Innate immunity: the first line of defense against SARS-CoV-2

Abstract

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2, continues to cause substantial morbidity and mortality. While most infections are mild, some patients experience severe and potentially fatal systemic inflammation, tissue damage, cytokine storm and acute respiratory distress syndrome. The innate immune system acts as the first line of defense, sensing the virus through pattern recognition receptors and activating inflammatory pathways that promote viral clearance. Here, we discuss innate immune processes involved in SARS-CoV-2 recognition and the resultant inflammation. Improved understanding of how the innate immune system detects and responds to SARS-CoV-2 will help identify targeted therapeutic modalities that mitigate severe disease and improve patient outcomes.

Figure 1.. Clinical manifestations of COVID-19.

SARS-CoV-2 infection affects several body systems, including the cardiovascular, gastro-intestinal, nervous, vascular/lymphatic, rheumatological systems and others.

Figure 2.. SARS-CoV-2 viral entry.

On most cells, SARS-CoV-2 spike protein (S) binds to the cell surface and its cognate receptor angiotensin-converting enzyme 2 (ACE2). The host transmembrane protease serine 2 (TMPRSS2) helps mediate entry by cleaving S. Other potential host receptors and co-factors have been implicated in this process, including neuropilin-1, heparin sulfate proteoglycans, C-type lectins and/or furin. The virion enters through membrane fusion or endocytosis. After entry, the viral RNA is released and translated into the viral polyproteins pp1a and pp1ab. These polyproteins are processed by virus-encoded proteases to facilitate replication and produce the full-length negative-strand RNA and subgenomic RNA. The subgenomic RNA is translated into the structural and accessory proteins, including S, membrane (M), envelope (E) and nucleocapsid (N). The structural proteins are inserted into the endoplasmic reticulum (ER) and Golgi membranes and transverse to the ER-Golgi intermediate compartment (ERGIC), where the virions can assemble. Fully formed virions are exocytosed.

Figure 3.. Putative activation of PRR signaling during SARS-CoV-2 infection based on current data.

Pattern recognition receptors (PRRs) on the cell surface and endosomal membranes and in the cytosol may respond to SARS-CoV-2 pathogen-associated molecular patterns (PAMPs) to activate innate immune signaling pathways. Toll-like receptors (TLRs) 1, 2, 4 and 6 can signal through MyD88 to activate the NF-κB and MAPK signaling pathways to induce the transcription of pro-inflammatory cytokines and other sensors. TLR3 and 4 can signal through TRIF to activate IRF3 and induce the expression of type I and type III IFNs. Strong experimental evidence supports SARS-CoV-2–mediated activation of TLR2, while activation of TLR1, 3, 4 and 6 has been suggested bioinformatically and through associative studies. Signaling through RIG-I, MDA5 and STING also activates IRF3 and type I and type III IFN production. Data regarding the activation of RIG-I during SARS-CoV-2 infection remain mixed. NLRP3 inflammasome formation also can occur in response to SARS-CoV-2 infection, leading to cleavage of gasdermin D (GSDMD) to form membrane pores and release IL-1β and IL-18 and induce pyroptosis. Red question marks indicate sensors that are expected to be involved in SARS-CoV-2 sensing but that have not been experimentally validated to date.

Figure 4.. PANoptosis and cytokine storm during SARS-CoV-2 infection.

The induction of innate immune signaling during SARS-CoV-2 infection leads to the production of pro-inflammatory cytokines. TNF and IFN-γ induce a form of inflammatory cell death called PANoptosis, which is mediated through the formation of a multiprotein complex called the PANoptosome. TNF and IFN-γ–mediated PANoptosis can lead to a cytokine storm loop, featuring further pathogenic cytokine release that can perpetuate PANoptosis as well as systemic inflammation, multi-organ failure and lethality.