Pathogenesis Of COVID-19 Research Articles

Advances in Understanding the Envelope Protein in Coronavirus Infection

The COVID-19 pandemic continues to impart devastating effects on human health, healthcare systems, and the economy. Vaccination, monoclonal antibodies, and antiviral therapies prevent and limit early infection. Unfortunately, few strategies exist to mitigate the disease burden in the vast number of individuals who seek medical attention with established infection and severe disease. While we have a limited understanding of the mechanistic basis by which SARS-CoV-2 causes critical illness, increasing evidence suggests that host-pathogen interactions shape immune responses that drive the pathogenesis of COVID-19. Therefore, it is imperative to understand the roles of the viral proteins and how they shape the course of infection. One interesting protein is the envelope (E) protein of SARS-CoV-2; this tiny structural protein has been implicated in many phases of the viral life cycle. Importantly, the E protein facilitates viral packaging and replication, and its deletion reduces viral pathogenicity. The E protein also possesses ion channel functions, interacts with host proteins, and has the potential to have various structural topologies. This review aims to establish an updated understanding by highlighting recent developments in the investigation of the SARS-CoV-2 E protein, particularly in comparison to the envelope protein of SARS-CoV. thorough knowledge of this protein will enable targeted studies in hopes of tailored efficacious treatments.

Pro- or anti-inflammatory properties of cytokines in COVID-19: which offer better protection against disease?

Pro- or anti-inflammatory properties of cytokines in COVID-19: which offer better protection against disease I read the article by Al-Mquter et al. that compared circulating levels of 3 cytokines(IL-6, IL-25 and IL-35) amongst healthy controls(HC) and patients with COVID-19. They reported a significant increase in the serum concentration of these cytokines in patients versus HC(1). Their results confirmed again that assessment of cytokine profiles could be used as COVID-19 markers and may also provide practical implications for disease treatment. Nonetheless, understanding the role of cytokines in COVID-19 is complicated because of the complex nature of cytokine networks and the pathogenesis of COVID-19(2). IL-6 is one of the first cytokines produced during COVID-19 and increasing evidence suggests that its alteration may be associated with disease outcome. IL-6 is a pleotropic cytokine and has both pro- and anti- inflammatory effects. Therefore, it appears to operate in protective or pathological immunity to COVID-19. IL-6 can promote immune processes associated with resistance to different pathogens including COVID-19. It contributes to host defense via different pathways, including the stimulation of acute phase responses and hematopoiesis. Nonetheless, dysregulated and persistent synthesis of IL-6 can be resulted to the onset and development of pathological conditions. These different effector functions may be associated with different concentration of IL-6 that may result from different signaling pathwaysIL-6 signaling includes at least three distinct pathways: cis-signalling; trans-signalling and trans-presentation. It seems that IL-6 trans-signalling and trans-presentation are probably responsible for severe progressive COVID-19. These signaling pathways can trigger diffuse inflammation at various levels. Conversely, IL-6 cis-signalling mediates negative feedback mechanisms on proinflammatory cytokines, including suppression of their production, stimulation of their decoy receptors, and inhibition the maturation of Th17 cells. Circulatory IL-6 in COVID-19 patients reaches the peak level at advanced stages around two weeks of disease. Elevated IL-6 (e.g., > 100-120 pg/mL) levels in critical COVID-19 may reflect augmented IL-6 cis-signalling in an attempt to exert homeostatic functions, although there is no general consensus on this issue(3).

