Red Blood Cell DNA Capture and Delivery Drives Host Responses During Polymicrobial Sepsis

Abstract Nucleic acid sensing is an essential function of the immune system critical for detecting infection and sterile injury. Red blood cells (RBCs) express the DNA-sensing receptor TLR9 and detect excess CpG-DNA during pathologic states, triggering rapid clearance and immune activation. These findings suggest that RBCs modulate immune responses, yet whether RBCs detect microbial DNA during infection is unknown. We show that RBCs acquire microbial DNA during sepsis. In vitro, RBCs bind microbial DNA and enhance DNA delivery to macrophages. Erythroid-specific deletion of TLR9 attenuated cytokine production and increased splenic bacterial dissemination during polymicrobial sepsis. Congruently, RBC-bound bacterial DNA is elevated in septic patients when compared with healthy subjects, and 16S rRNA gene sequencing of RBC-bound DNA revealed distinct microbial communities that associated are associated with host inflammatory cytokines. These findings identify RBCs as immunomodulatory cells that mediate host inflammatory responses through microbial DNA delivery during sepsis.