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Viruses utilize cell surface glycans and plasma membrane receptors to attain an adequate attachment strength for initiating cellular entry. We show that SARS-CoV-2 particles bind to endogenous ACE2 receptors and added sialylated gangliosides in near-native membranes. This was explored using supported membrane bilayers (SMBs) that were formed using plasma membrane vesicles having endogenous ACE2 and GD1a gangliosides reconstituted in lipid vesicles. The virus binding rate to the SMBs is influenced by GD1a and inhibition of the ganglioside reduces the extent of virus binding to the membrane receptors. Using combinations of inhibition assays, we confirm that added GD1a in lipid membranes increases the availability of the endogenous ACE2 receptor and results in the synergistic binding of SARS-CoV-2 to the membrane receptors in SMBs.

Multiple recent reports indicate that the S protein of SARS-CoV-2 specifically interacts with membrane receptors and attachment factors other than ACE2. They likely have an active role in cellular attachment and entry of the virus. In this article, we examined the binding of SARS-CoV-2 particles to gangliosides embedded in supported lipid bilayers (SLBs), mimicking the cell membrane-like environment. We show that the virus specifically binds to sialylated (sialic acid (SIA)) gangliosides, i.e., GD1a, GM3, and GM1, as determined from the acquired single-particle fluorescence images using a time-lapse total internal reflection fluorescence (TIRF) microscope. The data of virus binding events, the apparent binding rate constant, and the maximum virus coverage on the ganglioside-rich SLBs show that the virus particles have a higher binding affinity toward the GD1a and GM3 compared to the GM1 ganglioside. Enzymatic hydrolysis of the SIA-Gal bond of the gangliosides confirms that the SIA sugar unit of GD1a and GM3 is essential for virus attachment to the SLBs and even the cell surface sialic acid is critical for the cellular attachment of the virus. The structural difference between GM3/GD1a and GM1 is the presence of SIA at the main or branched chain. We conclude that the number of SIA per ganglioside can weakly influence the initial binding rate of SARS-CoV-2 particles, whereas the terminal or more exposed SIA is critical for the virus binding to the gangliosides in SLBs.

The distinct disease progression patterns of severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2) indicate diverse host immune responses. SARS-CoV-2 severely impairs type I interferon (IFN) cell signaling, resulting in uncontrolled late-phase lung damage in patients. For better pharmacological properties, cytokine modifications may sometimes result in a loss of biological activity against the virus. Here, we employed the genetic code expansion and engineered IFN-β, a phase II clinical cytokine with 3-amino tyrosine (IFN-β-A) that reactivates STAT2 expression in virus-infected human cells through JAK/STAT cell signaling without affecting signal activation and serum half-life. This study identified that genetically encoded IFN-β-A might stabilize the protein-receptor complex and trigger JAK-STAT cell signaling, which is a promising modality for controlling SARS-CoV-2 infection., (© 2023 Wiley Periodicals LLC.)

As COVID-19 cases begin to decrease in the USA, learning from the pandemic experience will provide insights regarding disparities of care delivery. We sought to determine if specific populations hospitalized with COVID-19 are equally likely to be enrolled in clinical trials. We examined patients hospitalized with COVID-19 at centers participating in the American Heart Association's COVID-19 CVD Registry. The primary outcome was odds of enrollment in a clinical trial, according to sex, race, and ethnicity. Among 14,397 adults hospitalized with COVID-19, 9.5% (n = 1,377) were enrolled in a clinical trial. The proportion of enrolled patients was the lowest for Black patients (8%); in multivariable analysis, female and Black patients were less likely to be enrolled in a clinical trial related to COVID-19 compared to men and other racial groups, respectively. Determination of specific reasons for the disparities in trial participation related to COVID-19 in these populations should be further investigated., (© 2022. W. Montague Cobb-NMA Health Institute.)

