# Single-cell genomic profiling to identify immune signatures of bacterial sepsis in humans

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $1,019,588

## Abstract

Sepsis, life-threatening organ dysfunction due to a dysregulated host response to infection, is prevalent and
highly lethal. Early detection is a major challenge, largely because, as we and others showed, sepsis is a
heterogeneous syndrome, with many patients presenting with vague symptoms and signs; improved biomarkers
would enable earlier diagnosis, especially of these patients. A second major challenge is the shortage of
treatments, as mechanisms of immune dysfunction and vascular leakage in sepsis are poorly understood,
limiting therapeutic development. We hypothesize that unbiased single-cell transcriptional profiling (scRNA-seq)
of circulating immune cells will identify transcriptional signatures that address both challenges. In our proof-of-
principle study (Reyes et al. Nat Med 2020), we discovered a unique monocyte cell state (MS1) that is expanded
in patients with urosepsis and absent in patients with milder urinary tract infection or healthy controls. MS1
discriminates septic patients from patients with other diseases in public transcriptomic data, in a second cohort
of bacterial sepsis, and in preliminary data from our new cohort of patients with sepsis from any body site. Our
goals in this proposal are to test the hypothesis that when extended to patients with sepsis from all body sites,
unbiased single-cell approaches will generate immune signatures that distinguish sepsis from non-infectious
organ dysfunction, define new clinically-relevant sepsis endotypes, identify markers that enhance sepsis
diagnostics and subtyping, and reveal critical mechanistic biology underlying the immune dysfunction and
vascular leak present in sepsis, thus facilitating future development of endotype-specific therapeutics. In this
proposal, we will test our hypothesis that among patients presenting to the ED with acute organ dysfunction,
transcriptional signatures can be identified that distinguish those with sepsis from those with non-infectious
etiologies. We propose to: (1) discover blood single-cell transcriptional signatures that discriminate sepsis from
non-infectious organ dysfunction, define unbiased molecular endotypes, and associate with clinical outcomes
(Aim 1); (2) identify cell surface markers associated with scRNA-seq-defined cell states, including MS1, that are
significantly expanded in sepsis (Aim 2); (3) define alterations in cellular functions in patients and mice with
sepsis and in response to sepsis-induced MS1 cells (Aim 3). The proposed studies are highly likely to lead to
substantially improved cellular and molecular signatures for sepsis that could be translated into clinical use and
to new insights into the nature of immune dysregulation in sepsis. Investigations into the function of genes and
pathways identified in our studies will impact mechanistic understanding of sepsis and may lead to new
therapeutic concepts, especially for subsets of sepsis patients stratified based on single cell-derived molecular
endotypes. Whereas sep...

## Key facts

- **NIH application ID:** 10363752
- **Project number:** 5R01AI153142-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Michael Filbin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,019,588
- **Award type:** 5
- **Project period:** 2021-03-03 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10363752

## Citation

> US National Institutes of Health, RePORTER application 10363752, Single-cell genomic profiling to identify immune signatures of bacterial sepsis in humans (5R01AI153142-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10363752. Licensed CC0.

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