R01AI153142

Single-Cell Genomic Profiling to Identify Immune Signatures of Bacterial Sepsis in Humans

Sepsis, a 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 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 sepsis remains among the most challenging problems in human health, our use of a high-resolution unbiased approaches to address the major questions of heterogeneity and mechanism will provide highly useful datasets for the field and promote the development of new targeted therapeutics.

The General Hospital Corporation

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Boston, Massachusetts 02115 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 389% from $1,014,363 to $4,956,855.