV-2 on the liver, substantiated by in vitro observations of viral entry mechanisms and the actual presence of viral particles in liver samples resulting in a variety of cellular changes, including mitochondrial swelling, endoplasmic reticulum dilatation, and hepatocyte apoptosis. Additionally, we describe the diverse liver pathology observed during COVID-19 infection, encompassing necrosis, steatosis, cholestasis, and lobular inflammation. We also discuss the emergence of long-term complications, notably COVID-19-related secondary sclerosing cholangitis. Recognizing the histopathological liver changes occurring during COVID-19 infection is pivotal for improving patient recovery and guiding decision-making.

Severe acute respiratory syndrome coronavirus 2 pathology and cell tropism in tongue tissues of COVID-19 autopsies.

Since 2019, Coronavirus Disease 2019(COVID-19) has affected millions of people worldwide. Except for acute respiratory distress syndrome, dysgeusis is also a common symptom of COVID-19 that burdens patients for weeks or permanently. However, the mechanisms underlying taste dysfunctions remain unclear. Here, we performed complete autopsies of five patients who died of COVID-19. Integrated tongue samples, including numerous taste buds, salivary glands, vessels, and nerves were collected to map the pathology, distribution, cell tropism, and receptor distribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the tongue. Our results revealed that all patients had moderate lymphocyte infiltration around the salivary glands and in the lamina propria adjacent to the mucosa, and pyknosis in the epithelia of taste buds and salivary glands. This may be because the serous acini, salivary gland ducts, and taste buds are the primary sites of SARS-CoV-2 infection. Multicolor immunofluorescence showed that SARS-CoV-2 readily infects Keratin (KRT)7+ taste receptor cells in taste buds, secretory cells in serous acini, and inner epithelial cells in the ducts. The major receptors, angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine subtype 2 (TMPRSS2), were both abundantly expressed in these cells. Viral antigens and receptor were both rarely detected in vessels and nerves. This indicates that SARS-CoV-2 infection triggers pathological injury in the tongue, and that dysgeusis may be directly related to viral infection and cellular damage.

Remote work transition amidst COVID-19: Impacts on presenteeism, absenteeism, and worker well-being-A scoping review.

BACKGROUND: The COVID-19 pandemic has accelerated the transition to remote work, leading to increased attention on presenteeism and absenteeism among remote workers. Understanding the implications of these phenomena on worker health and productivity is crucial for optimizing remote work arrangements and developing policies to improve employee well-being. OBJECTIVES: This scoping review aims to examine the occurrence of presenteeism and absenteeism among remote workers during the COVID-19 pandemic and the interrelated physical and mental health issues during these periods. METHODS: PsycINFO, Medline, Embase, CINAHL, Eric, Business Source Premier, SCOPUS, and sociological abstracts were searched resulting in 1792 articles. Articles were included if the population of interest was 18+ (i.e., working age), engaged in full or part-time work, and the employees shifted from in-person to remote work due to the COVID-19 pandemic. All study designs, geographical areas, and papers written post-onset of the COVID-19 pandemic were included; however, systematic reviews were excluded. Data was charted into Microsoft Excel by 2 independent reviewers. RESULTS: The literature search identified 10 studies (i.e., seven cross-sectional studies, two qualitative studies, and one observational study). Five major overarching themes were identified specifically (1) telework and mental health (2) telework and physical health (3) worker benefits (4) gender dynamics and (5) difficulty navigating the teleworking environment. While remote work offers flexibility in terms of saved commute time and flexible work schedules, it also exacerbates challenges related to presenteeism, absenteeism, and work-life balance. These challenges include experiencing psychological distress, depression, anxiety, stress, sleep deprivation, musculoskeletal pain, difficulties concentrating at work for both women and working parents, struggles disconnecting after hours, and the inability to delineate between the work and home environment. DISCUSSION: The findings suggest that remote work during the COVID-19 pandemic has both positive and negative implications for worker well-being and productivity. However, future research needs to incorporate the potential effects of telework frequency (full time vs. part time) on employee productivity and its role on presenteeism and absenteeism, to gain a more comprehensive understanding on remote work difficulties. Addressing these challenges requires proactive interventions and support mechanisms to promote worker health and productivity in remote settings.

COVID-19's psychological toll on oral health: A cross-sectional study in Iranian adults.

