COVID-19 Severity Is Associated with Differential Antibody Fc-mediated Innate Immune Functions

Beyond neutralization, antibodies elicit several innate immune functions including complement deposition (ADCD), phagocytosis (ADCP), and cytotoxicity (ADCC). These functions can be both beneficial (by clearing pathogens) and/or detrimental (by inducing inflammation). We tested the possibility that qualitative differences in SARS-CoV-2 specific antibody-mediated innate immune functions contribute to Coronavirus disease 2019 (COVID-19) severity. We found that antibodies from hospitalized COVID-19 patients elicited higher ADCD but lower ADCP compared to antibodies from non-hospitalized COVID-19 patients. Consistently, higher ADCD was associated with higher systemic inflammation during COVID-19. Our study points to qualitative, differential features of anti-SARS-CoV-2 antibodies as potential contributors to COVID-19 severity.

Severe COVID-19 Is Fueled by Disrupted Gut Barrier Integrity

A disruption of the crosstalk between the gut and the lung has been implicated as a driver of severity during 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 aimed to test whether severe Coronavirus disease 2019 (COVID-19) is associated with markers of disrupted gut permeability. We applied a multi-omic systems biology approach to analyze plasma samples from COVID-19 patients with varying disease severity and SARS-CoV-2 negative controls. We investigated the potential links between plasma markers of gut barrier integrity, microbial translocation, systemic inflammation, metabolome, lipidome, and glycome, and COVID-19 severity. We found that severe COVID-19 is associated with high levels of markers of tight junction permeability and translocation of bacterial and fungal products into the blood. These markers of disrupted intestinal barrier integrity and microbial translocation correlate strongly with higher levels of markers of systemic inflammation and immune activation, lower levels of markers of intestinal function, disrupted plasma metabolome and glycome, and higher mortality rate. Our study highlights an underappreciated factor with significant clinical implications, disruption in gut functions, as a potential force that may contribute to COVID-19 severity.