The Innate Immune System: Fighting on the Front Lines or Fanning the Flames of COVID-19?

Abstract

The coronavirus disease 2019 (COVID-19) pandemic caused by SARS-CoV-2 has had devastating global impacts and will continue to have dramatic effects on public health for years to come. A better understanding of the immune response to SARS-CoV-2 will be critical for the application and development of therapeutics. The degree to which the innate immune response confers protection or induces pathogenesis through a dysregulated immune response remains unclear. In this review, we discuss what is known about the role of the innate immune system during SARS-CoV-2 infection, suggest directions for future studies, and evaluate proposed COVID-19 immunomodulating therapeutics.

Keywords: COVID-19; SARS-CoV-2; complement; cytokines; innate immune response; myeloid cells; natural killer cells.

Figure 1

The Peripheral Innate Immune Response to Severe SARS-CoV-2 Infection Some peripheral CD14⁺ monocytes have an inflammatory phenotype and secrete T cell-activating cytokines, whereas others have decreased HLA class II expression, which could result in decreased antigen presentation to naive T cells. Monocytes and activated granulocytes, such as neutrophils, might phagocytose or degranulate in response to opsonized infected cells. Prior to exhaustion, NK cells might kill infected cells via direct killing or ADCC. Although a decrease in the abundance of DCs is reported, the behavior of DCs is currently unknown. Solid lines represent interactions that have been reported. Dashed lines represent interactions that have not been reported and warrant future studies. Abbreviations: DC, dendritic cell; NK cell, natural killer cell; ADCC, antibody-dependent cellular cytotoxicity.

Figure 2

The Innate Immune Response to Severe SARS-CoV-2 Infection of the Lung There are increased levels of both inflammatory macrophages and activated neutrophils in the lung. Inflammatory macrophages secrete IL-1β, activating T cells. Activated DCs are also present and likely take up viral antigens to present to naive T cells. NK cells, inflammatory macrophages, and activated neutrophils could kill infected type II alveolar epithelial cells by a variety of mechanisms. Additionally, formation of the MAC might also result in lysis of infected cells. Complement proteins and chemokines produced by lung epithelial cells and other cell types at the site of infection recruit additional immune cells. Solid lines represent interactions that have been reported. Dashed lines represent interactions that have not been reported and warrant future studies. Abbreviations: DC, dendritic cell; NK cell, natural killer cell; MAC, complement membrane attack complex.