The Delta variant of SARS-CoV-2 has caused more severe infections than its previous variants. We studied the host innate immune response to Delta, Alpha, and two earlier variants to map the evolution of the recent ones. Our biochemical and transcriptomic studies in human colon epithelial cell line Caco2 reveal that Alpha and Delta have progressively evolved over the ancestral variants by silencing the innate immune response, thereby limiting cytokine and chemokine production. Though Alpha silenced the retinoic acid-inducible gene (RIG)-I-like receptor (RLR) pathway just like Delta did, it failed to persistently silence the innate immune response, unlike Delta. Both Alpha and Delta have evolved to resist interferon (IFN) treatment, while they are still susceptible to RLR activation, further highlighting the importance of RLR-mediated, IFN-independent mechanisms in restricting SARS-CoV-2. Our studies reveal that SARS-CoV-2 Delta has integrated multiple mechanisms to silence the host innate immune response and evade the IFN response. We speculate that Delta's silent replication and sustained suppression of the host innate immune response, thereby resulting in delayed or reduced intervention by the adaptive immune response, could have potentially contributed to the severe symptoms and poor recovery index associated with it. It is likely that this altered association with the host would play an important role in the coevolution of SARS-CoV-2 with humans. IMPORTANCE Viruses generally learn to coexist with the host during the process of evolution. It is expected that SARS-CoV-2 would also evolve to coexist in humans by trading off its virulence for longer persistence, causing milder disease. Clinically, the fatality associated with COVID-19 has been declining due to vaccination and preinfections, but the Delta variant caused the most severe disease and fatality across several parts of the world. Our study identified an evolving trend of SARS-CoV-2 variants where the variants that emerged during early parts of the pandemic caused a more robust innate immune response, while the later emerging variant Delta showed features of suppression of the response. The features that Delta has acquired could have strongly influenced the distinct pathophysiology associated with its infection. How these changed associations with the host influence the long-term evolution of the virus and the disease outcome should be closely studied to understand the process of viral evolution.

Background & Objectives: COVID-19 has been a global pandemic since early 2020. It has diverse clinical manifestations, but consistent immunological and metabolic correlates of disease severity and protection are not clear. This study was undertaken to compare seropositivity rate, antibody levels against nucleocapsid and spike proteins, virus neutralization and metabolites between adult and child COVID-19 patients., Methods: Plasma samples from naïve control (n=14) and reverse transcription (RT)-PCR positive COVID-19 participants (n=132) were tested for reactivity with nucleocapsid and spike proteins by ELISA, neutralization of SARS-CoV-2 infectivity in Vero cells and metabolites by [1] H nuclear magnetic resonance (NMR) spectroscopy., Results: An ELISA platform was developed using nucleocapsid and spike proteins for COVID-19 serosurvey. The participants showed greater seropositivity for nucleocapsid (72%) than spike (55.3%), and males showed higher seropositivity than females for both the proteins. Antibody levels to both the proteins were higher in intensive care unit (ICU) than ward patients. Children showed lower seropositivity and antibody levels than adults. In contrast to ICU adults (81.3%), ICU children (33.3%) showed lower seropositivity for spike. Notably, the neutralization efficiency correlated with levels of anti-nucleocapsid antibodies. The levels of plasma metabolites were perturbed differentially in COVID-19 patients as compared with the naive controls., Interpretation & Conclusions: Our results reflect the complexity of human immune response and metabolome to SARS-CoV-2 infection. While innate and cellular immune responses are likely to be a major determinant of disease severity and protection, antibodies to multiple viral proteins likely affect COVID-19 pathogenesis. In children, not adults, lower seropositivity rate for spike was associated with disease severity.

