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ResearchIn-Press PreviewInflammationPulmonology Open Access | 10.1172/JCI182127

Red Blood Cells Capture and Deliver Bacterial DNA to Drive Host Responses During Polymicrobial Sepsis

LK Metthew Lam,1 Nathan J. Klingensmith,2 Layal Sayegh,1 Emily Oatman,2 Joshua S. Jose,1 Christopher V. Cosgriff,3 Kaitlyn A. Eckart,1 John McGinnis,1 Piyush Ranjan,4 Matthew Lanza,5 Nadir Yehya,6 Nuala J. Meyer,1 Robert P. Dickson,4 and Nilam S. Mangalmurti1

1Division of Pulmonary, Allergy, and Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

2Division of Traumatology, Surgical Critical Care and Emergency Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

3Pulmonary and Critical Care Unit,, Department of Medicine, Massachusetts General Hospital, Boston, United States of America

4Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, United States of America

5Department of Comparative Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, United States of America

6Division of Pediatric Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

Find articles by Lam, L. in: JCI | PubMed | Google Scholar

1Division of Pulmonary, Allergy, and Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

2Division of Traumatology, Surgical Critical Care and Emergency Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

3Pulmonary and Critical Care Unit,, Department of Medicine, Massachusetts General Hospital, Boston, United States of America

4Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, United States of America

5Department of Comparative Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, United States of America

6Division of Pediatric Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

Find articles by Klingensmith, N. in: JCI | PubMed | Google Scholar

1Division of Pulmonary, Allergy, and Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

2Division of Traumatology, Surgical Critical Care and Emergency Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

3Pulmonary and Critical Care Unit,, Department of Medicine, Massachusetts General Hospital, Boston, United States of America

4Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, United States of America

5Department of Comparative Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, United States of America

6Division of Pediatric Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

Find articles by Sayegh, L. in: JCI | PubMed | Google Scholar

1Division of Pulmonary, Allergy, and Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

2Division of Traumatology, Surgical Critical Care and Emergency Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

3Pulmonary and Critical Care Unit,, Department of Medicine, Massachusetts General Hospital, Boston, United States of America

4Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, United States of America

5Department of Comparative Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, United States of America

6Division of Pediatric Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

Find articles by Oatman, E. in: JCI | PubMed | Google Scholar

1Division of Pulmonary, Allergy, and Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

2Division of Traumatology, Surgical Critical Care and Emergency Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

3Pulmonary and Critical Care Unit,, Department of Medicine, Massachusetts General Hospital, Boston, United States of America

4Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, United States of America

5Department of Comparative Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, United States of America

6Division of Pediatric Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

Find articles by Jose, J. in: JCI | PubMed | Google Scholar

1Division of Pulmonary, Allergy, and Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

2Division of Traumatology, Surgical Critical Care and Emergency Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

3Pulmonary and Critical Care Unit,, Department of Medicine, Massachusetts General Hospital, Boston, United States of America

4Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, United States of America

5Department of Comparative Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, United States of America

6Division of Pediatric Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

Find articles by Cosgriff, C. in: JCI | PubMed | Google Scholar

1Division of Pulmonary, Allergy, and Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

2Division of Traumatology, Surgical Critical Care and Emergency Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

3Pulmonary and Critical Care Unit,, Department of Medicine, Massachusetts General Hospital, Boston, United States of America

4Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, United States of America

5Department of Comparative Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, United States of America

6Division of Pediatric Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

Find articles by Eckart, K. in: JCI | PubMed | Google Scholar

1Division of Pulmonary, Allergy, and Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

2Division of Traumatology, Surgical Critical Care and Emergency Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

3Pulmonary and Critical Care Unit,, Department of Medicine, Massachusetts General Hospital, Boston, United States of America

4Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, United States of America

5Department of Comparative Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, United States of America

6Division of Pediatric Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

Find articles by McGinnis, J. in: JCI | PubMed | Google Scholar

1Division of Pulmonary, Allergy, and Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

