Investigating the contribution of a novel monocyte transcriptional state to sepsis immunopathogenesis and patient heterogeneity

/Abstract Sepsis is characterized by life-threatening organ failure caused by dysfunctional immune responses to infection; however, the specifics of immune dysfunction are poorly understood and vary widely among patients. Single-cell RNA sequencing (scRNA-seq) enables gene-level analysis of individual immune cell responses during sepsis and has the potential to provide transformational understanding of sepsis immunopathogenesis. Recent studies using this approach identified a novel monocyte transcriptional state, termed monocyte substate 1 (MS1), which was enriched in a small exploratory cohort of patients with urosepsis. Preliminary scRNA- seq analysis of serial blood samples from patients with all-cause bacterial sepsis (i.e., sepsis from various infectious sources) demonstrates a decline in MS1 monocytes early in sepsis that is inversely correlated with CD4+ T and CD8+ T cell kinetics. Further analysis shows enrichment of the MS1 gene signature in a subtype (or “endotype”) of patients with an immunosuppressed response during sepsis. This project will apply scRNA-seq and functional immunological assays to investigate the immunomodulatory role of MS1 and its contribution to patient heterogeneity in sepsis. The findings have the potential to advance understanding of sepsis immunopathogenesis, resolve phenotypic heterogeneity, and guide development of subtype-specific treatment strategies. The candidate is an Instructor in Medicine at Harvard Medical School and Assistant in Medicine in the Division of Infectious Diseases at Massachusetts General Hospital (MGH). He has prior doctoral training in investigations of microbial population and evolutionary dynamics within human hosts. This proposal expands his scientific scope to include transcriptomic, computational, and functional analysis of host immune responses to infection. He will conduct his research under the co-mentorship of Dr. Nir Hacohen and Dr. Roby Bhattacharyya at the Broad Institute of MIT and Harvard. The proposal includes a five-year career development plan with research content, didactic and hands-on training in computational genomics and systems immunology, and career advisement from a committee of established scientists with complementary expertise. The proposed training will equip the candidate with the skills, data, and publication portfolio needed to establish an independent research career as a physician- scientist with a niche investigating pathogen and immunological heterogeneity in infections. The ultimate goal is to contribute to the development of precision therapies in infectious diseases. Project Number: 1K08AI185298-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Peter Ankomah | Institution: MASSACHUSETTS GENERAL HOSPITAL, BOSTON, MA | Award Amount: $197,640 | Activity Code: K08 | Study Section: Allergy, Immunology, and Transplantation Research Committee[AITC] View on NIH RePORTER: https://reporter.nih.gov/project-details/1K08AI18529801A1