PROJECT SUMMARY / ABSTRACT Background: The global burden of sepsis is concentrated in sub-Saharan Africa (SSA), where epidemic HIV, broad pathogen diversity, and limited critical care capacity challenge effective management of life-threatening infections. In this context, where attempts to implement sepsis treatment protocols developed in high-income countries (HICs) have failed to show benefit, data informing locally-relevant models of sepsis pathobiology are scarce. As treatment responses likely depend, in part, on modifying complex host responses incited by an array of pathogens, imprecise understanding of biological heterogeneity inherent to sepsis in SSA represents a crucial barrier to development of effective management strategies. Research: The research component of this proposal will utilize data and biological samples from NIAID- and foundation-funded prospective cohort studies of sepsis in Uganda conducted through an established collaboration between Columbia University and Uganda Virus Research Institute (UVRI). Within this framework, I will establish novel clinico-molecular sepsis subtypes in Uganda using latent class analysis of clinical, microbiological, and host biomarker data (Aim 1); derive and validate transcriptomic sepsis subtypes in Uganda by applying machine learning techniques to whole-blood RNA sequencing data (Aim 2) and; determine innate and cell-mediated immune profiles associated with severe organ failure and mortality in HIV-associated sepsis (Aim 3). Candidate: As outlined in this K23 Award application, my career objective is to become an independent clinical and translational investigator focused on sepsis and infection-related critical illness in resource-limited settings, with the goal to establish more precise, biologically-informed clinical management strategies that can be tested in locally-relevant clinical trials. I am well-qualified to undertake the scientific and training Aims proposed here, having spent much of the past decade working to characterize the clinical and molecular epidemiology of emerging infections associated with severe and critical illness in Uganda. Mentors/Environment: Under the primary mentorship of Dr. Max O’Donnell, an R01-funded investigator at Columbia with >15 years of clinical research experience in SSA, I have assembled a team of co-mentors and collaborators at Columbia (Dr. Ian Lipkin, Dr. Jason Che) and UVRI (Dr. Barnabas Bakamutumaho) with expertise in patient-oriented and translational research in infectious diseases and critical care, global health, molecular laboratory methods, and advanced biostatistics and bioinformatics. Training: With guidance from my mentors and collaborators, I have crafted a rigorous five-year career development plan that includes necessary training in: clinical study design, ethics, and conduct relevant to resource-limited settings (Drs. O’Donnell, Bakamutumaho), high-throughput RNA sequencing and biomarker measurement (Dr. Lipkin), advanced biostatistics and bioinformatics (Dr. Che), and research dissemination and professional development (all mentors). Completion of the proposed training and related Aims will facilitate my development as an independent clinical-translational investigator and leader in global sepsis research.

PROJECT NARRATIVE The global burden of sepsis is concentrated in sub-Saharan Africa where epidemic HIV, broad pathogen diversity, and limited health system capacity challenge effective management of life-threatening infections. This research will stratify sepsis patients in Uganda into meaningful subtypes to enhance diagnosis, clinical trial design, and management of sepsis in sub-Saharan Africa.