COVID-19 vaccination may enhance hippocampal neurogenesis in adults.

Emerging evidence suggests a detrimental impact of COVID-19 illness on the continued hippocampal neurogenesis in adults. In contrast, the existing literature supports an enhancing effect of COVID-19 vaccination on adult hippocampal neurogenesis. Vaccines against respiratory infections, including influenza, have been shown to enhance hippocampal neurogenesis in adult-age animals. We propose that a similar benefit may happen in COVID-19 vaccinated adults. The vaccine-induced enhancement of the hippocampal neurogenesis in adults thus may protect against age-related cognitive decline and mental disorders. It alsohints at an added mental health benefit of the COVID-19 vaccination programs in adults.

SARS-CoV-2 Omicron Variant Genomic Sequences and Their Epidemiological Correlates Regarding the End of the Pandemic: In Silico Analysis.

Background: Emergence of the new SARS-CoV-2 variant B.1.1.529 worried health policy makers worldwide due to a large number of mutations in its genomic sequence, especially in the spike protein region. The World Health Organization (WHO) designated this variant as a global variant of concern (VOC), which was named "Omicron." Following Omicron's emergence, a surge of new COVID-19 cases was reported globally, primarily in South Africa. Objective: The aim of this study was to understand whether Omicron had an epidemiological advantage over existing variants. Methods: We performed an in silico analysis of the complete genomic sequences of Omicron available on the Global Initiative on Sharing Avian Influenza Data (GISAID) database to analyze the functional impact of the mutations present in this variant on virus-host interactions in terms of viral transmissibility, virulence/lethality, and immune escape. In addition, we performed a correlation analysis of the relative proportion of the genomic sequences of specific SARS-CoV-2 variants (in the period from October 1 to November 29, 2021) with matched epidemiological data (new COVID-19 cases and deaths) from South Africa. Results: Compared with the current list of global VOCs/variants of interest (VOIs), as per the WHO, Omicron bears more sequence variation, specifically in the spike protein and host receptor-binding motif (RBM). Omicron showed the closest nucleotide and protein sequence homology with the Alpha variant for the complete sequence and the RBM. The mutations were found to be primarily condensed in the spike region (n=28-48) of the virus. Further mutational analysis showed enrichment for the mutations decreasing binding affinity to angiotensin-converting enzyme 2 receptor and receptor-binding domain protein expression, and for increasing the propensity of immune escape. An inverse correlation of Omicron with the Delta variant was noted (r=-0.99, P<.001; 95% CI -0.99 to -0.97) in the sequences reported from South Africa postemergence of the new variant, subsequently showing a decrease. There was a steep rise in new COVID-19 cases in parallel with the increase in the proportion of Omicron isolates since the report of the first case (74%-100%). By contrast, the incidence of new deaths did not increase (r=-0.04, P>.05; 95% CI -0.52 to 0.58). Conclusions: In silico analysis of viral genomic sequences suggests that the Omicron variant has more remarkable immune-escape ability than existing VOCs/VOIs, including Delta, but reduced virulence/lethality than other reported variants. The higher power for immune escape for Omicron was a likely reason for the resurgence in COVID-19 cases and its rapid rise as the globally dominant strain. Being more infectious but less lethal than the existing variants, Omicron could have plausibly led to widespread unnoticed new, repeated, and vaccine breakthrough infections, raising the population-level immunity barrier against the emergence of new lethal variants. The Omicron variant could have thus paved the way for the end of the pandemic.

COVID-19 vaccination may enhance hippocampal neurogenesis in adults

Graphical Emerging evidence suggests a detrimental impact of COVID-19 illness on the continued hippocampal neurogenesis in adults. In contrast, the existing literature supports an enhancing effect of COVID-19 vaccination on adult hippocampal neurogenesis. Vaccines against respiratory infections, including influenza, have been shown to enhance hippocampal neurogenesis in adult-age animals. We propose that a similar benefit may happen in COVID-19 vaccinated adults. The vaccine-induced enhancement of the hippocampal neurogenesis in adults thus may protect against age-related cognitive decline and mental disorders. It also hints at an added mental health benefit of the COVID-19 vaccination programs in adults.

