Mechanisms coordinating the local and systemic resistance to pathogens

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Summary: Mechanisms coordinating the local and systemic resistance to pathogens. Defending a host against pathogens to ensure homeostasis and health requires the coordinated effort of multiple cell types. Many pathogens that enter the host via a specific tissue portal can often disseminate to multiple tissues over time and cause significant damage to additional host organs. Cells of the innate and adaptive immune system respond to the initial infection as well as disseminated infection to mount robust defense against both phases of pathogen attack. Importantly, in some cases, dissemination is delayed from the primary infection. Intuitively, if the eventual sites of disseminated infection were immunologically prepared to expect the arrival of potential infection from the primary site of pathogen growth, the host would be better able to control systemic disease. Significantly, the preliminary data leading to this proposal suggests that such a mechanism for long range coordination between local dendritic cells (DC) and distant stromal cells operates via a hitherto unappreciated pathway for making the heterodimeric cytokine IL-12. We hypothesize that pathogen-activated Dendritic Cells at the original site of infection secrete inert IL-12p40 monomers which circulate to distant organs, combine with IL-12p35 released locally by stromal cells to tailor tissue-specific anticipatory immunity. This long- distance combination of inert subunits of IL-12 within tissue niches allows individual sites to not only prime the immune cells in that microenvironment in anticipation of potential infection, but also fine-tune immunity in a tissue-specific fashion (e.g. by releasing the protein IL-23p19 instead of IL-12p35, which would lead to the local assembly of IL-23 and eventual amplification of type17 immunity instead of type1). In this proposal, we evaluate the molecular, cellular and systems level mechanisms of this hypothesis using three independent and convergent Specific Aims (SA). SA1: examines the cellular and molecular mechanisms underlying the release of both subunits (P40 and P35) as well as the principles which facilitate their tissue-level assembly into IL-12. DC subsets producing P40, selective mechanisms favoring monomer release and adaptations allowing tissue retention will be dissected. Tissue signals initiating P35 release as well as significance for P19 (the P40-partner responsible for IL-23) will also be evaluated. SA2: studies how host defense is facilitated by the innovative concept of Immunological premonition in tissues at a cellular level. Immune cells that respond to locally assembled IL-12 and the duration of the immune modifications resulting from this will be measured in the context of immunizations as well as infectious challenge. SA3: defines the systemic consequences of immunological premonition by using a physiological co-infection model. Organisms that can modify local vs systemic P40 are expected to be natural part of our host-microbe relationships. We will measure responses to acute infections in the presence of bacteria with defined impact on local IL-12 to understand how immunity at primary and distal sites are coordinated to effect optimal host defense to multiple pathogens in parallel. Taken together, we expect these studies to be transformative by revealing the cellular and molecular mechanisms underlying a critical inter-tissue communication and coordination axis in host defense. Future studies can develop clinical therapeutics targeting these pathways to improve tissue-specific immunity from vaccines administered at distant sites, reducing systemic immunopathology from local infections, and improving host resistance to pathogen dissemination or colonization.