Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Determining the role of RBCs in sepsis heterogeneity

Award Number: R01HL183080
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/06/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2030

Group Awards By:

View Award Description

Determining the role of RBCs in sepsis heterogeneity - Project Summary/Abstract: Sepsis, the dysregulated host response to infection, is a leading cause of death. A comprehensive understanding of the mechanisms driving the host response during sepsis is imperative, as it is often the aberrant immune response, rather than the pathogen itself, that leads to organ failure and mortality. Furthermore, the failure to translate preclinical findings into successful therapies is largely attributed to an incomplete understanding of the dysregulated immune response and the significant heterogeneity in host responses to sepsis. Central to the immune response during infection is the detection of pro-inflammatory bacterial DNA. While pathogen-derived nucleic acid sensing is essential for initiating inflammation and clearing infections, aberrant nucleic acid signaling can result in excessive inflammation, cell death, tissue damage, and ultimately, organ injury. Despite the critical role of extracellular DNA in sepsis-related organ failure, the mechanisms regulating cell-free DNA (cf-DNA) remain unclear. We recently demonstrated that red blood cells (RBCs) play a previously unrecognized role in capturing and delivering cf-DNA to immune cells and distant organs during sepsis. In a polymicrobial sepsis model, we found that impaired RBC-TLR9-mediated microbial DNA trapping reduced systemic inflammation, attenuated cytokine signaling in remote organs, and increased pathogen dissemination in severely ill mice. These findings reveal that RBC-DNA interactions are a key driver of the host response in sepsis and provide novel mechanistic insights into sepsis pathophysiology. Importantly, RBC-TLR9 plays a critical role in initiating inflammation by capturing and delivering DNA to immune cells, which is essential for controlling pathogens. Despite these advances, critical knowledge gaps remain. Our long-term objective is to define the immunomodulatory functions of RBCs in sepsis, focusing on how variability in the RBC-mediated DNA sensing and delivery pathway contributes to host heterogeneity. We hypothesize that differences in DNA sensing by RBCs—driven by variability in TLR9 surface expression, DNA capture, and uptake by phagocytes—underlie the heterogeneous immune responses observed in sepsis. This five-year proposal will investigate the role of RBCs in driving sepsis heterogeneity by addressing three fundamental questions: What are the intrinsic RBC factors that contribute to variability in DNA sensing? How does dysbiosis affect RBC-mediated pathogen DNA capture and subsequent host responses? How does RBC-delivered microbial DNA alter immune cell function? We will analyze samples from a well-phenotyped cohort of critically ill sepsis patients and conduct mechanistic studies using genetically modified mice and human erythrocytes to investigate RBC-TLR9 and microbial DNA sensing and delivery to immune cells. To study the impact of dysbiosis, we will use gnotobiotic and dysbiotic mice models to determine how microbial community alterations affect RBC-mediated DNA capture. Ultimately, this work seeks to achieve a mechanistic understanding of how RBCs and microbial DNA-induced immune dysfunction contribute to sepsis heterogeneity. By identifying novel therapeutic targets and elucidating a key mechanism underlying heterogeneous host responses, this research has the potential to address the critical need for effective treatments for sepsis-associated immune dysregulation.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $718,991 )
2026	2026	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Blood Diseases and Resources Research	000	1	7/8/2026	NEW	$718,991
														Subtotal = $718,991

Grand Total All Awards = $718,991

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Determining the role of RBCs in sepsis heterogeneity

Award Number: R01HL183080

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/06/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2030

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer