Microbiomes regulate neutrophil responses in sepsis

Sepsis is defined as a systemic inflammatory response to infection that causes vital organ dysfunction. Although sepsis is one of the most common causes of hospital death, patient responses to this disease are highly heterogeneous, making IT difficult to identify the critical pathophysiologic processes that lead to sepsis mortality. The normal human microbiota, which plays a fundamental role in the induction and training of the host immune system, is known for its highly heterogeneous composition across different individuals in homeostasis. Growing evidence suggests that the diverse homeostatic microbiome factors are responsible for the heterogeneous host responses to infection and inflammation. The main question to be addressed in this proposal is whether microbiomes in healthy blood differentially prime the immune system, thus differentially predisposing patients to sepsis. Here, we present unpublished preliminary evidence from our laboratory suggesting that (1) in healthy human blood, neutrophils are differentially "trained" (or "primed") by the microbiome, leading to altered responses to inflammatory stimulation; (2) unlike in human, neutrophils isolated from mice kept in specific-pathogen-free (SPF) facilities ("clean" mice), do not show the microbiome-mediated priming; (3) however, mice that carry wild mouse microbiomes ( dirty mice) successfully recapitulate the microbiome-mediated training of neutrophils; and (4) furthermore, adoptive transfer of neutrophils from dirty mice significantly improves septic survivals in "clean" mice. Migration of neutrophils to sites of tissue infection is vital for pathogen clearance and, thus, host survival. However, neutrophils become hyperactive during sepsis, and they mediate much of the morbidity and mortality associated with the disease. Our overarching hypothesis in this proposal is that the microbiome-mediated priming of neutrophils during homeostasis influences the exaggerated inflammatory response during sepsis. Aim 1 investigate the mechanism underlying the microbiome-mediated immune priming of human neutrophils. Will aim 2 will determine the effects of the microbiome-mediated priming on sepsis mortality using "dirty" mouse models. This proposal addresses mechanisms regarding how the dysregulated host response threatens patient survival and offers a molecular target for dampening the destructive arms of the hyperinflammatory response while promoting disease resolution and tissue recovery.