2Division of Traumatology, Surgical Critical Care and Emergency Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

3Pulmonary and Critical Care Unit,, Department of Medicine, Massachusetts General Hospital, Boston, United States of America

4Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, United States of America

5Department of Comparative Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, United States of America

6Division of Pediatric Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

Find articles by Ranjan, P. in: JCI | PubMed | Google Scholar |

1Division of Pulmonary, Allergy, and Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

2Division of Traumatology, Surgical Critical Care and Emergency Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

3Pulmonary and Critical Care Unit,, Department of Medicine, Massachusetts General Hospital, Boston, United States of America

4Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, United States of America

5Department of Comparative Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, United States of America

6Division of Pediatric Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

Find articles by Lanza, M. in: JCI | PubMed | Google Scholar

1Division of Pulmonary, Allergy, and Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

2Division of Traumatology, Surgical Critical Care and Emergency Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

3Pulmonary and Critical Care Unit,, Department of Medicine, Massachusetts General Hospital, Boston, United States of America

4Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, United States of America

5Department of Comparative Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, United States of America

6Division of Pediatric Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

Find articles by Yehya, N. in: JCI | PubMed | Google Scholar

1Division of Pulmonary, Allergy, and Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

2Division of Traumatology, Surgical Critical Care and Emergency Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

3Pulmonary and Critical Care Unit,, Department of Medicine, Massachusetts General Hospital, Boston, United States of America

4Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, United States of America

5Department of Comparative Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, United States of America

6Division of Pediatric Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

Find articles by Meyer, N. in: JCI | PubMed | Google Scholar |

1Division of Pulmonary, Allergy, and Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

2Division of Traumatology, Surgical Critical Care and Emergency Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

3Pulmonary and Critical Care Unit,, Department of Medicine, Massachusetts General Hospital, Boston, United States of America

4Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, United States of America

5Department of Comparative Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, United States of America

6Division of Pediatric Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

Find articles by Dickson, R. in: JCI | PubMed | Google Scholar

1Division of Pulmonary, Allergy, and Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

2Division of Traumatology, Surgical Critical Care and Emergency Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

3Pulmonary and Critical Care Unit,, Department of Medicine, Massachusetts General Hospital, Boston, United States of America

4Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, United States of America

5Department of Comparative Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, United States of America

6Division of Pediatric Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

Find articles by Mangalmurti, N. in: JCI | PubMed | Google Scholar |

Published December 12, 2024 - More info

J Clin Invest. https://doi.org/10.1172/JCI182127.
Copyright © 2024, Lam et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published December 12, 2024 - Version history
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Abstract

Red blood cells (RBCs), traditionally recognized for their role in transporting oxygen, play a pivotal role in the body's immune response by expressing TLR9 and scavenging excess host cell-free DNA. DNA capture by RBCs leads to accelerated RBC clearance and triggers inflammation. Whether RBCs can also acquire microbial DNA during infections is unknown. Murine RBCs acquire microbial DNA in vitro and bacterial-DNA-induced macrophage activation was augmented by WT but not Tlr9-deleted RBCs. In a mouse model of polymicrobial sepsis, RBC-bound bacterial DNA was elevated in WT but not in erythroid Tlr9-deleted mice. Plasma cytokine analysis in these mice revealed distinct sepsis clusters characterized by persistent hypothermia and hyperinflammation in the most severely affected subjects. RBC-Tlr9 deletion attenuated plasma and tissue IL-6 production in the most severe group. Parallel findings in human subjects confirmed that RBCs from septic patients harbored more bacterial DNA compared to healthy individuals. Further analysis through 16S sequencing of RBC-bound DNA illustrated distinct microbial communities, with RBC-bound DNA composition correlating with plasma IL-6 in patients with sepsis. Collectively, these findings unveil RBCs as overlooked reservoirs and couriers of microbial DNA, capable of influencing host inflammatory responses in sepsis.

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  • Version 1 (December 12, 2024): In-Press Preview
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