Defining the role of microbiota-derived cyclic dinucleotides in priming antiviral immune defenses.

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Enteric pathogens represent a major group of disease-causing agents, and must overcome the physical and immunological barrier of the gastrointestinal tract. The resident microbiota presents with a large array of ligands and pathogen-associated molecular patterns (PAMPs) which can prime immune defenses, through pattern recognition receptors (PRRs), both on enterocytes and immune resident cells. Indeed, microbial-derived TLR ligands are necessary for the development and maintenance of the intestinal barrier and immune homeostasis. Moreover, the microbiota is not static and imbalanced bacterial communities, termed dysbiosis, impact immunity, in particular during aging. Aging is associated with increased susceptibility to enteric pathogens, and how the dysbiotic microbiota alters susceptibility is largely unknown. The complement of microbial-derived ligands that are sensed and that can prime antiviral immunity is incomplete. A better understanding of the molecular mechanisms by which immunity is maintained, how the microbiota and epithelia interact, and how this impacts infection and pathogenesis has the potential to reveal novel strategies to treat enteric viral infections. Studies exploring the role of the microbiota and host genes in the context of aging in enteric infections are challenging in small animal models due to costs and technical hurdles. To overcome our gap in knowledge of the molecular mechanisms that control enteric viral infection, we developed an oral model of infection using the powerful genetic model organism, Drosophila. We found that the gut presents a high barrier to infection: young wild type flies are refractory to oral challenge with human viruses, while inoculation into the body cavity, which bypasses the gut, results in robust infection. The spectrum of antiviral pathways engaged in the gut, and how the microbiota shapes immunity in the intestine is incompletely understood. Preliminarily, we found that Drosophila STING controls infection in the intestine; dSTING mutants are more susceptible to enteric viral infection. STING is known to be activated by cyclic dinucleotides (CDNs). While cGAS can produce CDNs endogenously, STING can also be activated by bacterially derived CDNs. This led us to explore the possibility that commensal bacteria-derived CDNs may impact innate defenses in the gut through STING, as it is known that microbiota-derived CDNs are present in the gut. Our new data identifies a role for microbiota-derived CDNs in antiviral defense. Ablation of the microbiota in young animals leads to increased infection, and feeding these microbiota-deficient flies CDNs was protective. In Aim 1 we will define the role of dSTING in antiviral defense and in Aim 2 we will define the role of commensal-derived CDNs in antiviral defense in young and old animals.