Curcumin as a Promising Therapy for COVID-19: A Review

The ongoing COVID-19 pandemic has spurred intense research efforts to identify effective therapeutic options. Among the potential candidates, curcumin, a naturally occurring polyphenol obtained from turmeric, has gained considerable attention due to its diverse pharmacological properties. This review examines the existing literature on curcumin’s potential as a new promising treatment for COVID-19. Curcumin demonstrates antiviral effects by modulating key signaling pathways for entry and multiplication of SARS-CoV-2 in host cells. It limits viral entry in host cells as it binds and inhibits S-protein, TMPRSS2, and ADAM17 enzymes required for cytoadherence and membrane fusion. It also downregulates SARS-CoV-2 replication by preventing the release of the viral genomic RNA into the cytoplasm from virus-containing vacuoles and subsequently inhibits enzymes required for viral replication. Rennin–angiotensin–aldosterone system (RAS) dysfunction, especially increased angiotensin-converting enzyme (ACE)-Angiotensin II-AT1R axis activity, is associated with prothrombotic state, acute respiratory distress syndrome, and lung injury in COVID-19 patients. Curcumin increases soluble ACE2 cellular ACE2 activity, restores RAS normal function, and mitigates these complications. Curcumin also exerts anti-inflammatory and immunomodulatory actions. It reduces the secretion of pro-inflammatory cytokines through inhibition of toll-like receptors (TLRs), namely, TLR2, TLR4, and TLR9, and enhances the production of anti-inflammatory cytokines like interleukin-10. In addition, it prevents the progression of tissue damage and inflammation by reactive oxygen species (ROS) through ROS scavenging enzymes. Due to its antiviral, anti-inflammatory, antioxidant, and immunomodulatory properties, curcumin has emerged as an attractive candidate for combating various aspects of COVID-19 pathogenesis, such as excessive inflammation, oxidative stress, viral multiplication, and immune dysregulation. However, limited clinical evidence is currently available to support its efficacy, specifically against COVID-19. Thus, further research, including clinical trials, is warranted to evaluate curcumin’s therapeutic potential and determine its optimal dosage, formulation, and safety for COVID-19 patients. Overall, based on its favorable pharmacological properties and promising preclinical data, curcumin holds promise as a treatment for COVID-19, but its clinical utility requires further exploration.

СРАВНЕНИЕ ИНДЕКСА БИОРАЗНООБРАЗИЯ ПАРОДОНТАЛЬНЫХ ПРОСТРАНСТВ У ПАЦИЕНТОВ В ПОСТКОВИДНОМ ПЕРИОДЕ

Relevance. Improving the diagnosis and provision of periodontal care to patients with chronic periodontitis in combination with herpetic and candidal lesions is an urgent goal of many modern studies. The COVID-19 pandemic, and the post-COVID syndrome, have sufficiently changed the view of dentists on the diagnosis and treatment of these comorbid and associative diseases. Purpose: comparison of the Shannon biodiversity index of the studied groups. Materials and methods. We conducted a single-center, randomized, prospective, clinical-microbiological, controlled, open study to determine the comorbidity of herpes and candida infections with chronic generalized periodontitis; 61 patients (aged 18 to 19 years) were examined. Results: In general, I would like to emphasize that the less we record the Shannon biodiversity index, the healthier the space under study, in our case the periodontal area, is. Since less biodiversity is a formed stable microbial community, contributing to the preservation of constancy and protection from opportunistic and pathogenic forms. In conclusion, I would like to note that the pathogenesis of COVID-19 is truly interesting and unique, and there is practically no data on changes in the spectrum of periodontopathogenic and normal microbiota in the pathology under consideration, therefore the use of metagenomic analysis of the oral microbiome against the background of a coronavirus infection will expand the understanding of the course of these comorbid diseases. Therapeutic measures aimed at reducing the viral load in periodontal tissues can help not only reduce the number of possible niches for the life of the virus, but also strengthen periodontal tissues, preventing the development of comorbid and associative forms of diseases.

FOXO1 inhibitor has the antiviral and anti-inflammatory effects against SARS-CoV-2 infection in in vitro and in vivo models.