Neutralizing antibody-based passive immunotherapy could be an important therapeutic option against COVID-19. Herein, we demonstrate that equines hyper-immunized with chemically inactivated SARS-CoV-2 elicited high antibody titers with a strong virus-neutralizing potential, and F(ab') 2 fragments purified from them displayed strong neutralization potential against five different SARS-CoV-2 variants. F(ab') 2 fragments purified from the plasma of hyperimmunized horses showed high antigen-specific affinity. Experiments in rabbits suggested that the F(ab') 2 displays a linear pharmacokinetics with approximate plasma half-life of 47 h. In vitro microneutralization assays using the purified F(ab') 2 displayed high neutralization titers against five different variants of SARS-CoV-2 including the Delta variant, demonstrating its potential efficacy against the emerging viral variants. In conclusion, this study demonstrates that F(ab') 2 generated against SARS-CoV-2 in equines have high neutralization titers and have broad target-range against the evolving variants, making passive immunotherapy a potential regimen against the existing and evolving SARS-CoV-2 variants in combating COVID-19., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The coronavirus disease 2019 (COVID-19) pandemic has exposed longstanding racial and ethnic inequities in health risks and outcomes in the United States. We aimed to identify racial and ethnic differences in presentation and outcomes for patients hospitalized with COVID-19., Methods: The American Heart Association COVID-19 Cardiovascular Disease Registry is a retrospective observational registry capturing consecutive patients hospitalized with COVID-19. We present data on the first 7868 patients by race/ethnicity treated at 88 hospitals across the United States between January 17, 2020, and July 22, 2020. The primary outcome was in-hospital mortality. Secondary outcomes included major adverse cardiovascular events (death, myocardial infarction, stroke, heart failure) and COVID-19 cardiorespiratory ordinal severity score (worst to best: death, cardiac arrest, mechanical ventilation with mechanical circulatory support, mechanical ventilation with vasopressors/inotrope support, mechanical ventilation without hemodynamic support, and hospitalization alone. Multivariable logistic regression analyses were performed to assess the relationship between race/ethnicity and each outcome adjusting for differences in sociodemographic, clinical, and presentation features, and accounting for clustering by hospital., Results: Among 7868 patients hospitalized with COVID-19, 33.0% were Hispanic, 25.5% were non-Hispanic Black, 6.3% were Asian, and 35.2% were non-Hispanic White. Hispanic and Black patients were younger than non-Hispanic White and Asian patients and were more likely to be uninsured. Black patients had the highest prevalence of obesity, hypertension, and diabetes. Black patients also had the highest rates of mechanical ventilation (23.2%) and renal replacement therapy (6.6%) but the lowest rates of remdesivir use (6.1%). Overall mortality was 18.4% with 53% of all deaths occurring in Black and Hispanic patients. The adjusted odds ratios for mortality were 0.93 (95% CI, 0.76-1.14) for Black patients, 0.90 (95% CI, 0.73-1.11) for Hispanic patients, and 1.31 (95% CI, 0.96-1.80) for Asian patients compared with non-Hispanic White patients. The median odds ratio across hospitals was 1.99 (95% CI, 1.74-2.48). Results were similar for major adverse cardiovascular events. Asian patients had the highest COVID-19 cardiorespiratory severity at presentation (adjusted odds ratio, 1.48 [95% CI, 1.16-1.90])., Conclusions: Although in-hospital mortality and major adverse cardiovascular events did not differ by race/ethnicity after adjustment, Black and Hispanic patients bore a greater burden of mortality and morbidity because of their disproportionate representation among COVID-19 hospitalizations.

Background: In pandemic situations, it is essential that the limited resources are used judiciously to achieve most benefits. Prediction of the disease severity at the earliest will help in better allocation, thus, positively affecting prognosis and treatment. Aim and objective: To investigate patient characteristics and specific biomarkers as possible early predictors of disease severity of SARS-COV-2 infection. Materials and methods: Retrospective single-centric observational study conducted at 70-bedded intensive care unit of tertiary care hospital at Haryana, India. 100 consecutive RT-PCR positive coronavirus disease-2019 (COVID-19) adult patients. Demographics, acute physiology and chronic health evaluation II (Apache-II) score, and Inflammatory markers were compared with respect to oxygenation defect (PaO2/FiO2 ratio: <300 or ≥300 mm Hg), need of invasive ventilation, ICU length of stay and 28-day mortality. Findings: Mean age was significantly more in lower PF ratio group (58.01 ± 15.33 vs 50.97 ± 13.78, p = 0.023) whereas sex ratio was comparable among patients in two groups. Significantly, higher APACHE-II score (p ≤0.001) and presence of hypertension (43.54% vs 23.68%; p = 0·045) in low PF ratio group along with higher C-reactive protein (171.78 ± 124.45 vs 101.52 ± 88.70), IL-6 (173.51 vs 53.18) and ferritin (1677.60 ± 2271.13 vs 643.54 ± 718.68) levels. Procalcitonin, lactate dehydrogenase, and creatine phosphokinase (CPK) levels were not significant. Interpretation: Age and APACHE II score and among laboratory parameters CRP, ferritin, and IL-6 levels were significantly higher in low PF ratio group, patients requiring invasive ventilation and in mortality group. Use of this triad (CRP, ferritin, and IL-6 levels) at admission may predict the disease severity early in the course. Addition of APACHE-II may further improve the accuracy of the score. [ABSTRACT FROM AUTHOR]

There is little data describing trends in the use of hydroxychloroquine for COVID-19 following publication of randomized trials that failed to demonstrate a benefit of this therapy. We identified 13,957 patients admitted for active COVID-19 at 85 U.S. hospitals participating in a national registry between March 1 and August 31, 2020. The overall proportion of patients receiving hydroxychloroquine peaked at 55.2% in March and April and decreased to 4.8% in May and June and 0.8% in July and August. At the hospital-level, median use was 59.4% in March and April (IQR 48.5–71.5%, range 0–100%) and decreased to 0.3% (IQR 0–5.4%, range 0–100%) by May and June and 0% (IQR 0–1.3%, range 0–36.4%) by July and August. The rate and hospital-level uniformity in deimplementation of this ineffective therapy for COVID-19 reflects a rapid response to evolving clinical information and further study may offer strategies to inform deimplementation of ineffective clinical care. [ABSTRACT FROM AUTHOR]

