PROJECT SUMMARY/ABSTRACT This proposal describes a research, training, and career development plan for Dr. Matthew Cummings, a pulmonary/critical care fellow at Columbia University. Working with collaborators and mentors at Columbia and in Uganda, Dr. Cummings is establishing himself as a clinical-translational investigator focused on sepsis and infection-related critical illness in low-income settings. Sepsis, with ~30 million incident cases annually, is a severe, heterogeneous clinical syndrome of acute organ dysfunction resulting from a complex host response to infecting pathogens. In sub-Saharan Africa, a low-income region where limited diagnostic capacity and an expansive microbiological differential diagnosis challenge prompt and accurate diagnosis of severe infections, sepsis is a leading cause of death. Despite a high burden of disease, circulation of diverse pathogens, and unique host factors including epidemic HIV infection, understanding of the heterogeneous sepsis phenotype in sub-Saharan Africa and the impact of infecting pathogens on this heterogeneity remains imprecise. While latent class analyses (LCA) have identified distinct sepsis subphenotypes (subtypes) associated with differing sites of infection, illness severity, and mortality in high-income settings, the presence of clinically-meaningful sepsis subtypes requiring divergent diagnostic and treatment strategies remains unknown in sub-Saharan Africa. Elusiveness of the invading microorganism attributable to the insensitivity of traditional diagnostics has also challenged understanding of the extent to which phenotypic heterogeneity in sepsis involves the pathogen. To address these gaps, Dr. Cummings proposes to detect and characterize high-impact pathogens among adults with sepsis in Uganda using a novel, highly sensitive nucleic acid probe-capture sequencing platform (Aim 1) and; identify clinically-relevant sepsis subtypes in Uganda through integration of high- resolution microbiological data and LCA (Aim 2). The research component of this proposal will leverage data from a prospective cohort study of sepsis conducted through a collaboration between researchers at Columbia University and Uganda Virus Research Institute. The training component will provide the applicant with course- based and practical training in epidemiology, biostatistics, and cutting-edge molecular diagnostics that will facilitate his development into an independent clinical-translational investigator and leader in global health research. This proposal represents an innovative approach that will advance understanding of high-impact pathogens associated with sepsis in sub-Saharan Africa while classifying sepsis patients into meaningful subtypes for whom diagnostic and treatment strategies can be more precisely tailored. This research will also inform development of a prospective study focused on identifying sepsis biological endotypes in sub-Saharan Africa that will be proposed in a subsequent K-award application.

PROJECT NARRATIVE Sepsis is a heterogeneous syndrome that arises when the body's response to infection injures its own organs. In sub-Saharan Africa, a resource-limited region with a high-burden of HIV infection, sepsis is a leading cause of death. This research will classify sepsis patients in sub-Saharan Africa into meaningful subgroups for whom diagnostic and treatment strategies can be more precisely tailored.