Abstract COVID-19 treatment aims to inhibit SARS-CoV-2 replication and subsequent hyper-inflammatory responses. Forkhead box O1 (FOXO1) is a transcription factor involved in various physiological processes, including inflammation and immune systems. Here, we investigated the antiviral and anti-inflammatory effects of AS1842856 (AS), a FOXO1 inhibitor, against SARS-CoV-2 infection. We found that AS could suppress viral load and active virus titers in Calu-3, a human airway epithelial cell line, infected with SARS-CoV-2. In addition, the expression of inflammatory-related cytokines was reduced, while that of IL-10, an anti-inflammatory cytokine, was increased by AS. AS also reduced expressions of ACE2 and TMPRSS2, both host cell proteins required for SARS-CoV-2 infection. Moreover, we investigated the effects of AS in animal models. AS administration (50 mg/kg/day, i.p.) into a Syrian hamster model resulted in reduced weight loss, a decrease in viral load in lungs, and histological improvement of pneumonia. We also found AS improved survival rate in mouse COVID-19 models, generated by using mouse-adapted QHmusX strain. Single-cell RNA sequencing using hamster lungs indicated AS suppressed SARS-CoV-2 gene in alveolar epithelial cells and decreased CXCL10+ macrophages, which are related to pathogenesis of severe COVID-19 according to previous studies. Our results suggested AS could attenuate the severity of COVID-19 by modifying immune responses and suppressing SARS-CoV-2 infection.

A systematic scoping review of the neurological effects of COVID-19

BackgroundThe global coronavirus 2019 (COVID-19) pandemic began in early 2020, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In mid-2020 the CIAO (Modelling the Pathogenesis of COVID-19 Using the Adverse Outcome Pathway Framework) project was established, bringing together over 75 interdisciplinary scientists worldwide to collaboratively investigate the underlying biological mechanisms of COVID-19 and consolidate the data using the Adverse Outcome Pathway (AOP) Framework. Neurological symptoms such as anosmia and encephalitis have been frequently reported to be associated with infection with SARS-CoV-2. ObjectiveWithin CIAO, a working group was formed to conduct a systematic scoping review of COVID-19 and its related neurological symptoms to determine which key events and modulating factors are most commonly reported and to identify knowledge gaps. DesignLitCOVID was used to retrieve 86,075 papers of which 10,244 contained relevant keywords. After title and abstract screening, 2,328 remained and their full texts were reviewed based on predefined inclusion and exclusion criteria. 991 studies fulfilled the inclusion criteria and were retrieved to conduct knowledge synthesis. ResultsThe majority of publications reported human observational studies. Early key events were less likely to be reported compared to middle and late key events/adverse outcomes. The majority of modulating factors described related to age or sex. Less recognised COVID-19 associated AO or neurological effects of COVID-19 were also identified including multiple sclerosis/demyelination, neurodegeneration/cognitive effects and peripheral neuronal effects. ConclusionThere were many methodological and reporting issues noted in the reviewed studies. In particular, publication abstracts would benefit from clearer reporting of the methods and endpoints used and the key findings, to ensure relevant papers are included when systematic reviews are conducted. The information extracted from the scoping review may be useful in understanding the mechanisms of neurological effects of COVID-19 and to further develop or support existing AOPs linking COVID-19 and its neurological key events and adverse outcomes. Further evaluation of the less recognised COVID-19 effects is needed.

Correlation between the elevated level of interleukin-6 following actemra administration and the mortality rate of seven severe COVID-19 patients

The escalation and involvement of Interleukin 6 (IL-6) in the pathogenesis of COVID-19 have been documented in numerous studies and are recognized as a diagnostic criterion, disease biomarker, and therapeutic objective. Our study aims to explore the correlation between the elevated level of IL-6 following actemra administration and the mortality rate of seven severe COVID-19 patients who were admitted to the special care department of Ardabil city hospital. In this case-series study, 7 patients with severe COVID-19 were admitted to the special care department of Ardabil city hospital were included in the study. Venous blood samples (3 cc) were taken in admission and after actemra injection. The demographic characteristics of the patients, including age, sex, duration of hospitalization, need for intubation, BMI, and interleukin 6 levels, were recorded in a checklist. The patients were then monitored for their clinical course, disease outcome, and complications. The mean IL-6 before and after actemra was 413.57±138.38 and 805.50±128.18, respectively and the difference was significant. After treatment by actemra, 71.4% of patients were discharged from hospital without mortality. Although elevated IL-6 levels have been associated with cytokine storms and unfavorable consequences in COVID-19 patients. This report indicates that high interleukin levels do not guarantee mortality. Young individuals without underlying conditions were ultimately discharged from the ICU despite severe inflammation, thanks to timely treatment and albeit with severe disability.