COVID-19 and its associated disease control measures have greatly altered everyday life. The burden of these challenges has fallen disproportionately on women. Drawing on qualitative inquiry in agrarian north India and Nepal, this research note analyzes how South Asian COVID-19 lockdowns have affected women's labor responsibilities in sometimes surprising ways. We find increased responsibilities for caregiving within the household, substantial stress in responding to food insecurity, and growing expectations to fulfill public roles in disease response measures. However, we also find that the return of male migrants and youth has, in some cases, reduced women's farming responsibilities and created opportunities for household togetherness at a time of great uncertainty. We conclude that more research is needed to examine the nuanced aspects of COVID-19's gendered labor impacts to create comprehensive policy responses to address the multiple and sometimes conflicting effects the lockdown has had on agrarian women's informal labor and well-being. [ABSTRACT FROM AUTHOR]

The U.S. Food and Drug Administration (FDA) authorised the Rutgers University Clinical Genomics Laboratory and the Curative-Korva SARS-CoV-2 Assay (the Curative-Korva test) for diagnosis of SARS-Cov-2 in saliva samples [[1]]. Dear Editor, Salivary diagnostics has taken a major leap in infectious disease diagnosis with the SARS-CoV-2 pandemic. REFERENCES 1 Coronavirus (COVID-19) Update: FDA Authorizes First Diagnostic Test Using At-Home Collection of Saliva Specimens. [Extracted from the article]

• Large-scale virus cultures were established from patient VTM samples and using a dry-swab method. • BPL-mediated inactivation of SARS-CoV-2 affects the protein content of viral preparations. • Increasing concentrations of BPL reduce the antigenic potential and cause increased aggregation of viral particles as observed with DLS. • Viral RNA content correlated well with the antigenic content of the sample, but not with the infectious titer. Inactivated viral preparations are important resources in vaccine and antisera industry. Of the many vaccines that are being developed against COVID-19, inactivated whole-virus vaccines are also considered effective. β-propiolactone (BPL) is a widely used chemical inactivator of several viruses. Here, we analyze various concentrations of BPL to effectively inactivate SARS-CoV-2 and their effects on the biochemical properties of the virion particles. BPL at 1:2000 (v/v) concentrations effectively inactivated SARS-CoV-2. However, higher BPL concentrations resulted in the loss of both protein content as well as the antigenic integrity of the structural proteins. Higher concentrations also caused substantial aggregation of the virion particles possibly resulting in insufficient inactivation, and a loss in antigenic potential. We also identify that the viral RNA content in the culture supernatants can be a direct indicator of their antigenic content. Our findings may have important implications in the vaccine and antisera industry during COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

• We analyzed impacts of the COVID-19 lockdown on food and livelihood security in 16 villages in rural Himalayan India and Nepal. • Intensive qualitative enquiry reveals fear and uncertainty, food insecurity, and drastic reductions in livelihood opportunities. • However, diverse individual and collective responses, and a patchwork of policy support, have provided some basic security. • Local elected governments have played a critical role in coordinating responses and delivering social support. • Knowledge of vulnerability provides a foundation for analyzing the pandemic's long-term impacts and recovery. The global COVID-19 pandemic has brought unprecedented disruption to lives and livelihoods around the world. These disruptions have brought into sharp focus experiences of vulnerability but also, at times, evidence of resilience as people and institutions gear up to respond to the crisis. Drawing on intensive qualitative enquiry in 16 villages of Himalayan India and Nepal, this paper documents both dark and bright spots from the early days of the pandemic. We find intense experiences of fear and uncertainty, heightened food insecurity, and drastic reductions in livelihood opportunities. However, we also find a wide range of individual and collective responses as well as a patchwork of policy support mechanisms that have provided at least some measure of basic security. Local elected governments have played a critical role in coordinating responses and delivering social support, however the nature of their actions varies as a result of different institutional arrangements and state support systems in the two countries. Our findings highlight the changing nature of vulnerability in the present era, as demographic shifts, growing off-farm employment and dependence on remittances, and increasing market integration have all brought about new kinds of exposure to risk for rural populations in the context of the present disruption and beyond. Most importantly, our research shows the critical importance of strong systems of state support for protecting basic well-being in times of crises. Based on these findings, we argue that there is a need for greater knowledge of how local institutions work in tandem with a broader set of state support mechanisms to generate responses for urgent challenges; such knowledge holds the potential to develop governance systems that are better able to confront diverse shocks that households face, both now and in the future. [ABSTRACT FROM AUTHOR]