Mitochondrial ROS production by neutrophils is required for host antimicrobial function against Streptococcus pneumoniae and is controlled by A2B adenosine receptor signaling.

Autor: Herring SE; Department of Microbiology and Immunology, School of Medicine, University at Buffalo, Buffalo, New York, United States of America., Mao S; Department of Microbiology and Immunology, School of Medicine, University at Buffalo, Buffalo, New York, United States of America., Bhalla M; Department of Microbiology and Immunology, School of Medicine, University at Buffalo, Buffalo, New York, United States of America., Tchalla EYI; Department of Microbiology and Immunology, School of Medicine, University at Buffalo, Buffalo, New York, United States of America., Kramer JM; Department of Oral Biology, School of Dental Medicine, University at Buffalo, Buffalo, New York, United States of America., Bou Ghanem EN; Department of Microbiology and Immunology, School of Medicine, University at Buffalo, Buffalo, New York, United States of America.
Jazyk: angličtina
Zdroj: PLoS pathogens [PLoS Pathog] 2022 Nov 14; Vol. 18 (11), pp. e1010700. Date of Electronic Publication: 2022 Nov 14 (Print Publication: 2022).
DOI: 10.1371/journal.ppat.1010700
Abstrakt: Polymorphonuclear cells (PMNs) control Streptococcus pneumoniae (pneumococcus) infection through various antimicrobial activities. We previously found that reactive oxygen species (ROS) were required for optimal antibacterial function, however, the NADPH oxidase is known to be dispensable for the ability of PMNs to kill pneumococci. In this study, we explored the role of ROS produced by the mitochondria in PMN antimicrobial defense against pneumococci. We found that the mitochondria are an important source of overall intracellular ROS produced by murine PMNs in response to infection. We investigated the host and bacterial factors involved and found that mitochondrial ROS (MitROS) are produced independent of bacterial capsule or pneumolysin but presence of live bacteria that are in direct contact with PMNs enhanced the response. We further found that MyD88-/- PMNs produced less MitROS in response to pneumococcal infection suggesting that released bacterial products acting as TLR ligands are sufficient for inducing MitROS production in PMNs. To test the role of MitROS in PMN function, we used an opsonophagocytic killing assay and found that MitROS were required for the ability of PMNs to kill pneumococci. We then investigated the role of MitROS in host resistance and found that MitROS are produced by PMNs in response to pneumococcal infection. Importantly, treatment of mice with a MitROS scavenger prior to systemic challenge resulted in reduced survival of infected hosts. In exploring host pathways that control MitROS, we focused on extracellular adenosine, which is known to control PMN anti-pneumococcal activity, and found that signaling through the A2B adenosine receptor inhibits MitROS production by PMNs. A2BR-/- mice produced more MitROS and were significantly more resistant to infection. Finally, we verified the clinical relevance of our findings using human PMNs. In summary, we identified a novel pathway that controls MitROS production by PMNs, shaping host resistance against S. pneumoniae.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2022 Herring et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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