Cargando…
The opportunistic intracellular bacterial pathogen Rhodococcus equi elicits type I interferon by engaging cytosolic DNA sensing in macrophages
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 additi...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8443056/ https://www.ncbi.nlm.nih.gov/pubmed/34473814 http://dx.doi.org/10.1371/journal.ppat.1009888 |
_version_ | 1783753114602438656 |
---|---|
author | Vail, Krystal J. da Silveira, Bibiana Petri Bell, Samantha L. Cohen, Noah D. Bordin, Angela I. Patrick, Kristin L. Watson, Robert O. |
author_facet | Vail, Krystal J. da Silveira, Bibiana Petri Bell, Samantha L. Cohen, Noah D. Bordin, Angela I. Patrick, Kristin L. Watson, Robert O. |
author_sort | Vail, Krystal J. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8443056 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-84430562021-09-16 The opportunistic intracellular bacterial pathogen Rhodococcus equi elicits type I interferon by engaging cytosolic DNA sensing in macrophages Vail, Krystal J. da Silveira, Bibiana Petri Bell, Samantha L. Cohen, Noah D. Bordin, Angela I. Patrick, Kristin L. Watson, Robert O. PLoS Pathog Research Article 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. Public Library of Science 2021-09-02 /pmc/articles/PMC8443056/ /pubmed/34473814 http://dx.doi.org/10.1371/journal.ppat.1009888 Text en © 2021 Vail et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Vail, Krystal J. da Silveira, Bibiana Petri Bell, Samantha L. Cohen, Noah D. Bordin, Angela I. Patrick, Kristin L. Watson, Robert O. The opportunistic intracellular bacterial pathogen Rhodococcus equi elicits type I interferon by engaging cytosolic DNA sensing in macrophages |
title | The opportunistic intracellular bacterial pathogen Rhodococcus equi elicits type I interferon by engaging cytosolic DNA sensing in macrophages |
title_full | The opportunistic intracellular bacterial pathogen Rhodococcus equi elicits type I interferon by engaging cytosolic DNA sensing in macrophages |
title_fullStr | The opportunistic intracellular bacterial pathogen Rhodococcus equi elicits type I interferon by engaging cytosolic DNA sensing in macrophages |
title_full_unstemmed | The opportunistic intracellular bacterial pathogen Rhodococcus equi elicits type I interferon by engaging cytosolic DNA sensing in macrophages |
title_short | The opportunistic intracellular bacterial pathogen Rhodococcus equi elicits type I interferon by engaging cytosolic DNA sensing in macrophages |
title_sort | opportunistic intracellular bacterial pathogen rhodococcus equi elicits type i interferon by engaging cytosolic dna sensing in macrophages |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8443056/ https://www.ncbi.nlm.nih.gov/pubmed/34473814 http://dx.doi.org/10.1371/journal.ppat.1009888 |
work_keys_str_mv | AT vailkrystalj theopportunisticintracellularbacterialpathogenrhodococcusequielicitstypeiinterferonbyengagingcytosolicdnasensinginmacrophages AT dasilveirabibianapetri theopportunisticintracellularbacterialpathogenrhodococcusequielicitstypeiinterferonbyengagingcytosolicdnasensinginmacrophages AT bellsamanthal theopportunisticintracellularbacterialpathogenrhodococcusequielicitstypeiinterferonbyengagingcytosolicdnasensinginmacrophages AT cohennoahd theopportunisticintracellularbacterialpathogenrhodococcusequielicitstypeiinterferonbyengagingcytosolicdnasensinginmacrophages AT bordinangelai theopportunisticintracellularbacterialpathogenrhodococcusequielicitstypeiinterferonbyengagingcytosolicdnasensinginmacrophages AT patrickkristinl theopportunisticintracellularbacterialpathogenrhodococcusequielicitstypeiinterferonbyengagingcytosolicdnasensinginmacrophages AT watsonroberto theopportunisticintracellularbacterialpathogenrhodococcusequielicitstypeiinterferonbyengagingcytosolicdnasensinginmacrophages AT vailkrystalj opportunisticintracellularbacterialpathogenrhodococcusequielicitstypeiinterferonbyengagingcytosolicdnasensinginmacrophages AT dasilveirabibianapetri opportunisticintracellularbacterialpathogenrhodococcusequielicitstypeiinterferonbyengagingcytosolicdnasensinginmacrophages AT bellsamanthal opportunisticintracellularbacterialpathogenrhodococcusequielicitstypeiinterferonbyengagingcytosolicdnasensinginmacrophages AT cohennoahd opportunisticintracellularbacterialpathogenrhodococcusequielicitstypeiinterferonbyengagingcytosolicdnasensinginmacrophages AT bordinangelai opportunisticintracellularbacterialpathogenrhodococcusequielicitstypeiinterferonbyengagingcytosolicdnasensinginmacrophages AT patrickkristinl opportunisticintracellularbacterialpathogenrhodococcusequielicitstypeiinterferonbyengagingcytosolicdnasensinginmacrophages AT watsonroberto opportunisticintracellularbacterialpathogenrhodococcusequielicitstypeiinterferonbyengagingcytosolicdnasensinginmacrophages |