Host immunity increases Mycobacterium tuberculosis reliance on cytochrome bd oxidase
Authors
Cai, YiJaecklein, Eleni
Mackenzie, Jared S.
Papavinasasundaram, Kadamba
Olive, Andrew J.
Chen, Xinchun
Steyn, Adrie J.C.
Sassetti, Christopher M.
UMass Chan Affiliations
Graduate School of Biomedical SciencesDepartment of Microbiology and Physiological Systems
Document Type
Journal ArticlePublication Date
2021-07-28Keywords
Mycobacterium tuberculosisMacrophages
Respiratory infections
Mouse models
Operons
Phagosomes
Immunity
Protons
Bacterial Infections and Mycoses
Immunology and Infectious Disease
Microbiology
Metadata
Show full item recordAbstract
In order to sustain a persistent infection, Mycobacterium tuberculosis (Mtb) must adapt to a changing environment that is shaped by the developing immune response. This necessity to adapt is evident in the flexibility of many aspects of Mtb metabolism, including a respiratory chain that consists of two distinct terminal cytochrome oxidase complexes. Under the conditions tested thus far, the bc1/aa3 complex appears to play a dominant role, while the alternative bd oxidase is largely redundant. However, the presence of two terminal oxidases in this obligate pathogen implies that respiratory requirements might change during infection. We report that the cytochrome bd oxidase is specifically required for resisting the adaptive immune response. While the bd oxidase was dispensable for growth in resting macrophages and the establishment of infection in mice, this complex was necessary for optimal fitness after the initiation of adaptive immunity. This requirement was dependent on lymphocyte-derived interferon gamma (IFNgamma), but did not involve nitrogen and oxygen radicals that are known to inhibit respiration in other contexts. Instead, we found that DeltacydA mutants were hypersusceptible to the low pH encountered in IFNgamma-activated macrophages. Unlike wild type Mtb, cytochrome bd-deficient bacteria were unable to sustain a maximal oxygen consumption rate (OCR) at low pH, indicating that the remaining cytochrome bc1/aa3 complex is preferentially inhibited under acidic conditions. Consistent with this model, the potency of the cytochrome bc1/aa3 inhibitor, Q203, is dramatically enhanced at low pH. This work identifies a critical interaction between host immunity and pathogen respiration that influences both the progression of the infection and the efficacy of potential new TB drugs.Source
Cai Y, Jaecklein E, Mackenzie JS, Papavinasasundaram K, Olive AJ, Chen X, Steyn AJC, Sassetti CM. Host immunity increases Mycobacterium tuberculosis reliance on cytochrome bd oxidase. PLoS Pathog. 2021 Jul 28;17(7):e1008911. doi: 10.1371/journal.ppat.1008911. PMID: 34320028; PMCID: PMC8351954. Link to article on publisher's site
DOI
10.1371/journal.ppat.1008911Permanent Link to this Item
http://hdl.handle.net/20.500.14038/42059PubMed ID
34320028Related Resources
Rights
Copyright © 2021 Cai 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.Distribution License
http://creativecommons.org/licenses/by/4.0/ae974a485f413a2113503eed53cd6c53
10.1371/journal.ppat.1008911
Scopus Count
Except where otherwise noted, this item's license is described as Copyright © 2021 Cai 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.