Thapsigargin and Tunicamycin Block SARS-CoV-2 Entry into Host Cells via Differential Modulation of Unfolded Protein Response (UPR), AKT Signaling, and Apoptosis.

SARS-Co-V2 infection can induce ER stress-associated activation of unfolded protein response (UPR) in host cells, which may contribute to the pathogenesis of COVID-19. To understand the complex interplay between SARS-Co-V2 infection and UPR signaling, we examined the effects of acute pre-existing ER stress on SARS-Co-V2 infectivity. Huh-7 cells were treated with Tunicamycin (TUN) and Thapsigargin (THA) prior to SARS-CoV-2pp transduction (48 h p.i.) to induce ER stress. Pseudo-typed particles (SARS-CoV-2pp) entry into host cells was measured by Bright GloTM luciferase assay. Cell viability was assessed by cell titer Glo® luminescent assay. The mRNA and protein expression was evaluated by RT-qPCR and Western Blot. TUN (5 µg/mL) and THA (1 µM) efficiently inhibited the entry of SARS-CoV-2pp into host cells without any cytotoxic effect. TUN and THA's attenuation of virus entry was associated with differential modulation of ACE2 expression. Both TUN and THA significantly reduced the expression of stress-inducible ER chaperone GRP78/BiP in transduced cells. In contrast, the IRE1-XBP1s and PERK-eIF2α-ATF4-CHOP signaling pathways were downregulated with THA treatment, but not TUN in transduced cells. Insulin-mediated glucose uptake and phosphorylation of Ser307 IRS-1 and downstream p-AKT were enhanced with THA in transduced cells. Furthermore, TUN and THA differentially affected lipid metabolism and apoptotic signaling pathways. These findings suggest that short-term pre-existing ER stress prior to virus infection induces a specific UPR response in host cells capable of counteracting stress-inducible elements signaling, thereby depriving SARS-Co-V2 of essential components for entry and replication. Pharmacological manipulation of ER stress in host cells might provide new therapeutic strategies to alleviate SARS-CoV-2 infection.

The Immune Response of OAS1, IRF9, and IFI6 Genes in the Pathogenesis of COVID-19.

COVID-19 is characterized by a wide range of clinical manifestations, where aging, underlying diseases, and genetic background are related to worse outcomes. In the present study, the differential expression of seven genes related to immunity, IRF9, CCL5, IFI6, TGFB1, IL1B, OAS1, and TFRC, was analyzed in individuals with COVID-19 diagnoses of different disease severities. Two-step RT-qPCR was performed to determine the relative gene expression in whole-blood samples from 160 individuals. The expression of OAS1 (p < 0.05) and IFI6 (p < 0.05) was higher in moderate hospitalized cases than in severe ones. Increased gene expression of OAS1 (OR = 0.64, CI = 0.52-0.79; p = 0.001), IRF9 (OR = 0.581, CI = 0.43-0.79; p = 0.001), and IFI6 (OR = 0.544, CI = 0.39-0.69; p < 0.001) was associated with a lower risk of requiring IMV. Moreover, TGFB1 (OR = 0.646, CI = 0.50-0.83; p = 0.001), CCL5 (OR = 0.57, CI = 0.39-0.83; p = 0.003), IRF9 (OR = 0.80, CI = 0.653-0.979; p = 0.03), and IFI6 (OR = 0.827, CI = 0.69-0.991; p = 0.039) expression was associated with patient survival. In conclusion, the relevance of OAS1, IRF9, and IFI6 in controlling the viral infection was confirmed.

Natural Killer Cells Do Not Attenuate a Mouse-Adapted SARS-CoV-2-Induced Disease in Rag2-/- Mice.

