Innate Immunity in Protection and Pathogenesis During Coronavirus Infections and COVID-19

Abstract

The COVID-19 pandemic was caused by the recently emerged β-coronavirus SARS-CoV-2. SARS-CoV-2 has had a catastrophic impact, resulting in nearly 7 million fatalities worldwide to date. The innate immune system is the first line of defense against infections, including the detection and response to SARS-CoV-2. Here, we discuss the innate immune mechanisms that sense coronaviruses, with a focus on SARS-CoV-2 infection and how these protective responses can become detrimental in severe cases of COVID-19, contributing to cytokine storm, inflammation, long-COVID, and other complications. We also highlight the complex cross talk among cytokines and the cellular components of the innate immune system, which can aid in viral clearance but also contribute to inflammatory cell death, cytokine storm, and organ damage in severe COVID-19 pathogenesis. Furthermore, we discuss how SARS-CoV-2 evades key protective innate immune mechanisms to enhance its virulence and pathogenicity, as well as how innate immunity can be therapeutically targeted as part of the vaccination and treatment strategy. Overall, we highlight how a comprehensive understanding of innate immune mechanisms has been crucial in the fight against SARS-CoV-2 infections and the development of novel host-directed immunotherapeutic strategies for various diseases.

Keywords: PANoptosis; RIPK; SARS-CoV-2; caspase; cell death; cytokine storm; inflammasome; inflammation.

Figure 1

Betacoronavirus genomic structures and SARS-CoV-2 viral life cycle and innate immune detection in COVID-19 pathology. (a) The generic genome structure is presented in the 5′ to 3′ direction. ORF1a encodes a polyprotein, pp1a, and a ribosomal frameshift produces pp1ab polyprotein from ORF1b, which then undergoes proteolysis by PLpro and Mpro to produce 16 nsp’s. The annotated and protein-coding regions of the genomes from related betacoronaviruses are compared, while excluding ORF1a and ORF1b, and the length of the RNA genomes along with the names of the representative viruses are indicated on the left. The RNA lengths are not drawn to scale. (b) Schematic depicting the replication cycle of SARS-CoV-2. SARS-CoV-2 S protein binds to ACE2 receptors on the target cells and is further proteolytically activated by TMPRSS2, which then leads to membrane fusion and release of the viral genome into the host cells. The viral genome (positive-sense single-stranded RNA) is immediately translated by host cells to release pp1a and pp1ab polyproteins. Upon proteolysis, pp1a and pp1ab release several nsp’s, which serve multiple functions, including assembly of the replication–transcription complex by inducing double membrane vesicles to evade immune recognition, modulation of host cellular compartments such as the ER and Golgi (ERGIC) for generation of new virions, and the extracellular release of virions via exocytosis. (c) An overview of the innate immune response and immunopathogenesis in COVID-19. SARS-CoV-2 first infects the epithelial cells in the respiratory tract and then replicates, and new virions are released. Along with virions, PAMPs, DAMPs, and immune modulators are also released. These released virions, PAMPs, DAMPs, and immune modulators can all be sensed by cells of the innate immune system to initiate a robust multilayered inflammatory immune response and activate adaptive immune responses to clear the infection. However, if the virus persists due to a delay or defect in the primary immune response, it can result in overt activation of different immune cells, followed by inflammatory cell death and a cytokine storm that leads to the development of ARDS and MIS, thus damaging vital organs and resulting in fatal outcomes. Abbreviations: ACE2, angiotensin-converting enzyme 2; ARDS, acute respiratory distress syndrome; DAMP, damage-associated molecular pattern; E, envelope; ER, endoplasmic reticulum; ERGIC, endoplasmic reticulum–Golgi intermediate compartment; IFN, interferon; M, membrane; MERS, Middle East respiratory syndrome; MHV, mouse hepatitis virus; MIS-A/C, multisystem inflammatory syndrome in adults/children; Mpro, main protease; N, nucleocapsid; nsp, nonstructural protein; ORF, open reading frame; PAMP, pathogen-associated molecular pattern; PLpro, papain-like protease; pp, polyprotein; RdRp, RNA-dependent RNA polymerase; S, spike; TMPRSS2, transmembrane protease, serine 2.

Figure 2

PRR signaling during SARS-CoV-2 infection. Intracellular and cell surface TLRs recognize different components of SARS-CoV-2. While the cell surface receptors TLR2 and TLR4 recognize envelope protein and spike protein, respectively, the intracellular, endosomal receptors TLR3, TLR7, and TLR8 sense viral RNA and antiphospholipid antibodies. This leads to the activation of innate immune signaling and the production of inflammatory cytokines, which can be beneficial while clearing the virus but can also be detrimental and lead to COVID-19 pathogenesis. RLRs, such as RIG-I and MDA5, sense PAMPs and DAMPs from SARS-CoV-2 infection, leading to the production of IFNs, which are beneficial early in infection but detrimental at later time points. Inflammasome sensors, such as different NLRs and AIM2, sense SARS-CoV-2-induced DAMPs and PAMPs, including viral RNA and spike and nucleocapsid proteins, leading to the formation of an inflammasome, the induction of inflammatory cell death, and the release of inflammatory cytokines that drive COVID-19 pathology. CLRs, such as DC-SIGN, L-SIGN, and LSECtin, recognize spike proteins from SARS-CoV-2 upon virus entry into the cell, which leads to the production of inflammatory cytokines and COVID-19 pathogenesis. Abbreviations: AIM2, absent in melanoma 2; CASP, caspase; CLR, C-type lectin receptor; DAMP, damage-associated molecular pattern; DC-SIGN, dendritic cell–specific intercellular adhesion molecule 3-grabbing non-integrin; IFN, interferon; LSECtin, liver sinusoidal endothelial cell lectin; L-SIGN, liver/lymph node–specific intercellular adhesion molecule-3-grabbing integrin; MDA5, melanoma differentiation-associated protein 5; NLR, nucleotide-binding oligomerization domain-like receptor; PAMP, pathogen-associated molecular pattern; PRR, pattern-recognition receptor; RIG-I, retinoic acid–inducible gene-I; RLR, RIG-I-like receptor; TLR, Toll-like receptor.

