COVID-19: immunopathogenesis and Immunotherapeutics

Abstract

The recent novel coronavirus disease (COVID-19) outbreak, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is seeing a rapid increase in infected patients worldwide. The host immune response to SARS-CoV-2 appears to play a critical role in disease pathogenesis and clinical manifestations. SARS-CoV-2 not only activates antiviral immune responses, but can also cause uncontrolled inflammatory responses characterized by marked pro-inflammatory cytokine release in patients with severe COVID-19, leading to lymphopenia, lymphocyte dysfunction, and granulocyte and monocyte abnormalities. These SARS-CoV-2-induced immune abnormalities may lead to infections by microorganisms, septic shock, and severe multiple organ dysfunction. Therefore, mechanisms underlying immune abnormalities in patients with COVID-19 must be elucidated to guide clinical management of the disease. Moreover, rational management of the immune responses to SARS-CoV-2, which includes enhancing anti-viral immunity while inhibiting systemic inflammation, may be key to successful treatment. In this review, we discuss the immunopathology of COVID-19, its potential mechanisms, and clinical implications to aid the development of new therapeutic strategies against COVID-19.

Fig. 1

The immunopathology of COVID-19. The immune patterns of COVID-19 include lymphopenia, lymphocyte activation and dysfunction, abnormalities of granulocytes and monocytes, increased production of cytokines, and increased antibodies. Lymphopenia is a key feature of patients with COVID-19, especially in severe cases. CD69, CD38, and CD44 are highly expressed on CD4⁺ and CD8⁺ T cells of patients, and virus-specific T cells from severe cases exhibit a central memory phenotype with high levels of IFN-γ, TNF-α, and IL-2. However, lymphocytes show an exhaustion phenotype with programmed cell death protein-1 (PD1), T cell immunoglobulin domain and mucin domain-3 (TIM3), and killer cell lectin-like receptor subfamily C member 1 (NKG2A) upregulation. Neutrophil levels are significantly higher in severe patients, while the percentage of eosinophils, basophils, and monocytes are reduced. Increased cytokine production, especially of IL-1β, IL-6, and IL-10, is another key characteristic of severe COVID-19. IgG levels are also increased and there is a higher titer of total antibodies

Fig. 2

Potential mechanisms of SARS-CoV-2-induced immunopathology. a The potential mechanisms of depletion and exhaustion of lymphocytes. (1) ACE2 receptor expression on lymphocytes, especially on T cells, promotes SARS-CoV-2 entry into lymphocytes. (2) A concomitant increase in inflammatory cytokine levels promotes the depletion and exhaustion of T cells. (3) SARS-CoV-2 directly damages lymphatic organs, including the spleen and lymph nodes, inducing lymphopenia. (4) Increased lactic acid levels inhibit the proliferation and dysfunction of lymphocytes. b Lymphopenia may lead to infection with microbe, further promoting the activation and recruitment of neutrophils in the blood. c The potential mechanisms of cytokine storm induction. (1) CD4⁺ T cells can be rapidly activated into Th1 cells that secret GM-CSF, further inducing CD14⁺CD16⁺ monocytes with high IL-6 levels. (2) An increase in the CD14⁺IL-1β⁺ monocyte subpopulation promotes increased IL-1β production. (3) Th17 cells produce IL-17 to further recruit monocytes, macrophages, and neutrophils and stimulate other cytokine cascades, such as IL-1β and IL-6 among others. d A neutralizing monoclonal antibody targeting the virus can enhance virus entry into cells via the Fc region of the antibody bound to the Fc receptor (FcR) on cells; this is correlated with disease progression and poor outcomes of patients with COVID-19

Fig. 3

Clinical implications of SARS-CoV-2-induced immunopathology. Patients with COVID-19 and presenting with lymphopenia are more prone to infections with the microbe, which leads to disease progression and increased severity. In addition, cytokine storms can initiate inflammatory-induced multiple organ dysfunction, including lung injury that can lead to ARDS, respiratory failure, liver injury with alanine aminotransferase (ALT), aspartate aminotransferase (AST), and γ-glutamine transferase (γ-GT) upregulation, kidney injury with increased urea and creatine levels, and heart injury with increased creatine kinase (CK) and lactate dehydrogenase (LDH) levels