Immune responses in mildly versus critically ill COVID-19 patients

Abstract

The current coronavirus pandemic (COVID-19), caused by SARS-CoV-2, has had devastating effects on the global health and economic system. The cellular and molecular mediators of both the innate and adaptive immune systems are critical in controlling SARS-CoV-2 infections. However, dysregulated inflammatory responses and imbalanced adaptive immunity may contribute to tissue destruction and pathogenesis of the disease. Important mechanisms in severe forms of COVID-19 include overproduction of inflammatory cytokines, impairment of type I IFN response, overactivation of neutrophils and macrophages, decreased frequencies of DC cells, NK cells and ILCs, complement activation, lymphopenia, Th1 and Treg hypoactivation, Th2 and Th17 hyperactivation, as well as decreased clonal diversity and dysregulated B lymphocyte function. Given the relationship between disease severity and an imbalanced immune system, scientists have been led to manipulate the immune system as a therapeutic approach. For example, anti-cytokine, cell, and IVIG therapies have received attention in the treatment of severe COVID-19. In this review, the role of immunity in the development and progression of COVID-19 is discussed, focusing on molecular and cellular aspects of the immune system in mild vs. severe forms of the disease. Moreover, some immune- based therapeutic approaches to COVID-19 are being investigated. Understanding key processes involved in the disease progression is critical in developing therapeutic agents and optimizing related strategies.

Keywords: COVID-19; SARS-CoV-2; T cells; antibodies; cytokine storm; immune response; inflammation; therapeutic targets.

Figure 1

The frequency and function of innate immune cells in severe COVID-19. SARS-CoV-2 infects cells that present the surface receptor ACE2. It is recognized by tissue-resident immune cells in the lungs, which provoke a local immune response. More innate immune cells are recruited from the blood by chemokines and complement activation products. The amounts of neutrophils, CD16⁺ monocytes, M1 macrophages and MDSCs are bigger in severe COVID-19 patients, while the percentages of basophils, eosinophils, M2 macrophages, classical monocytes, DCs, ILCs, NK cells and unconventional T cells are reduced. Activated neutrophils can amplify inflammation by secretion of pro-inflammatory cytokines, MPO, elastase and defensins. They can also promote NET formation and Th17 cell differentiation. Activated basophils and eosinophils appear to predispose the development of ARDS by releasing inflammatory and vasoactive substances. Peripheral CD16⁺ monocytes and M1 macrophages are involved in a hyper-inflammatory response and cytokine storm during the inflammatory phase in severe COVID-19. Significant decrease in viral sensing and IFN signaling as well as suppressed antigen presentation by both pDC and cDC have been reported in severe COVID-19. Aberrant or ineffective responses of ILCs (ILC1, ILC2, ILC3 and NK cells), MDSCs and unconventional T cells (MAIT cells, γδ T cells) also have role in promoting inflammation in severe COVID-19. ACE2, Angiotensin-converting enzyme 2; MDSCs, Myeloid-derived suppressor cells; DC, Dendritic cell; ILCs, Innate-like lymphocyte; NK cell, Natural killer cell; MPO, Myeloperoxidase; NET, Neutrophil extracellular trap; Th, T helper; ARDS, Acute respiratory distress syndrome; MAS, Macrophage activation syndrome; PD-L1, Programmed cell death ligand 1; IFN: Interferon; cDC, Classical DC; pDC, Plasmacytoid DCiNOS, Inducible nitric oxide synthase; PMN-MDSCs, Polymorphonuclear-MDSCs; M-MDSCs, Monocytic-MDSCs; ADCC, antibody-dependent cellular cytotoxicity; NKG2A, NK cell lectin-like receptor subfamily C member 1. Figure was created by BioRender (Toronto, ON, Canada).

Figure 2

Cell-mediated immune responses during COVID-19 progression in mild versus severe disease. (A) Dendritic cells (DCs) promote activation of T cell responses by presentation of SARS-CoV-2 antigenic peptides in major histocompatibility complex (MHC) molecules along with costimulatory interactions and the secretion of chemokines and cytokines. T cell responses can mainly be polarized into T helper (Th) cells and effector cytotoxic cells (CTLs). In mild COVID-19, a higher proportion of Th1 cells plays an important role in defense against the virus by producing interleukin-2 (IL-2) and interferon-gamma (IFN-γ). Th1 cells and the cytokines they secrete activate macrophages, CTLs and natural killer (NK) cells. The Th2 cells stimulate the humoral response and activate eosinophils, basophils and mast cells through IL-4 and IL-5 secretion. The T follicular helper (Tfh) cells are essential for the formation of germinal centers (GCs), B cell maturation and immunoglobulin (Ig) production. CD8⁺ T cells, which coordinate the protective antiviral activities in COVID-19, secrete cytotoxic granules containing perforin and granzyme B as well as IFN-γ in patients who developed mild disease. (B) Lymphopenia is a hallmark feature of patients with severe COVID-19. This may be the result of the migration of enormous numbers of T cells to the lungs and other sites of inflammation. Both CD4⁺ and CD8⁺ T cells express strongly CD69, CD38, CD45RO, CD44, HLA-DR, programmed cell death protein-1 (PD-1), T cell immunoglobulin domain and mucin domain-3 (TIM-3) and killer cell lectin-like receptor subfamily C member 1 (NKG2A), which can represent hyperactivated, exhausted or a hypoactivated state of T cells in severe patients. Furthermore, the numbers and functions of regulatory T cells (Treg) are significantly reduced in these patients. Smaller proportions of CD4⁺ and/or CD8⁺ effector cells (CD45RO⁺ CD45RA⁻ CCR7⁻CD28⁻ CD62L^low), central memory cells (CD45RO⁺ CD45RA⁻ CCR7⁺ CD28⁺) and tissue-resident memory (CD69⁺ CD103⁺ CD49a⁺) T cells were demonstrated in severe COVID-19 patients. Figure was created by BioRender (Toronto, ON, Canada).

Figure 3

Humoral immune responses during COVID-19 progression in mild versus severe disease. (A) During mild COVID-19, B cells contribute to antiviral immune responses in many ways. The first is through production of neutralizing antibodies (Abs), which will bind to the virion and block its entry to the host cells, thus impeding further infection. The second is through a process called antibody-dependent cellular cytotoxicity (ADCC), in which Fc receptor-bearing effector cells can recognize and kill antibody-coated target cells expressing pathogen-derived antigens. The third is through antigen presentation to T cells and activation of cell-mediated immunity. B cells also produce some cytokines to regulate inflammation and activation of adaptive responses. Lastly, B cells can differentiate into antibody-secreting plasma cells, which produce high affinity and class-switched Abs. (B) B cell immune responses in severe COVID-19 may exacerbate disease progression by excessive secretion of cytokines and production of autoantibodies. As an adverse effect anti-viral antibodies can facilitate the entry of virus into monocytes/macrophages and granulocytic cells through interaction with Fc and/or complement receptors in a process that is called antibody dependent enhancement (ADE). In addition, increased clonal expansion of B cells, higher frequency of plasmablasts as well as reduced frequency of CD24⁺ switched and CD24^-CD27⁺ IgD⁺ IgM⁺ unswitched memory B cells have been reported in severe COVID-19 cases. Figure was created by BioRender (Toronto, ON, Canada).