Binge drinking alcohol and circadian misalignment in night shift nurses is associated with decreased resiliency to COVID-19 infection

Background: Nurses and other first responders are at high risk of exposure to the SARS-CoV2 virus, and many have developed severe COVID-19 infection. A better understanding of the factors that increase the risk of infection after exposure to the virus could help to address this. Although several risk factors such as obesity, diabetes, and hypertension have been associated with an increased risk of infection, many first responders develop severe COVID-19 without established risk factors. As inflammation and cytokine storm are the primary mechanisms in severe COVID-19, other factors that promote an inflammatory state could increase the risk of COVID-19 in exposed individuals. Alcohol misuse and shift work with subsequent misaligned circadian rhythms are known to promote a pro-inflammatory state and thus could increase susceptibility to COVID-19. To test this hypothesis, we conducted a prospective, cross-sectional observational survey-based study in nurses using the American Nursing Association network. Method(s): We used validated structured questionnaires to assess alcohol consumption (the Alcohol Use Disorders Identification Test) and circadian typology or chronotype (the Munich Chronotype Questionnaire Shift -MCTQ-Shift). Result(s): By latent class analysis (LCA), high-risk features of alcohol misuse were associated with a later chronotype, and binge drinking was greater in night shift workers. The night shift was associated with more than double the odds of COVID-19 infection of the standard shift (OR 2.67, 95% CI: 1.18 to 6.07). Binge drinkers had twice the odds of COVID-19 infection of those with low-risk features by LCA (OR: 2.08, 95% CI: 0.75 to 5.79). Conclusion(s): Working night shifts or binge drinking may be risk factors for COVID-19 infection among nurses. Understanding the mechanisms underlying these risk factors could help to mitigate the impact of COVID-19 on our at-risk healthcare workforce.Copyright © 2023 The Authors. Alcohol: Clinical and Experimental Research published by Wiley Periodicals LLC on behalf of Research Society on Alcohol.

SIGLEC-9 RESTRAINS ANTIBODY-DEPENDENT NK CELL CYTOTOXICITY AGAINST SARS-CoV-2

Background: SARS CoV 2 infection alters the immunological profiles of natural killer (NK) cells. However, whether NK anti-viral functions (direct cytotoxicity and/or antibody-dependent cell cytotoxicity (ADCC)) are impaired during severe COVID-19 and what host factors modulate these functions remain unclear. Method(s): Using functional assays, we examined the ability of NK cells from SARS-CoV-2 negative controls (n=12), mild COVID-19 patients (n=26), and hospitalized COVID-19 patients (n=41) to elicit direct cytotoxicity and ADCC [NK degranulation by flow] against cells expressing SARS-CoV-2 antigens. SARS-CoV- 2 N antigen plasma load was measured using an ultra-sensitive Simoa assay. We also phenotypically characterized the baseline expression of NK activating (CD16 and NKG2C), maturation (CD57), and inhibitory (NKG2A and the glyco-immune negative checkpoint Siglec-9) by flow cytometry. Finally, an anti-Siglec-9 blocking antibody was used to examine the impact of Siglec-9 expression on anti-SARS-CoV-2-specific ADCC [degranulation and target cell lysis]. Result(s): NK cells from hospitalized COVID-19 patients degranulate less against SARS-CoV-2-antigen-expressing cells (in direct cytolytic and ADCC assays) than did cells from mild COVID-19 patients or negative controls (Fig. 1A). The lower NK degranulation was associated with higher plasma levels of SARS-CoV-2 N-antigen (P<=0.02). Phenotypic and functional analyses showed that NK cells expressing Siglec-9 elicited higher ADCC than Siglec-9- NK cells (P<0.05;Fig. 1B). Consistently, Siglec-9+ NK cells expressed an activated and mature phenotype with higher expression of CD16, CD57, and NKG2C, and lower expression of NKG2A, than Siglec-9- NK cells (P<=0.03). These data are consistent with the concept that the NK cell subpopulation expressing Siglec-9 is highly activated and cytotoxic. However, the Siglec-9 molecule itself is an inhibitory receptor that restrains NK cytotoxicity during cancer and other infections. Indeed, blocking Siglec-9 significantly enhanced the ADCC-mediated NK degranulation and lysis of SARS-CoV-2-antigen-positive target cells (P<=0.05;Fig. 1C). Conclusion(s): These data support a model (Fig. 1D) in which the Siglec-9+ CD56dim NK subpopulation is cytotoxic even while being restrained by the inhibitory effects of Siglec-9. However, alleviating the Siglec-9-mediated restriction on NK cytotoxicity can further improve NK immune surveillance and presents an opportunity to develop novel immunotherapeutic tools against SARS-CoV-2 infected cells. (Figure Presented).

Severe COVID-19 is fueled by disrupted gut barrier integrity

Background: A disruption of the crosstalk between gut and lung has been implicated as a driver of severity during several respiratory-related diseases. Lung injury causes systemic inflammation, which disrupts gut barrier integrity, increasing the permeability to gut microbes and their products. This exacerbates inflammation, resulting in positive feedback. We applied a multi-omic systems biology approach to investigate the potential link between loss of gut barrier integrity and Coronavirus disease 2019 (COVID-19) severity. Methods: We analyzed plasma samples from age and gender-matched COVID-19 patients (n=60) with varying disease severity (mild, moderate, and severe) and 20 SARS-CoV2 negative controls. We measured markers and drivers of tight junction permeability and microbial translocation using ELISA;inflammation and immune activation markers using ELISA and multiplex cytokine arrays;untargeted metabolomic and lipidomic analyses using mass spectrometry;and plasma glycomes using capillary electrophoresis and lectin microarray. False discovery rate (FDR) was calculated to account for multiple comparisons. Results: Our data indicate, first, that severe COVID-19 is associated with a dramatic increase in the level of zonulin (FDR<0.00001), the only known physiological driver of intestinal tight junction permeability. This increased permeability associated with translocation of both bacterial (LPS binding protein (LBP) levels) and fungal (β-glucan levels) products into blood (FDR<0.01). The degree of intestinal permeability and microbial translocation strongly correlated with increased systemic inflammation (correlations with IL-6 and other inflammatory cytokines and markers) (FDR>0.05). Second, levels of metabolomic and lipidomic markers of gut and gut microbiota functionality including citrulline (a marker of healthy gut;decreased), succinic acid, and tryptophan catabolism metabolites (markers of microbial dysbiosis;increased) were disrupted during severe COVID-19 (FDR<0.05). Finally, the gut microbiome is known to release enzymes that degrade plasma glycans, which regulate inflammation and complement activation. Indeed, severe COVID-19 was associated with loss of the anti-complement activation galactosylated glycans from plasma and IgG glycoproteins (FDR<0.05). Conclusion: Our data provide multiple layers of evidence that a previously unappreciated factor with significant clinical implications, disruption in gut barrier integrity, is a potential force that contributes to COVID-19 severity.