A Bioinformatics Tool for Predicting Future COVID-19 Waves Based on a Retrospective Analysis of the Second Wave in India: Model Development Study

Background Since the start of the COVID-19 pandemic, health policymakers globally have been attempting to predict an impending wave of COVID-19. India experienced a devastating second wave of COVID-19 in the late first week of May 2021. We retrospectively analyzed the viral genomic sequences and epidemiological data reflecting the emergence and spread of the second wave of COVID-19 in India to construct a prediction model. Objective We aimed to develop a bioinformatics tool that can predict an impending COVID-19 wave. Methods We analyzed the time series distribution of genomic sequence data for SARS-CoV-2 and correlated it with epidemiological data for new cases and deaths for the corresponding period of the second wave. In addition, we analyzed the phylodynamics of circulating SARS-CoV-2 variants in the Indian population during the study period. Results Our prediction analysis showed that the first signs of the arrival of the second wave could be seen by the end of January 2021, about 2 months before its peak in May 2021. By the end of March 2021, it was distinct. B.1.617 lineage variants powered the wave, most notably B.1.617.2 (Delta variant). Conclusions Based on the observations of this study, we propose that genomic surveillance of SARS-CoV-2 variants, complemented with epidemiological data, can be a promising tool to predict impending COVID-19 waves.

Emerging SARS-CoV-2 variants can potentially break set epidemiological barriers in COVID-19.

Young age, female sex, absence of comorbidities, and prior infection or vaccination are known epidemiological barriers for contracting the new infection and/or increased disease severity. Demographic trends from the recent coronavirus disease 2019 waves, which are believed to be driven by newer severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, indicate that the aforementioned epidemiological barriers are being breached and a larger number of younger and healthy individuals are developing severe disease. The new SARS-CoV-2 variants have key mutations that can induce significant changes in the virus-host interactions. Recent studies report that, some of these mutations, singly or in a group, enhance key mechanisms, such as binding of the receptor-binding domain (RBD) of the viral spike protein with the angiotensin-converting enzyme 2 (ACE2) receptor in the host-cells, increase the glycosylation of spike protein at the antigenic sites, and enhance the proteolytic cleavage of the spike protein, thus leading to improved host-cell entry and the replication of the virus. The putative changes in the virus-host interactions imparted by the mutations in the RBD sequence can potentially be the reason behind the breach of the observed epidemiological barriers. Susceptibility for contracting SARS-CoV-2 infection and the disease outcomes are known to be influenced by host-cell expressions of ACE2 and other proteases. The new variants can act more efficiently, and even with the lesser availability of the viral entry-receptor and the associated proteases, can have more efficient host-cell entry and greater replication resulting in high viral loads and prolonged viral shedding, widespread tissue-injury, and severe inflammation leading to increased transmissibility and lethality. Furthermore, the accumulating evidence shows that multiple new variants have reduced neutralization by both, natural and vaccine-acquired antibodies, indicating that repeated and vaccine breakthrough infections may arise as serious health concerns in the ongoing pandemic.

COVID-19 Mechanisms in the Human Body-What We Know So Far.

More than one and a half years have elapsed since the commencement of the coronavirus disease 2019 (COVID-19) pandemic, and the world is struggling to contain it. Being caused by a previously unknown virus, in the initial period, there had been an extreme paucity of knowledge about the disease mechanisms, which hampered preventive and therapeutic measures against COVID-19. In an endeavor to understand the pathogenic mechanisms, extensive experimental studies have been conducted across the globe involving cell culture-based experiments, human tissue organoids, and animal models, targeted to various aspects of the disease, viz., viral properties, tissue tropism and organ-specific pathogenesis, involvement of physiological systems, and the human immune response against the infection. The vastly accumulated scientific knowledge on all aspects of COVID-19 has currently changed the scenario from great despair to hope. Even though spectacular progress has been made in all of these aspects, multiple knowledge gaps are remaining that need to be addressed in future studies. Moreover, multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have emerged across the globe since the onset of the first COVID-19 wave, with seemingly greater transmissibility/virulence and immune escape capabilities than the wild-type strain. In this review, we narrate the progress made since the commencement of the pandemic regarding the knowledge on COVID-19 mechanisms in the human body, including virus-host interactions, pulmonary and other systemic manifestations, immunological dysregulations, complications, host-specific vulnerability, and long-term health consequences in the survivors. Additionally, we provide a brief review of the current evidence explaining molecular mechanisms imparting greater transmissibility and virulence and immune escape capabilities to the emerging SARS-CoV-2 variants.

Expression of SARS-CoV-2 Host Cell Entry Factors in Immune System Components of Healthy Individuals and Its Relevance for COVID-19 Immunopathology.

