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

Area of Science:

• Immunology
• Hematology
• Microbiology

Background:

• Red blood cells (RBCs) are known to scavenge host cell-free DNA and express Toll-like receptor 9 (TLR9), influencing inflammation.
• The role of RBCs in acquiring and transporting microbial DNA during infections, particularly sepsis, remains largely unexplored.

Approach:

• Investigated murine RBCs' ability to acquire microbial DNA in vitro and in vivo using a polymicrobial sepsis model.
• Assessed the impact of RBC-bound bacterial DNA on macrophage activation and host inflammatory responses, including cytokine production (e.g., IL-6).
• Analyzed RBC-bound DNA in human septic patients using 16S sequencing and correlated findings with clinical endotypes and plasma IL-6 levels.

Key Points:

• Murine RBCs acquire microbial DNA in vitro, and this acquisition augments bacterial DNA-induced macrophage activation.
• RBC-bound bacterial DNA is elevated in wild-type mice during polymicrobial sepsis, but not in mice lacking erythroid TLR9.
• RBC-TLR9 deletion attenuates IL-6 production in severe sepsis endotypes, and human septic patients show increased RBC-bound bacterial DNA.

Conclusions:

• Red blood cells serve as significant reservoirs and couriers of microbial DNA during sepsis.
• RBCs' interaction with microbial DNA can modulate host inflammatory responses, impacting sepsis severity and endotypes.
• These findings reveal a novel role for RBCs in the innate immune response to bacterial infections.