The opportunistic intracellular bacterial pathogen Rhodococcus equi elicits type I interferon by engaging cytosolic DNA sensing in macrophages.
Abstract: Rhodococcus equi is a major cause of foal pneumonia and an opportunistic pathogen in immunocompromised humans. While alveolar macrophages constitute the primary replicative niche for R. equi, little is known about how intracellular R. equi is sensed by macrophages. Here, we discovered that in addition to previously characterized pro-inflammatory cytokines (e.g., Tnfa, Il6, Il1b), macrophages infected with R. equi induce a robust type I IFN response, including Ifnb and interferon-stimulated genes (ISGs), similar to the evolutionarily related pathogen, Mycobacterium tuberculosis. Follow up studies using a combination of mammalian and bacterial genetics demonstrated that induction of this type I IFN expression program is largely dependent on the cGAS/STING/TBK1 axis of the cytosolic DNA sensing pathway, suggesting that R. equi perturbs the phagosomal membrane and causes DNA release into the cytosol following phagocytosis. Consistent with this, we found that a population of ~12% of R. equi phagosomes recruits the galectin-3,-8 and -9 danger receptors. Interestingly, neither phagosomal damage nor induction of type I IFN require the R. equi's virulence-associated plasmid. Importantly, R. equi infection of both mice and foals stimulates ISG expression, in organs (mice) and circulating monocytes (foals). By demonstrating that R. equi activates cytosolic DNA sensing in macrophages and elicits type I IFN responses in animal models, our work provides novel insights into how R. equi engages the innate immune system and furthers our understanding how this zoonotic pathogen causes inflammation and disease.
Publication Date: 2021-09-02 PubMed ID: 34473814PubMed Central: PMC8443056DOI: 10.1371/journal.ppat.1009888Google Scholar: Lookup
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- Journal Article
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- Non-U.S. Gov't
Summary
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The intracellular bacterial pathogen Rhodococcus equi triggers a type I interferon response by sequestering cytosolic DNA from macrophages. This complex process aids in developing understanding of how R. equi interacts with the immune system and contributes to disease and inflammation.
Understanding Rhodococcus equi and Its Interaction with Macrophages
- Rhodococcus equi is a bacterium causing pneumonia in foals and poses a risk to immunocompromised humans. Though recognized that alveolar macrophages, our immunity’s frontline cells, are a favorable habitat for R. equi, the exact interaction between the bacteria and these cells remains unclear.
Identifying Additional Cytokine Response
- R. equi-affected macrophages have been observed to trigger pro-inflammatory cytokines (such as Tnfa, Il6, Il1b) and a potent type I IFN response similar to that prompted by the related pathogen, Mycobacterium tuberculosis. These cytokines play crucial roles in immune responses.
The Role of the cGAS/STING/TBK1 Axis
- The study utilized mammalian and bacterial genetics to demonstrate that the induction of the type I IFN expression program was mainly reliant on the cGAS/STING/TBK1 axis of the cytosolic DNA sensing pathway. The findings suggest that R. equi disrupts the phagosomal membrane, releasing DNA into the cytosol after phagocytosis.
Understanding Phagosome Recruitment and Response
- Approximately 12% of R. equi phagosomes were found to recruit the danger signal galectin-3, -8 and -9 receptors. Neither the phagosomal damage nor the induction of type I IFN was found to require the bacterial virulence-associated plasmid.
Practical Implications and Future Research
- Notably, R. equi infections in mice and foals were found to induce ISG expression, in bodily organs and the immune system’s circulating monocytes, respectively. This highlights the general applicability and relevance of the findings to other animal models.
- By showing how R. equi stimulates cytosolic DNA sensing in macrophages and provokes type I IFN responses, this research offers new understanding of interactions between this zoonotic pathogen and the immune system. This knowledge can be invaluable in future research for therapeutics and preventive measures against infections by this bacteria.
Cite This Article
APA
Vail KJ, da Silveira BP, Bell SL, Cohen ND, Bordin AI, Patrick KL, Watson RO.
(2021).
The opportunistic intracellular bacterial pathogen Rhodococcus equi elicits type I interferon by engaging cytosolic DNA sensing in macrophages.
PLoS Pathog, 17(9), e1009888.
https://doi.org/10.1371/journal.ppat.1009888 Publication
Researcher Affiliations
- Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, Texas, United States of America.
- Department of Veterinary Pathology, Texas A&M University, College Station, Texas, United States of America.
- Department of Large Animal Clinical Sciences, Texas A&M University, College Station, Texas, United States of America.
- Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, Texas, United States of America.
- Department of Large Animal Clinical Sciences, Texas A&M University, College Station, Texas, United States of America.
- Department of Large Animal Clinical Sciences, Texas A&M University, College Station, Texas, United States of America.
- Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, Texas, United States of America.
- Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, Texas, United States of America.
MeSH Terms
- Actinomycetales Infections / immunology
- Animals
- Cytosol / immunology
- DNA / immunology
- Female
- Horse Diseases / immunology
- Horses
- Immunity, Innate / immunology
- Interferon Type I / immunology
- Macrophages / immunology
- Male
- Mice
- Rhodococcus equi / immunology
Grant Funding
- P51 OD011104 / NIH HHS
- R01 AI125512 / NIAID NIH HHS
- R01 AI155621 / NIAID NIH HHS
- T32 OD011083 / NIH HHS
Conflict of Interest Statement
The authors have declared that no competing interests exist.
References
This article includes 81 references
Citations
This article has been cited 4 times.- Hansen P, Haubenthal T, Reiter C, Kniewel J, Bosse-Plois K, Niemann HH, von Bargen K, Haas A. Differential Effects of Rhodococcus equi Virulence-Associated Proteins on Macrophages and Artificial Lipid Membranes.. Microbiol Spectr 2023 Feb 14;11(2):e0341722.
- Lee W, Kim MH, Park J, Kim YJ, Kim E, Heo EJ, Kim SH, Kim G, Shin H, Kim SH, Kim HY. Seasonal Changes in the Microbial Communities on Lettuce (Lactuca sativa L.) in Chungcheong-do, South Korea.. J Microbiol Biotechnol 2023 Feb 28;33(2):219-227.
- Xu Z, Hao X, Li M, Luo H. Rhodococcus equi-Derived Extracellular Vesicles Promoting Inflammatory Response in Macrophage through TLR2-NF-κB/MAPK Pathways.. Int J Mol Sci 2022 Aug 28;23(17).
- Xu L, Li M, Yang Y, Zhang C, Xie Z, Tang J, Shi Z, Chen S, Li G, Gu Y, Wang X, Zhang F, Wang Y, Shen X. Salmonella Induces the cGAS-STING-Dependent Type I Interferon Response in Murine Macrophages by Triggering mtDNA Release.. mBio 2022 Jun 28;13(3):e0363221.
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