PROJECT SUMMARY Sepsis is a life-threatening systemic inflammatory condition that is initiated by the presence of microorganisms in the bloodstream or tissues. During sepsis, the generation of excessive inflammatory mediators, including cytokines and reactive oxygen species, can result in vascular leakage, disseminated intravascular coagulation, and organ failure. In the United States, sepsis kills over a quarter of a million people each year and is associated with extremely high health care costs. Clinically, sepsis patients can have variable, often non-specific signs and symptoms that make it difficult to accurately assess disease severity or predict outcomes. This variability is frequently attributed to differences in the genetic background and immune status of individual hosts. However, the nature of the infecting microbes can also impact disease severity. Strains of Extraintestinal Pathogenic Escherichia coli (ExPEC) are the principal cause of bloodstream infections and a leading cause of sepsis. Similarly lethal ExPEC isolates can trigger markedly different host responses, irrespective of host background characteristics. These variances correlate with differential stimulation of Toll-Like Receptor 5 (TLR5) by discrete flagellar serotypes. Here we propose to 1) determine if flagellin variants influence the severity and outcomes of sepsis, 2) establish how flagellin variants trigger differential host responses, and 3) define roles for flagellin receptors in relevant models of sepsis. These studies will consider both sex and age as variables, with an emphasis on ExPEC-induced sepsis in children and neonates. By the end of this study we will have a clear mechanistic understanding of the effects that flagellin variants and TLR5 have on ExPEC-induced sepsis. This work will challenge prevailing views of what can drive variability in the signs and symptoms of sepsis and will consequently aid the development of improved diagnostic tools and therapeutics.