This study investigates the roles of T, B, and Natural Killer (NK) cells in the pathogenesis of severe COVID-19, utilizing mouse-adapted SARS-CoV-2-MA30 (MA30). To evaluate this MA30 mouse model, we characterized MA30-infected C57BL/6 mice (B6) and compared them with SARS-CoV-2-WA1 (an original SARS-CoV-2 strain) infected K18-human ACE2 (K18-hACE2) mice. We found that the infected B6 mice developed severe peribronchial inflammation and rapid severe pulmonary edema, but less lung interstitial inflammation than the infected K18-hACE2 mice. These pathological findings recapitulate some pathological changes seen in severe COVID-19 patients. Using this MA30-infected mouse model, we further demonstrate that T and/or B cells are essential in mounting an effective immune response against SARS-CoV-2. This was evident as Rag2-/- showed heightened vulnerability to infection and inhibited viral clearance. Conversely, the depletion of NK cells did not significantly alter the disease course in Rag2-/- mice, underscoring the minimal role of NK cells in the acute phase of MA30-induced disease. Together, our results indicate that T and/or B cells, but not NK cells, mitigate MA30-induced disease in mice and the infected mouse model can be used for dissecting the pathogenesis and immunology of severe COVID-19.

Plasma Proteomics Elucidated a Protein Signature in COVID-19 Patients with Comorbidities and Early-Diagnosis Biomarkers.

Despite great scientific efforts, deep understanding of coronavirus-19 disease (COVID-19) immunopathology and clinical biomarkers remains a challenge. Pre-existing comorbidities increase the mortality rate and aggravate the exacerbated immune response against the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, which can result in more severe symptoms as well as long-COVID and post-COVID complications. In this study, we applied proteomics analysis of plasma samples from 28 patients with SARS-CoV-2, with and without pre-existing comorbidities, as well as their corresponding controls to determine the systemic protein changes caused by the SARS-CoV-2 infection. As a result, the protein signature shared amongst COVID-19 patients with comorbidities was revealed to be characterized by alterations in the coagulation and complement pathways, acute-phase response proteins, tissue damage and remodeling, as well as cholesterol metabolism. These altered proteins may play a relevant role in COVID-19 pathophysiology. Moreover, several novel potential biomarkers for early diagnosis of the SARS-CoV-2 infection were detected, such as increased levels of keratin K22E, extracellular matrix protein-1 (ECM1), and acute-phase response protein α-2-antiplasmin (A2AP). Importantly, elevated A2AP may contribute to persistent clotting complications associated with the long-COVID syndrome in patients with comorbidities. This study provides new insights into COVID-19 pathogenesis and proposes novel potential biomarkers for early diagnosis that could be facilitated for clinical application by further validation studies.

Neutrophil proteases are protective against SARS-CoV-2 by degrading the spike protein and dampening virus-mediated inflammation.

Studies on severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) have highlighted the crucial role of host proteases for viral replication and the immune response. The serine proteases furin and TMPRSS2 and lysosomal cysteine proteases facilitate viral entry by limited proteolytic processing of the spike (S) protein. While neutrophils are recruited to the lungs during COVID-19 pneumonia, little is known about the role of the neutrophil serine proteases (NSPs) cathepsin G (CatG), elastase (NE), and proteinase 3 (PR3) on SARS-CoV-2 entry and replication. Furthermore, the current paradigm is that NSPs may contribute to the pathogenesis of severe COVID-19. Here, we show that these proteases cleaved the S protein at multiple sites and abrogated viral entry and replication in vitro. In mouse models, CatG significantly inhibited viral replication in the lung. Importantly, lung inflammation and pathology were increased in mice deficient in NE and/or CatG. These results reveal that NSPs contribute to innate defenses against SARS-CoV-2 infection via proteolytic inactivation of the S protein and that NE and CatG limit lung inflammation in vivo. We conclude that therapeutic interventions aiming to reduce the activity of NSPs may interfere with viral clearance and inflammation in COVID-19 patients.

Identification and characterization of endogenous retroviruses upon SARS-CoV-2 infection.

