SARS-CoV-2 innate immune recognition and implications for respiratory health

Abstract

The ongoing global health impact of SARS-CoV-2, particularly on lung and respiratory health, underscores the critical need to decipher the intricate interplay between the virus and the host innate immune system. This review provides an analysis of the key pattern recognition receptors (PRRs) involved in SARS-CoV-2 recognition within the lung, including toll-like receptors (TLRs), RIG-I-like receptors (RLRs), NOD-like receptors (NLRs), and C-type lectin receptors (CLRs). We discuss how the engagement of these innate sentinels triggers crucial downstream consequences, ranging from protective antiviral interferon (IFN) responses to detrimental hyperinflammation characteristic of severe COVID-19. Numerous studies have identified sophisticated mechanisms employed by SARS-CoV-2 to evade or suppress early IFN induction, contributing to unchecked viral replication and subsequent immunopathology. We explore how this aberrant innate immune response drives the "cytokine storm", leading to acute respiratory distress syndrome (ARDS) and long-term sequelae. Furthermore, this review critically assesses current and emerging therapeutic strategies aimed at modulating innate immunity, including TLR agonists/antagonists, RIG-I/MDA5 modulators, NLRP3 inflammasome inhibitors, and IFN-based therapies, highlighting their potential and associated challenges. Finally, we identify key research gaps, emphasizing the need for cell-type-specific PRR studies, comprehensive mapping of viral evasion mechanisms, and the development of precision immunotherapies to enhance protective responses and mitigate pathogenic inflammation for future respiratory viral threats.

Keywords: COVID-19 Pathogenesis; Cytokine Storm; Innate Immunity; Interferon (IFN) Response; Pattern Recognition Receptors (PRRs); Respiratory Health; SARS-CoV-2.

Fig. 1.

Dynamic interplay between SARS-CoV-2 and the host innate immune system in the lung. (A). Spike (S) and Envelope (E) proteins of SARS-CoV-2 are detected by surface Toll-like receptors (TLRs), TLR4 and TLR2; endosomal TLRs, TLR3, TLR7, and TLR8 on alveolar epithelial cells (AECs). These sensors activate MyD88 and TIR domain containing adaptor molecule 1 (TRIF), respectively, leading to NF-κB and IRF3/7 activation, resulting in the production and pro-inflammatory cytokines and type I interferons (IFN-I). (B) The virus enters the AECs via ACE2 and TMPRSS2. Viral RNA intermediates are recognized by cytosolic RIG-I-like receptors (RLRs), RIG-I and MDA5. These sensors activate IRF3/7 and lead to the production of IFN-I. SARS-CoV-2 employs multiple strategies to evade and suppress host antiviral defenses: N protein and Nsp5 cleave RLR adaptor components such as mitochondria anti-viral signaling (MAVS), and Nsp16 is involved in modifying viral RNA to evade recognition by RIG-I and MDA-5. M protein interaction with MAVS disrupts downstream signaling. Nsp6 and Nsp13 interact with the MAVS-IRF3 signaling cascade, thereby limiting IRF3 activation. ORF6 and Nsp13 impede the nuclear translocation of IRF3. (C) In alveolar macrophages, N protein, ORF3, and Nsp5 activate the NLRP3 inflammasome, promoting maturation and secretion of IL-1β and IL-18.

Fig. 2.

Therapeutic targeting of innate immune and inflammatory pathways during SARS-CoV-2 infection. Alveolar epithelial cells release DAMPs (Damage-associated molecular patterns) such as High Mobility Group Box 1 (HMGB1) and mitochondrial DNA (mtDNA). These DAMPs create a self-perpetuating pathogenic loop by engaging TLR2/4 (on the endothelium) and the NLRP3 inflammasome (in alveolar macrophages), leading to massive and uncontrolled production of pro-inflammatory cytokines. Additionally, DAMPs-driven activation massively amplifies the release of a diverse array of pro-inflammatory cytokines (IL-17A, IL-18, IL-1β, TNF-α, IL-6) and type I/III interferons. This leads to a cytokine storm, which drives systemic inflammation and multi-organ failure. The figure also highlights key therapeutic intervention points (marked by T in red circle) targeting pro-inflammatory cytokines, the JAK/STAT signaling pathway, DAMP sensors (TLR2/4 and NLRP3), TLR receptor inhibitors, and type I/III IFNs, to break this hyper-inflammatory feedback loop.