Innate immunology in COVID-19—a living review. Part II: dysregulated inflammation drives immunopathology

Abstract

The current pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a global health crisis and will likely continue to impact public health for years. As the effectiveness of the innate immune response is crucial to patient outcome, huge efforts have been made to understand how dysregulated immune responses may contribute to disease progression. Here we have reviewed current knowledge of cellular innate immune responses to SARS-CoV-2 infection, highlighting areas for further investigation and suggesting potential strategies for intervention. We conclude that in severe COVID-19 initial innate responses, primarily type I interferon, are suppressed or sabotaged which results in an early interleukin (IL)-6, IL-10 and IL-1β-enhanced hyperinflammation. This inflammatory environment is driven by aberrant function of innate immune cells: monocytes, macrophages and natural killer cells dispersing viral pathogen-associated molecular patterns and damage-associated molecular patterns into tissues. This results in primarily neutrophil-driven pathology including fibrosis that causes acute respiratory distress syndrome. Activated leukocytes and neutrophil extracellular traps also promote immunothrombotic clots that embed into the lungs and kidneys of severe COVID-19 patients, are worsened by immobility in the intensive care unit and are perhaps responsible for the high mortality. Therefore, treatments that target inflammation and coagulation are promising strategies for reducing mortality in COVID-19.

On Deep Landscape Exploration of COVID-19 Patients Cells and Severity Markers

“…Our data analysis revealed massive recruitment of T cells in the alveolar compartment for moderate patients ( Figure 1C ). T cells promote the recruitment and activation of monocyte-derived inflammatory macrophages leading to a positive loop of immune overactivation and mass migration to the lungs, contributing to tissue damage ( 156 , 157 ). Moreover, their role in the disease severity remains unknown.…”

SARS-CoV-2 Variants, Vaccines, and Host Immunity

“…Monocytes, macrophages, neutrophils, NK cells, and DCs have been implicated as key contributors to the hyperinflammation observed in COVID-19 patients with severe disease. The dysregulated function of these cells that results in over-production of cytokines and the viral mechanisms leading to these outcomes has been extensively reviewed (18,(21)(22)(23)(24)(25)(26). However, their contribution to the acute innate response that leads to successful SARS-CoV-2 control remains poorly understood.…”

Pattern Recognition Proteins: First Line of Defense Against Coronaviruses

“…Excessive cytokine production during cytokine storm in SARS-CoV-2 infection causes severe tissue damage and organ failure (245,246). Neutrophils produce a network of fibers containing webs of chromatin, microbicidal proteins, and oxidant enzymes called neutrophil extracellular traps (NETs) that contain infections, but when not properly regulated, NETs can propagate inflammation and vascular thrombosis (247)(248)(249)(250)(251)(252)(253)(254)(255)(256)(257)(258)(259)(260)(261)(262)(263). Extracellular traps are not limited to neutrophils but include eosinophils, basophils and mast cells (264) (Figure 11).…”