Innate Immune Responses to Mucosal Infection are Regulated by RELMα

Preclinical models of infection, such as murine infection models and transgenic mice, provide critical knowledge for the treatment and diagnosis of infections of significant public health concern. In particular, the mucosal barrier, such as the lung and intestine are susceptible to multiple infectious pathogens given their exposure to the external environment. The goal of this dissertation was to investigate the function of RELMα and CX3CR1 in mucosal infections with parasitic helminths and influenza virus, as these are pathogens of significant health concern worldwide. RELMα is a mouse protein, which has orthologs in humans such as resistin and RELMβ. First, we tested the function of RELMα and investigated factors that may regulate its expression in infection. RELMα accelerated resolution of inflammation and tissue repair in infection with mouse intestinal helminth Heligmosomoides polygyrus. We also discovered that choline kinase signaling was critical for optimal RELMα expression: when mice were infected with H. polygyrus and injected with choline kinase alpha inhibitor, RSM-932A, alternative activation of macrophages and RELMα expression was downregulated in RSM-932A-injected mice. Previous studies have reported RELMα expression in type 2 cytokine inflammation, however, the functional relevance of RELMα in other infectious contexts, such as viral infections, is unclear. RELMα was induced by IAV infection in the BALF and airway epithelial cells. RELMα induced influenza infections in mouse lung epithelial cells in vitro and in vivo, suggesting that RELMα expressed in lung epithelial cells promotes influenza infection of neighboring cells. In the last chapter of this thesis, we broadened our research scope to investigate the function of myeloid-derived cells in helminth infection by targeting CX3CR1, a critical chemokine receptor for monocyte recruitment from the blood vessel to the site of infection. CX3CR1 deficiency induced a more inflammatory response but lower parasite burden in the lung. CX3CR1-deficient monocytes were more cytotoxic and active than WT monocytes, demonstrating the regulatory function of CX3CR1 in monocytes. Collectively, these studies demonstrate diverse functions of RELMα and CX3CR1 in different infectious diseases and identify putative downstream targets by which RELMα and CX3CR1 modulate the immune response and tissue repair