BACKGROUND: The Coronavirus disease 2019 pandemic increased global psychological distress, emotional distress, and sleep disturbances, all known risk factors for compromised oral health. Despite this, there is limited understanding of the impacts of these psychological factors on oral health in certain populations, including Iranians. Thus, the present study investigates the associations between sociodemographic characteristics, emotional distress, sleep pattern changes, tooth brushing frequency, and oral ulcer reports in a sample of Iranian adults during the Coronavirus disease 2019 pandemic. MATERIALS AND METHODS: This cross-sectional, web-based study collected data from Iranian adults between July and September 2022 using respondent-driven sampling. The Mental Health and Wellness questionnaire was used to gather information on sociodemographic characteristics, emotional distress, sleep pattern changes, toothbrushing frequency, and oral ulcer reports. Simple and multiple logistic regression served for statistical analysis. RESULTS: Among the 240 participants, comprising 164 females and 76 males, with a mean age of 35.3 years (±13.3), 28 individuals (11.7%) reported reduced tooth brushing frequency, and 35 individuals (14.6%) reported oral ulcers. Male gender (OR = 2.75, p = 0.016) and sleep patterns changes (OR = 2.93, p = 0.01) increased the likelihood of reduced tooth brushing frequency. Additionally, being younger than 30 (OR = 2.87, p = 0.025) and fearing coronavirus transmission (OR = 3.42, p = 0.009) increased the odds of oral ulcers. CONCLUSIONS: Male gender and sleep pattern changes were risk factors for reduced tooth brushing frequency among the present sample of Iranian adults during the Coronavirus disease 2019 pandemic. Additionally, being under 30 and fearing coronavirus transmission were identified as risk factors for oral ulcers in this population. To preserve and promote adults' oral health during public health crises, targeted educational initiatives, public health awareness campaigns, and integrated mental and oral healthcare approaches are encouraged.

Studying the impacts of variant evolution for a generalized age-group transmission model.

The differences of SARS-CoV-2 variants brought the changes of transmission characteristics and clinical manifestations during the prevalence of COVID-19. In order to explore the evolution mechanisms of SARS-CoV-2 variants and the impacts of variant evolution, the classic SIR (Susceptible-Infected-Recovered) compartment model was modified to a generalized SVEIR (Susceptible-Vaccinated-Exposed-Infected-Recovered) compartment model with age-group and varying variants in this study. By using of the SVEIR model and least squares method, the optimal fittings against the surveillance data from Fujian Provincial Center for Disease Control and Prevention were performed for the five epidemics of Fujian Province. The main epidemiological characteristics such as basic reproduction number, effective reproduction number, sensitivity analysis, and cross-variant scenario investigations were extensively investigated during dynamic zero-COVID policy. The study results showed that the infectivities of the variants became fast from wild strain to the Delta variant, further to the Omicron variant. Meanwhile, the cross-variant investigations showed that the average incubation periods were shortened, and that the infection scales quickly enhanced. Further, the risk estimations with the new variants were performed without implements of the non-pharmaceutical interventions, based on the dominant variants XBB.1.9.1 and EG.5. The results of the risk estimations suggested that non-pharmaceutical interventions were necessary on the Chinese mainland for controlling severe infections and deaths, and also that the regular variant monitors were still workable against the aggressive variant evolution and the emergency of new transmission risks in the future.

Attenuated replication and damaging effects of SARS-CoV-2 Omicron variants in an intestinal epithelial barrier model.

Many COVID-19 patients suffer from gastrointestinal symptoms and impaired intestinal barrier function is thought to play a key role in Long COVID. Despite its importance, the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on intestinal epithelia is poorly understood. To address this, we established an intestinal barrier model integrating epithelial Caco-2 cells, mucus-secreting HT29 cells and Raji cells. This gut epithelial model allows efficient differentiation of Caco-2 cells into microfold-like cells, faithfully mimics intestinal barrier function, and is highly permissive to SARS-CoV-2 infection. Early strains of SARS-CoV-2 and the Delta variant replicated with high efficiency, severely disrupted barrier function, and depleted tight junction proteins, such as claudin-1, occludin, and ZO-1. In comparison, Omicron subvariants also depleted ZO-1 from tight junctions but had fewer damaging effects on mucosal integrity and barrier function. Remdesivir, the fusion inhibitor EK1 and the transmembrane serine protease 2 inhibitor Camostat inhibited SARS-CoV-2 replication and thus epithelial barrier damage, while the Cathepsin inhibitor E64d was ineffective. Our results support that SARS-CoV-2 disrupts intestinal barrier function but further suggest that circulating Omicron variants are less damaging than earlier viral strains.

SARS-CoV-2 envelope protein-derived extracellular vesicles act as potential media for viral spillover.

Extracellular vesicles (EVs) are shown to be a novel viral transmission model capable of increasing a virus's tropism. According to our earlier research, cells infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or transfected with envelope protein plasmids generate a novel type of EVs that are micrometer-sized and able to encase virus particles. Here, we showed the capacity of these EVs to invade various animals both in vitro and in vivo independent of the angiotensin-converting enzyme 2 receptor. First, via macropinocytosis, intact EVs produced from Vero E6 (monkey) cells were able to enter cells from a variety of animals, including cats, dogs, bats, hamsters, and minks, and vice versa. Second, when given to zebrafish with cutaneous wounds, the EVs showed favorable stability in aqueous environments and entered the fish. Moreover, infection of wild-type (WT) mice with heterogeneous EVs carrying SARS-CoV-2 particles led to a strong cytokine response and a notable amount of lung damage. Conversely, free viral particles did not infect WT mice. These results highlight the variety of processes behind viral transmission and cross-species evolution by indicating that EVs may be possible vehicles for SARS-CoV-2 spillover and raising risk concerns over EVs' potential for viral gene transfer.

