Resolution Pathways in the Context of Viral Infections

Inflammation is a central host response against viral infections. However, accumulating evidence indicates that when excessive, misdirected, or unresolved, the inflammatory response becomes a driver of disease, ultimately contributing to tissue damage, dysfunction, and death. The proper termination of inflammation relies on the timely engagement of resolution programs, and pro-resolving mediators have been extensively investigated in a variety of inflammatory settings. Although much is known in the context of bacterial infections, the role of resolution pathways in viral diseases remains relatively underexplored. Here, we summarize current evidence showing (1) that the levels of pro-resolving mediators are modulated during viral infections and are correlated with severe disease; (2) preclinical studies supporting their endogenous roles; and (3) the effects of the exogenous administration of mediators of inflammation resolution and their receptors during viral infection in humans and experimental models. We further discuss the capacity of viruses to hijack resolution pathways, as exemplified by the AnxA1/FPR2 axis during herpes simplex and influenza A virus infection. Finally, we propose that therapeutic strategies aimed at enhancing resolution may extend beyond the acute phase of infection, offering benefits in post-viral sequelae, including secondary bacterial infections and neurological complications, as observed in COVID-19 and arbovirus-associated disorders.