Intense immunological dysregulation including immune cell lesions has been characteristically observed in severe cases of coronavirus disease-2019 (COVID-19), for which molecular mechanisms are not properly understood. A study of physiological expressions of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) host cell entry-related factors in immune system components may help explain molecular mechanisms involved in COVID-19 immunopathology. We analyzed transcriptomic and proteomic expression metadata for SARS-CoV-2 host cell entry receptor ACE2 and entry associated proteases (TMPRSS2, CTSL, and FURIN) in silico across immune system components including the blood lineage cells. ACE2 was not detected in any of the studied immune cell components; however, varying transcriptomic and proteomic expressions were observed for TMPRSS2, CTSL, and FURIN. Nondetectable expressions of SARS-CoV-2 host cell entry receptor ACE2 in immune system components or blood lineage cells indicate it does not mediate immune cell lesions in COVID-19. Alternative mechanisms need to be explored for COVID-19 immunopathogenesis.

COVID-19 pandemic: insights into molecular mechanisms leading to sex-based differences in patient outcomes.

Recent epidemiological studies analysing sex-disaggregated patient data of coronavirus disease 2019 (COVID-19) across the world revealed a distinct sex bias in the disease morbidity as well as the mortality - both being higher for the men. Similar antecedents have been known for the previous viral infections, including from coronaviruses, such as severe acute respiratory syndrome (SARS) and middle-east respiratory syndrome (MERS). A sound understanding of molecular mechanisms leading to the biological sex bias in the survival outcomes of the patients in relation to COVID-19 will act as an essential requisite for developing a sex-differentiated approach for therapeutic management of this disease. Recent studies which have explored molecular mechanism(s) behind sex-based differences in COVID-19 pathogenesis are scarce; however, existing evidence, for other respiratory viral infections, viz. SARS, MERS and influenza, provides important clues in this regard. In attempt to consolidate the available knowledge on this issue, we conducted a systematic review of the existing empirical knowledge and recent experimental studies following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The qualitative analysis of the collected data unravelled multiple molecular mechanisms, such as evolutionary and genetic/epigenetic factors, sex-linkage of viral host cell entry receptor and immune response genes, sex hormone and gut microbiome-mediated immune-modulation, as the possible key reasons for the sex-based differences in patient outcomes in COVID-19.

Pathogenesis guided therapeutic management of COVID-19: an immunological perspective.

Lack of standardized therapeutic approaches is arguably the significant contributor to the high burden of mortality observed in the ongoing pandemic of the Coronavirus disease, 2019 (COVID-19). Evidence is accumulating on SARS-CoV-2 specific immune cell dysregulation and consequent tissue injury in COVID-19. Currently, no definite drugs or vaccines are available against the disease; however initial results of the ongoing clinical trials have raised some hope. In this article, taking insights from the emerging empirical evidence about host-virus interactions, we deliberate upon plausible pathogenic mechanisms and suitable therapeutic approaches for COVID-19.

SARS-CoV-2-specific virulence factors in COVID-19.

The paucity of knowledge about severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific virulence factors has greatly hampered the therapeutic management of patients with coronavirus disease 2019 (COVID-19). Recently, a cluster of studies appeared, which presented empirical evidence for SARS-CoV-2-specific virulence factors that can explain key elements of COVID-19 pathology. These studies unravel multiple structural and nonstructural specifics of SARS-CoV-2, such as a unique FURIN cleavage site, papain-like protease (SCoV2-PLpro), ORF3b and nonstructural proteins, and dynamic conformational changes in the structure of spike protein during host cell fusion, which give it an edge in infectivity and virulence over previous coronaviruses causing pandemics. Investigators provided robust evidence that SARS-CoV-2-specific virulence factors may have an impact on viral infectivity and transmissibility and disease severity as well as the development of immunity against the infection, including response to the vaccines. In this article, we are presenting a summarized account of the newly reported studies.

Predicting susceptibility for SARS-CoV-2 infection in domestic and wildlife animals using ACE2 protein sequence homology.

The article is presenting a bioinformatics based method predicting susceptibility for SARS-CoV-2 infection in domestic and wildlife animals. Recently, there were reports of cats and ferrets, dogs, minks, golden hamster, rhesus monkeys, tigers, and lions testing for SARS-CoV-2 RNA which indicated for the possible interspecies viral transmission. Our method successfully predicted the susceptibility of these animals for contracting SARS-CoV-2 infection. This method can be used as a screening tool for guiding viral RNA testing for domestic and wildlife animals at risk of getting COVID-19. We provide a list of the animals at risk of developing COVID-19 based on the susceptibility score.

SARS-CoV-2 cell entry receptor ACE2 mediated endothelial dysfunction leads to vascular thrombosis in COVID-19 patients.

