Comparative progress on the mechanisms of airway mucosal injury induced by different pathogens: SARS-CoV-2, influenza A virus, and Mycoplasma pneumoniae.

Respiratory infectious diseases remain a major global public health challenge. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), Influenza A Virus (IAV), and Mycoplasma pneumoniae (MP), as three representative respiratory pathogens, all clinically cause airway epithelial shedding, ciliary dysfunction, and Acute Respiratory Distress Syndrome (ARDS). Notably, they are the common triggers of acute respiratory infections characterized by persistent and severe cough, a clinical hallmark rooted in the structural disintegration of the airway mucosal barrier. However, the molecular mechanisms by which they compromise the airway mucosal barrier exhibit significant heterogeneity. Currently, there is a paucity of systematic reviews offering a comparative analysis between these viral and atypical bacterial pathogens. This review comprehensively examines the pathogenic mechanisms of these three agents across four dimensions: receptor recognition, direct cytotoxicity, immunopathology, and abnormal tissue repair. Studies indicate that during the invasion phase, SARS-CoV-2 relies on the Angiotensin-converting enzyme 2 (ACE2) receptor and Transmembrane protease, serine 2 (TMPRSS2) -mediated membrane fusion; IAV identifies sialic acid receptors via hemagglutinin, whereas MP utilizes specialized attachment organelles for "gliding" colonization. Regarding cellular injury mechanisms, SARS-CoV-2 primarily hijacks the endoplasmic reticulum (ER) to induce stress responses and promote syncytium formation; IAV predominantly targets mitochondria to trigger apoptosis and cellular necrosis; while MP utilizes hydrogen peroxide and Community-Acquired Respiratory Distress Syndrome (CARDS) toxin to implement oxidative damage and vacuolating toxicity. At the immunopathological level, SARS-CoV-2-induced delayed interferon response and cytokine storm, IAV-triggered excessive formation of neutrophil extracellular traps (NETs), and MP-mediated activation of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome are key drivers exacerbating airway injury. Furthermore, distinct acute injury mechanisms determine differentiated long-term prognoses, such as pulmonary fibrosis, airway hyperresponsiveness, and airway remodeling. In summary, elucidating the commonalities and specificities of these mechanisms has significant clinical guidance value for precisely distinguishing clinical phenotypes, predicting disease progression, and developing host-directed therapies targeting specific injury pathways.