Endogenous retroviruses (ERVs) derived from the long terminal repeat (LTR) family of transposons constitute a significant portion of the mammalian genome, with origins tracing back to ancient viral infections. Despite comprising approximately 8% of the human genome, the specific role of ERVs in the pathogenesis of COVID-19 remains unclear. In this study, we conducted a genome-wide identification of ERVs in human peripheral blood mononuclear cells (hPBMCs) and primary lung epithelial cells from monkeys and mice, both infected and uninfected with SARS-CoV-2. We identified 405, 283, and 206 significantly up-regulated transposable elements (TEs) in hPBMCs, monkeys, and mice, respectively. This included 254, 119, 68, and 28 ERVs found in hPBMCs from severe and mild COVID-19 patients, monkeys, and transgenic mice expressing the human ACE2 receptor (hACE2) and infected with SARS-CoV-2. Furthermore, analysis using the Genomic Regions Enrichment of Annotations Tool (GREAT) revealed certain parental genomic sequences of these up-regulated ERVs in COVID-19 patients may be involved in various biological processes, including histone modification and viral replication. Of particular interest, we identified 210 ERVs specifically up-regulated in the severe COVID-19 group. The genes associated with these differentially expressed ERVs were enriched in processes such as immune response activation and histone modification. HERV1_I-int: ERV1:LTR and LTR7Y: ERV1:LTR were highlighted as potential biomarkers for evaluating the severity of COVID-19. Additionally, validation of our findings using RT-qPCR in Bone Marrow-Derived Macrophages (BMDMs) from mice infected by HSV-1 and VSV provided further support to our results. This study offers insights into the expression patterns and potential roles of ERVs following viral infection, providing a valuable resource for future studies on ERVs and their interaction with SARS-CoV-2.

Gastrointestinal microbiota and metabolites possibly contribute to distinct pathogenicity of SARS-CoV-2 proto or its variants in rhesus monkeys

ABSTRACT Gastrointestinal (GI) infection is evidenced with involvement in COVID-19 pathogenesis caused by SARS-CoV-2. However, the correlation between GI microbiota and the distinct pathogenicity of SARS-CoV-2 Proto and its emerging variants remains unclear. In this study, we aimed to determine if GI microbiota impacted COVID-19 pathogenesis and if the effect varied between SARS-CoV-2 Proto and its variants. We performed an integrative analysis of histopathology, microbiomics, and transcriptomics on the GI tract fragments from rhesus monkeys infected with SARS-CoV-2 proto or its variants. Based on the degree of pathological damage and microbiota profile in the GI tract, five of SARS-CoV-2 strains were classified into two distinct clusters, namely, the clusters of Alpha, Beta and Delta (ABD), and Proto and Omicron (PO). Notably, the abundance of potentially pathogenic microorganisms increased in ABD but not in the PO-infected rhesus monkeys. Specifically, the high abundance of UCG-002, UCG-005, and Treponema in ABD virus-infected animals positively correlated with interleukin, integrins, and antiviral genes. Overall, this study revealed that infection-induced alteration of GI microbiota and metabolites could increase the systemic burdens of inflammation or pathological injury in infected animals, especially in those infected with ABD viruses. Distinct GI microbiota and metabolite profiles may be responsible for the differential pathological phenotypes of PO and ABD virus-infected animals. These findings improve our understanding the roles of the GI microbiota in SARS-CoV-2 infection and provide important information for the precise prevention, control, and treatment of COVID-19.

Integration of metalloproteome and immunoproteome reveals a tight link of iron-related proteins with COVID-19 pathogenesis and immunity

Increasing clinical data show that the imbalance of host metallome is closely associated with different kinds of disease, however, the intrinsic mechanisms of action of metals in immunity and pathogenesis of disease remain largely undefined. There is lack of multiplexed profiling system to integrate the metalloproteome-immunoproteome information at systemic level for exploring the roles of metals in immunity and disease pathogenesis. In this study, we build up a metal-coding assisted multiplexed proteome assay platform for serum metalloproteomic and immunoproteomic profiling. By taking COVID-19 as a showcase, we unbiasedly uncovered the most evident modulation of iron-related proteins, i.e., Ft and Tf, in serum of severe COVID-19 patients, and the value of Ft/Tf could work as a robust biomarker for COVID-19 severity stratification, which overtakes the well-established clinical risk factors (cytokines). We further uncovered a tight association of transferrin with inflammation mediator IL-10 in COVID-19 patients, which was proved to be mainly governed by the monocyte/macrophage of liver, shedding light on new pathophysiological and immune regulatory mechanisms of COVID-19 disease. We finally validated the beneficial effects of iron chelators as anti-viral agents in SARS-CoV-2-infected K18-hACE2 mice through modulation of iron dyshomeostasis and alleviating inflammation response. Our findings highlight the critical role of liver-mediated iron dysregulation in COVID-19 disease severity, providing solid evidence on the involvement of iron-related proteins in COVID-19 pathophysiology and immunity.

