Associate Professor University of Wisconsin, Madison Madison, Wisconsin, United States
Disclosure(s):
Amali E. Samarasinghe, PhD: No financial relationships to disclose
Introduction/Rationale: Resistin-like molecules (RELMs) are cysteine-rich epithelial secreted proteins implicated in mucosal immunity. RELMα is broadly immunoregulatory, whereas RELMβ is associated with pro-inflammatory activity. We previously showed that acute allergic asthma protects against influenza morbidity and observed markedly increased RELMα and RELMβ in the lungs during asthma and influenza comorbidity, leading us to hypothesize that RELMs contribute to enhanced antiviral defense.
Methods: Both loss- (knockout mice) and gain-of-function (recombinant proteins) approaches were used.
Results: Allergic Retnla and Retnlb deficient mice infected with pandemic A/CA/04/2009 influenza A virus exhibited altered disease kinetics relative to wild-type allergic controls, with knockout mice showing distinct viral clearance patterns, indicating that endogenous RELMs influence influenza pathogenesis during allergic inflammation. Our scRNA sequencing data revealed that Retnl gene expression in immune and structural cells were significantly different between the asthma- and influenza-only controls. RELM-deficiency was associated with worsened airway physiology after infection, supporting a functional role for these proteins in preserving lung integrity during viral challenge. In complementary prophylactic studies, recombinant RELMα, RELMβ, or both administered intranasally to wild-type mice significantly reduced lung viral burden and improved airway mechanics. RELM treatment remodeled the airway immune landscape, increasing macrophages, neutrophils, and CD8⁺ T cells, with corresponding shifts in CD4⁺ T cell frequency and humoral responses.
Conclusion: Together, these data identify RELMs as epithelial-derived modulators of antiviral immunity that contribute to the protection observed in the asthma and influenza comorbidity setting. Ongoing studies are aimed at testing post-infection therapeutic administration and combined delivery to determine whether RELMs can be harnessed to enhance host resistance to respiratory viral disease.