Figure 3

Inflammatory cell death in SARS-CoV-2 infection. PRRs located on the cell surface and in the cytosol lead to the upregulation of NLRs, inflammatory cytokines, and IFNs in response to SARS-CoV-2 infection. NLRP1, NLRP3, and AIM2 sense cytosolic DAMPs and PAMPs, which are released during SARS-CoV-2 infection, and form the inflammasome, leading to pyroptosis. IFNs signal in both paracrine and autocrine manners to upregulate hundreds of ISGs, including ZBP1, AIM2, and ISG15, among others. Upregulated ZBP1 may sense viral RNA from SARS-CoV-2 and form a multiprotein complex known as the ZBP1-PANoptosome, leading to PANoptosis. In addition, AIM2 may sense mitochondrial DNA, cell-free DNA, or endogenous DNA released during SARS-CoV-2 infection and form a multiprotein complex known as the AIM2-PANoptosome. These cytosolic multimeric cell death complexes activated downstream of PRR sensing in response to DAMPs and PAMPs lead to PANoptosis, an inflammatory form of cell death, and may contribute to host defense against SARS-CoV-2 infection. Abbreviations: AIM2, absent in melanoma 2; DAMP, damage-associated molecular pattern; IFN, interferon; ISG, interferon-stimulated gene; JAK1/2, Janus kinase 1/2; NLR, nucleotide-binding oligomerization domain-like receptor; NLRP1/3, NLR pyrin domain–containing 1/3; PAMP, pathogen-associated molecular pattern; PRR, pattern-recognition receptor; STAT, signal transducer and activator of transcription; ZBP1, Z-DNA-binding protein 1.

Figure 4

SARS-CoV-2 immune evasion mechanisms and therapeutic targeting. SARS-CoV-2 evades multiple steps of innate immune signaling (indicated by red blocking arrows), beginning from the initial sensing of the virus to the downstream signaling and upregulation of ISGs. For example, the viral protease 3CLpro and the structural proteins M and N directly inhibit RIG-I. Similarly, nsp3 (also known as PLpro) of SARS-CoV-2 inhibits MDA5. The viral protein ORF9b has far-reaching effects that are not fully illustrated here due to space constraints, and it interacts with multiple innate immune components such as RLR, TLR, and cGAS–STING pathways and their downstream effectors. Additionally, ORF9b blocks the polyubiquitination of IKKγ and phosphorylation of IRF-3 to abrogate NF-κB signaling and IFN induction. The cGAS pathway is also blocked by viral proteases, 3CLpro and ORF3a, at the level of STING activation. Moreover, many SARS-CoV-2 proteins, including nsp1, nsp6, nsp13, ORF3a, ORF7a, ORF7b, and N and M proteins inhibit STAT signaling, which is required for ISGF-3 complex formation and ISG expression. Several therapeutics have been repurposed to treat COVID-19 pathogenesis, and their points of action are indicated by blue activating or blocking arrows. RIG-I and STING agonists promote the production of IFNs and maintain the level of ISGs, which are crucial to restrict viral replication. JAK inhibitors such as baricitinib block signals from cytokine receptors, and baricitinib specifically is FDA approved for adult patients and has received EUA for pediatric patients with COVID-19. In addition, several inflammatory cytokine antagonists, such as infliximab (against TNF), anakinra (against IL-1R), and tocilizumab (against IL-6), have been used therapeutically. Abbreviations: 3CLpro, 3-chymotrypsin-like protease; cGAS, cyclic GMP-AMP synthase; EUA, emergency use authorization; FDA, US Food and Drug Administration; IFN, interferon; IKK, inhibitor of NF-κB kinase; IRF, interferon regulatory factor; ISG, interferon-stimulated gene; ISGF-3, interferon-stimulated gene factor 3; JAK, Janus kinase; LGP-2, laboratory of genetics and physiology 2; M, membrane protein; MDA5, melanoma differentiation-associated protein 5; N, nucleocapsid protein; NLR, nucleotide oligomerization domain-like receptor; NLRP3, NLR pyrin domain–containing 3; nsp, nonstructural protein; ORF, open reading frame; PLpro, papain-like protease; RIG-I, retinoic acid-inducible gene-I; RLR, RIG-I-like receptor; STAT, signal transducer and activator of transcription; STING, stimulator of interferon genes; TNF, tumor necrosis factor; TLR, Toll-like receptor; ZBP1, Z-DNA-binding protein 1.