Emerging Treatment Approaches for COVID-19 Infection: A Critical Review.

In the present scenario, the SARS-CoV-2 virus has imposed enormous damage on human survival and the global financial system. It has been estimated that around 111 million people all around the world have been infected, and about 2.47 million people died due to this pandemic. The major symptoms were sneezing, coughing, cold, difficulty breathing, pneumonia, and multi-organ failure associated 1with SARS-CoV-2. Currently, two key problems, namely insufficient attempts to develop drugs against SARSCoV-2 and the lack of any biological regulating process, are mostly responsible for the havoc caused by this virus. Henceforth, developing a few novel drugs is urgently required to cure this pandemic. It has been noticed that the pathogenesis of COVID-19 is caused by two main events: infection and immune deficiency, that occur during the pathological process. Antiviral medication can treat both the virus and the host cells. Therefore, in the present review, the major approaches for the treatment have been divided into "target virus" and "target host" groups. These two mechanisms primarily rely on drug repositioning, novel approaches, and possible targets. Initially, we discussed the traditional drugs per the physicians' recommendations. Moreover, such therapeutics have no potential to fight against COVID-19. After that, detailed investigation and analysis were conducted to find some novel vaccines and monoclonal antibodies and conduct a few clinical trials to check their effectiveness against SARSCoV- 2 and mutant strains. Additionally, this study presents the most successful methods for its treatment, including combinatorial therapy. Nanotechnology was studied to build efficient nanocarriers to overcome the traditional constraints of antiviral and biological therapies.

Correlation of Serum Calcium with Severity and Outcomes in Patients of COVID-19 Pneumonia.

Calcium is an essential electrolyte with critical physiological functions. Recently, it has been implicated in the pathogenesis and outcomes of COVID-19. This retrospective study was conducted to estimate serum ionic calcium and its correlation with clinical severity, inflammatory markers, and in-hospital outcomes in moderate to severe COVID-19 patients. We retrospectively analyzed data from 377 COVID-19 patients, aged between 23 and 79 years, with a mean age of 54.17±11.53 years. Severity of the disease was determined using ICMR criteria. Parameters including age, gender, inflammatory markers, calcium levels, and clinical outcomes were assessed. The study showed a prevalence of moderate and severe COVID-19 in 58.1% and 41.9% patients, respectively. Severity was significantly associated with younger age, higher mean inflammatory markers, notably IL-6, procalcitonin, D-Dimer, and lower ionic and total calcium levels, as well as vitamin D levels. Mortality and referral rate were significantly higher in the severe group. Hypocalcemia was prevalent in 39% of the patients and was significantly associated with disease severity, ARDS, and mortality. On multivariate assessment, only age and ionic calcium were significantly associated with COVID-19 severity. Lower serum ionic calcium levels are associated with increased severity and poor outcomes, including higher mortality in COVID-19 patients, underscoring the potential role of calcium as a diagnostic and prognostic marker in COVID-19 pneumonia and may be an important factor in various other forms of pneumonia.

The Influence of Microglia on Neuroplasticity and Long-Term Cognitive Sequelae in Long COVID: Impacts on Brain Development and Beyond.

Microglial cells, the immune cells of the central nervous system, are key elements regulating brain development and brain health. These cells are fully responsive to stressors, microenvironmental alterations and are actively involved in the construction of neural circuits in children and the ability to undergo full experience-dependent plasticity in adults. Since neuroinflammation is a known key element in the pathogenesis of COVID-19, one might expect the dysregulation of microglial function to severely impact both functional and structural plasticity, leading to the cognitive sequelae that appear in the pathogenesis of Long COVID. Therefore, understanding this complex scenario is mandatory for establishing the possible molecular mechanisms related to these symptoms. In the present review, we will discuss Long COVID and its association with reduced levels of BDNF, altered crosstalk between circulating immune cells and microglia, increased levels of inflammasomes, cytokines and chemokines, as well as the alterations in signaling pathways that impact neural synaptic remodeling and plasticity, such as fractalkines, the complement system, the expression of SIRPα and CD47 molecules and altered matrix remodeling. Together, these complex mechanisms may help us understand consequences of Long COVID for brain development and its association with altered brain plasticity, impacting learning disabilities, neurodevelopmental disorders, as well as cognitive decline in adults.