A Comparative Experimental and Computational Study on the Nature of the Pangolin-CoV and COVID-19 Omicron.

The relationship between pangolin-CoV and SARS-CoV-2 has been a subject of debate. Further evidence of a special relationship between the two viruses can be found by the fact that all known COVID-19 viruses have an abnormally hard outer shell (low M disorder, i.e., low content of intrinsically disordered residues in the membrane (M) protein) that so far has been found in CoVs associated with burrowing animals, such as rabbits and pangolins, in which transmission involves virus remaining in buried feces for a long time. While a hard outer shell is necessary for viral survival, a harder inner shell could also help. For this reason, the N disorder range of pangolin-CoVs, not bat-CoVs, more closely matches that of SARS-CoV-2, especially when Omicron is included. The low N disorder (i.e., low content of intrinsically disordered residues in the nucleocapsid (N) protein), first observed in pangolin-CoV-2017 and later in Omicron, is associated with attenuation according to the Shell-Disorder Model. Our experimental study revealed that pangolin-CoV-2017 and SARS-CoV-2 Omicron (XBB.1.16 subvariant) show similar attenuations with respect to viral growth and plaque formation. Subtle differences have been observed that are consistent with disorder-centric computational analysis.

Neuropathogenesis of SARS-CoV-2 in human neuronal, microglial and glial cells.

Neurological complications, both acute and chronic, are reported commonly in COVID-19 affected individuals. In this context, the understanding of pathogenesis of SARS-CoV-2 in specific cells of central nervous system (CNS) origin is relevant. The present study explores infection biology of a clinical isolate of SARS-CoV-2 in human cell lines of neural origin such as the glioblastoma (U87-MG), neuroblastoma (SHSY5Y) and microglia (C20). Despite showing clear evidence of infection by immunofluorescence with an anti-spike protein antibody, all the three neural cell lines were observed to be highly restrictive to the replication of the infecting virus. While the U87-MG glioblastoma cells demonstrated no cytopathic effects and a low viral titre with no signs of replication, the SHSY5Y neuroblastoma cells exhibited cytopathic effects with bleb formation but no evidence of viable virus. The C20 microglial cells showed neither signs of cytopathic effects nor viable virus. Ultrastructural studies demonstrated intracellular virions in infected neural cells. The presence of lipid droplets in infected SHSY5Y cells suggested an impact on host cell metabolism. The decrease in viral RNA levels over time in all the neural cell lines suggested restricted viral replication. In conclusion, this study highlights the limited susceptibility of neural cells to SARS-CoV-2 infection. This reduced permissibility of neural cell lines to SARS-CoV-2 may point to their inherent lower expression of receptors that support viral entry in addition to the intracellular factors that potently inhibit viral replication. The study findings prompt further investigation into the mechanisms of SARS-CoV-2 infection of neural cells.

SARS-CoV-2 Nucleocapsid Protein Induces Tau Pathological Changes That Can Be Counteracted by SUMO2.

Neurologic manifestations are an immediate consequence of SARS-CoV-2 infection, the etiologic agent of COVID-19, which, however, may also trigger long-term neurological effects. Notably, COVID-19 patients with neurological symptoms show elevated levels of biomarkers associated with brain injury, including Tau proteins linked to Alzheimer's pathology. Studies in brain organoids revealed that SARS-CoV-2 alters the phosphorylation and distribution of Tau in infected neurons, but the mechanisms are currently unknown. We hypothesize that these pathological changes are due to the recruitment of Tau into stress granules (SGs) operated by the nucleocapsid protein (NCAP) of SARS-CoV-2. To test this hypothesis, we investigated whether NCAP interacts with Tau and localizes to SGs in hippocampal neurons in vitro and in vivo. Mechanistically, we tested whether SUMOylation, a posttranslational modification of NCAP and Tau, modulates their distribution in SGs and their pathological interaction. We found that NCAP and Tau colocalize and physically interact. We also found that NCAP induces hyperphosphorylation of Tau and causes cognitive impairment in mice infected with NCAP in their hippocampus. Finally, we found that SUMOylation modulates NCAP SG formation in vitro and cognitive performance in infected mice. Our data demonstrate that NCAP induces Tau pathological changes both in vitro and in vivo. Moreover, we demonstrate that SUMO2 ameliorates NCAP-induced Tau pathology, highlighting the importance of the SUMOylation pathway as a target of intervention against neurotoxic insults, such as Tau oligomers and viral infection.