Severe COVID-19 infection is associated with aberrant cytokine production by infected lung epithelial cells rather than by systemic immune dysfunction

Abstract

The mechanisms explaining progression to severe COVID-19 remain poorly understood. It has been proposed that immune system dysregulation/over-stimulation may be implicated, but it is not clear how such processes would lead to respiratory failure. We performed comprehensive multiparameter immune monitoring in a tightly controlled cohort of 128 COVID-19 patients, and used the ratio of oxygen saturation to fraction of inspired oxygen (SpO2 / FiO2) as a physiologic measure of disease severity. Machine learning algorithms integrating 139 parameters identified IL-6 and CCL2 as two factors predictive of severe disease, consistent with the therapeutic benefit observed with anti-IL6-R antibody treatment. However, transcripts encoding these cytokines were not detected among circulating immune cells. Rather, in situ analysis of lung specimens using RNAscope and immunofluorescent staining revealed that elevated IL-6 and CCL2 were dominantly produced by infected lung type II pneumocytes. Severe disease was not associated with higher viral load, deficient antibody responses, or dysfunctional T cell responses. These results refine our understanding of severe COVID-19 pathophysiology, indicating that aberrant cytokine production by infected lung epithelial cells is a major driver of immunopathology. We propose that these factors cause local immune regulation towards the benefit of the virus.

Antibody and T cell responses to COVID-19 vaccination in patients receiving anticancer therapies

“…No healthy control had a known SARS-CoV-2 infection prior to vaccination. Antibody levels from non-immunocompromised patients and patients with cancer who were unvaccinated and had a SARS-CoV-2 infection were used as a comparison; results from the non-immunocompromised/non-cancer infected patient cohort have previously been reported separately as end-point titers 29 and were reanalyzed as midpoint titers in this study. Infected patients all had a clinical positive diagnostic SARS-CoV-2 PCR test; 98% of infections occurred between March and June 2020.…”

Neutrophil sub-types in maintaining immune homeostasis during steady state, infections and sterile inflammation

“…Pre-clinical and clinical models have demonstrated two independent mechanisms for neutrophil activation during COVID-19 infections. SARS-CoV-2 infected alveolar epithelial cells release abundant levels of IL-6, IL-8, CXCL1 and CXCL2 resulting in the recruitment of neutrophils and in-turn, these activated neutrophils form extracellular traps and contribute to organ damage [ 82 , 83 ]. On the other hand, Veras et al showed higher concentrations of NETs components in plasma, tracheal aspirates and lung autopsies in COVID-19 subjects.…”

Autoimmunity, cancer and COVID-19 abnormally activate wound healing pathways: critical role of inflammation

“…Thus, the type I pneumocyte population can be depleted after type II cells are destroyed owing to the viral cytopathic effect. Type II cells infected by SARS-CoV-2 produce high levels of IL-6 (Gajewski et al 2021). The massive infection and subsequent inflammation-induced swelling also increase mechanic tension that stimulates production of TGF-β by type II pneumocytes.…”