Multi-Omics Profiling Reveals Phenotypic and Functional Heterogeneity of Neutrophils in COVID-19.

Accumulating evidence has revealed unexpected phenotypic heterogeneity and diverse functions of neutrophils in several diseases. Coronavirus disease (COVID-19) can alter the leukocyte phenotype based on disease severity, including neutrophil activation in severe cases. However, the plasticity of neutrophil phenotypes and their relative impact on COVID-19 pathogenesis has not been well addressed. This study aimed to identify and validate the heterogeneity of neutrophils in COVID-19 and evaluate the functions of each subpopulation. We analyzed public single-cell RNA-seq, bulk RNA-seq, and proteome data from healthy donors and patients with COVID-19 to investigate neutrophil subpopulations and their response to disease pathogenesis. We identified eight neutrophil subtypes: pro-neutrophil, pre-neutrophil, immature neutrophil, and five mature neutrophil subpopulations. The subtypes exhibited distinct features, including diverse activation signatures and multiple enriched pathways. The pro-neutrophil subtype was associated with severe and fatal disease, while the pre-neutrophil subtype was particularly abundant in mild/moderate disease. One of the mature neutrophil subtypes showed consistently large fractions in patients with different disease severity. Bulk RNA-seq dataset analyses using a cellular deconvolution approach validated the relative abundances of neutrophil subtypes and the expansion of pro-neutrophils in severe COVID-19 patients. Cell-cell communication analysis revealed representative ligand-receptor interactions among the identified neutrophil subtypes. Further investigation into transcription factors and differential protein abundance revealed the regulatory network differences between healthy donors and patients with severe COVID-19. Overall, we demonstrated the complex interactions among heterogeneous neutrophil subtypes and other blood cell types during COVID-19 disease. Our work has great value in terms of both clinical and public health as it furthers our understanding of the phenotypic and functional heterogeneity of neutrophils and other cell populations in multiple diseases.

Development of a Mouse-Adapted Reporter SARS-CoV-2 as a Tool for Two-Photon In Vivo Imaging.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) often causes severe viral pneumonia. Although many studies using mouse models have examined the pathogenicity of SARS-CoV-2, COVID-19 pathogenesis remains poorly understood. In vivo imaging analysis using two-photon excitation microscopy (TPEM) is useful for elucidating the pathology of COVID-19, providing pathological insights that are not available from conventional histological analysis. However, there is no reporter SARS-CoV-2 that demonstrates pathogenicity in C57BL/6 mice and emits sufficient light intensity for two-photon in vivo imaging. Here, we generated a mouse-adapted strain of SARS-CoV-2 (named MASCV2-p25) and demonstrated its efficient replication in the lungs of C57BL/6 mice, causing fatal pneumonia. Histopathologic analysis revealed the severe inflammation and infiltration of immune cells in the lungs of MASCV2-p25-infected C57BL/6 mice, not unlike that observed in COVID-19 patients with severe pneumonia. Subsequently, we generated a mouse-adapted reporter SARS-CoV-2 (named MASCV-Venus-p9) by inserting the fluorescent protein-encoding gene Venus into MASCV2-p25 and sequential lung-to-lung passages in C57BL/6 mice. C57BL/6 mice infected with MASCV2-Venus-p9 exhibited severe pneumonia. In addition, the TPEM of the lungs of the infected C57BL/6J mice showed that the infected cells emitted sufficient levels of fluorescence for easy observation. These findings suggest that MASCV2-Venus-p9 will be useful for two-photon in vivo imaging studies of the pathogenesis of severe COVID-19 pneumonia.