Several studies have described unusually high incidence of vascular thrombosis in coronavirus disease-2019 (COVID-19) patients. Pathogenesis of the vascular thrombosis in COVID-19 is least understood for now and presents a challenge to the treating physicians. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative pathogen for COVID-19, has been shown to bind to angiotensin converting enzyme 2 (ACE2) protein in human epithelial cells which facilitates its entry in the organ and mediate tissue specific pathogenesis. For ACE2 mediated cell entry of the SARS-CoV-2, co-expression of one more protein-Transmembrane protease serine 2 (TMPRSS2) is essential. Existing studies suggested significant expression of ACE2 and TMPRSS2 in human vascular endothelium. Vascular endothelial dysfunction can potentially activate coagulation cascade eventually resulting in thrombosis. ACE2 has proven role in the maintenance of endothelial integrity inside the vessels. Existing in situ evidence for SARS-CoV-1 (the causative agent for SARS pandemic of 2002, which shared ACE2 as cell entry receptor) suggested that virus binding can downregulate ACE2, thus can induce endothelial dysfunction. Recently, in situ evidence has been presented that SARS-CoV-2 can infect cells in engineered human vascular endothelium, which can be effectively blocked by using clinical-grade recombinant human ACE2. Based on the circumstantial evidence present in the literature, we propose a SARS-CoV-2 cell entry receptor ACE2 based mechanism for vascular thrombosis in COVID-19 patients.

Relevance of SARS-CoV-2 related factors ACE2 and TMPRSS2 expressions in gastrointestinal tissue with pathogenesis of digestive symptoms, diabetes-associated mortality, and disease recurrence in COVID-19 patients.

COVID-19 is caused by a new strain of coronavirus called SARS-coronavirus-2 (SARS-CoV-2), which is a positive sense single strand RNA virus. In humans, it binds to angiotensin converting enzyme 2 (ACE2) with the help a structural protein on its surface called the S-spike. Further, cleavage of the viral spike protein (S) by the proteases like transmembrane serine protease 2 (TMPRSS2) or Cathepsin L (CTSL) is essential to effectuate host cell membrane fusion and virus infectivity. COVID-19 poses intriguing issues with imperative relevance to clinicians. The pathogenesis of GI symptoms, diabetes-associated mortality, and disease recurrence in COVID-19 are of particular relevance because they cannot be sufficiently explained from the existing knowledge of the viral diseases. Tissue specific variations of SARS-CoV-2 cell entry related receptors expression in healthy individuals can help in understanding the pathophysiological basis the aforementioned collection of symptoms. ACE2 mediated dysregulation of sodium dependent glucose transporter (SGLT1 or SLC5A1) in the intestinal epithelium also links it to the pathogenesis of diabetes mellitus which can be a possible reason for the associated mortality in COVID-19 patients with diabetes. High expression of ACE2 in mucosal cells of the intestine and GB make these organs potential sites for the virus entry and replication. Continued replication of the virus at these ACE2 enriched sites may be a basis for the disease recurrence reported in some, thought to be cured, patients. Based on the human tissue specific distribution of SARS-CoV-2 cell entry factors ACE2 and TMPRSS2 and other supportive evidence from the literature, we hypothesize that SARS-CoV-2 host cell entry receptor-ACE2 based mechanism in GI tissue may be involved in COVID-19 (i) in the pathogenesis of digestive symptoms, (ii) in increased diabetic complications, (iii) in disease recurrence.

Possible routes of SARS-CoV-2 invasion in brain: In context of neurological symptoms in COVID-19 patients.

Manifestation of neurological symptoms in certain patients of coronavirus disease-2019 (COVID-19) has warranted for their virus-induced etiogenesis. SARS-CoV-2, the causative agent of COVID-19, belongs to the genus of betacoronaviruses which also includes SARS-CoV-1 and MERS-CoV; causative agents for severe acute respiratory syndrome (SARS) in 2002 and Middle East respiratory syndrome (MERS) in 2012, respectively. Studies demonstrating the neural invasion of SARS-CoV-2 in vivo are still scarce, although such characteristics of certain other betacoronaviruses are well demonstrated in the literature. Based on the recent evidence for the presence of SARS-CoV-2 host cell entry receptors in specific components of the human nervous and vascular tissue, a neural (olfactory and/or vagal), and a hematogenous-crossing the blood-brain barrier, routes have been proposed. The neurological symptoms in COVID-19 may also arise as a consequence of the "cytokine storm" (characteristically present in severe disease) induced neuroinflammation, or co-morbidities. There is also a possibility that, there may be multiple routes of SARS-CoV-2 entry into the brain, or multiple mechanisms can be involved in the pathogenesis of the neurological symptoms. In this review article, we have discussed the possible routes of SARS-CoV-2 brain entry based on the emerging evidence for this virus, and that available for other betacoronaviruses in literature.