Innate Immune Responses to Highly Pathogenic Coronaviruses and Other Significant Respiratory Viral Infections

Abstract

The new pandemic virus SARS-CoV-2 emerged in China and spread around the world in <3 months, infecting millions of people, and causing countries to shut down public life and businesses. Nearly all nations were unprepared for this pandemic with healthcare systems stretched to their limits due to the lack of an effective vaccine and treatment. Infection with SARS-CoV-2 can lead to Coronavirus disease 2019 (COVID-19). COVID-19 is respiratory disease that can result in a cytokine storm with stark differences in morbidity and mortality between younger and older patient populations. Details regarding mechanisms of viral entry via the respiratory system and immune system correlates of protection or pathogenesis have not been fully elucidated. Here, we provide an overview of the innate immune responses in the lung to the coronaviruses MERS-CoV, SARS-CoV, and SARS-CoV-2. This review provides insight into key innate immune mechanisms that will aid in the development of therapeutics and preventive vaccines for SARS-CoV-2 infection.

Keywords: COVID-19; Coronavirus (2019-nCoV) outbreak; Coronavirus (CoV); SARS-CoV-2; innate immune responses.

Figure 1

Potential Immune Pathogenesis of SARS-Cov-2. (A) Replication cycle of SARS-CoV-2: Spike protein on the SARS-CoV-2 binds to angiotensin converting enzyme 2 (ACE2), a cell-surface protein. The virion releases its RNA. Some RNA is translated into proteins by the host cell's machinery. Proteins and RNA are assembled into a new virion in the Golgi and released. (B) The innate and adaptive immune responses to Coronavirus (CoV) infection. (I). Initiation of immune response via PAMPs/DAMPS. The host innate immune system detects CoV infections by using pattern recognition receptors (PRRs) to recognize pathogen-associated molecular patterns (PAMPs) and Damage (Danger)-Associated Molecular Patterns (DAMPs). (II) Activation of T-cells and B-cells via cytokines and activation of the complement system. CoV infection leads to macrophages activation and release of inflammatory cytokines. This in turn activates T and B cells and promotes differentiation. Multiple different T cell subsets (i.e., Th1 and Th17) are involved, releasing cytokines for immune response amplification. (III) Activation of Neutrophils (NET formation) Neutrophils, attracted by chemokines/cytokines swarm to the site of infection. Subsequently activated neutrophils undergo degranulation and NET formation releasing intracellular DAMPs, DNA, histones, neutrophil elastase that activate the PRRs of surrounding immune and non-immune cells to induce cytokine secretion. Neutrophils and neutrophil extracellular traps (NETs) drive necroinflammation in COVID-19. The extracellular DNA released by NETs activates platelets and aggregated NETs provide a scaffold for binding of erythrocytes and activated platelets that promote thrombus formation. (IV) Dendritic Cell mediated activation of T-cells. DCs present viral antigens to T-cells inducing activation. (V) Cytokine and C5a led to influx of immune cells. Secrete chemokines, cytokines and complement C5a attract immune cells. (C) Effects of CoV-mediated complement activation. SARS-CoV-2 has been shown to activate the lectin (MBL) complement pathway. Antibodies (early stage IgM or at a later stage IgG) to the virus can activate the classic complement pathway. Both pathways converge at C3. C3 can be converted into C3a and C3b. C3b mediates pathogen opsonization and activates the conversion of C5 into C5a and C5b. C5b mediates the formation of the membrane attack complex, which leads to cell lysis. C3a and C5a promote immune cell recruitment to the site of infection.