Abstract
<jats:p>Respiratory viral infections are a major cause of global morbidity and mortality, partly because they increase susceptibility to secondary bacterial pneumonia and sepsis. Coronaviruses, influenza viruses, parainfluenza viruses, rhinoviruses, and respiratory syncytial virus have each been associated with impaired macrophage antibacterial function, although the underlying evidence differs among virus families. Direct lysosomal-pH measurements and mechanistically resolved links between infection and lysosomal de-acidification are strongest for coronaviruses. Using β-coronaviruses as the primary model for the effect of direct lysosomal disruption on macrophage antimicrobial capacity, this review examines lysosomal exploitation during viral egress, impaired phagosome-lysosome fusion, E-protein-mediated proton conductance, and ORF3a-associated lysosomal injury. It further proposes that the magnitude of these effects is shaped by host-dependent immunometabolic processes. Mitochondrial dysfunction, NAD⁺ depletion, and disrupted mitochondria-lysosome coupling may reduce the ability of macrophages to preserve lysosomal acidity, autophagic competence, and bacterial killing during viral challenge. Together, these mechanisms describe how coronavirus infection compromises macrophage antibacterial defense, and how the resulting susceptibility to secondary bacterial infection is further modulated by the metabolic and inflammatory state of the host cell.</jats:p>