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

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.