Department of Microbiology and Physiological Systems; Graduate School of Biomedical Sciences
Bacterial Infections and Mycoses | Immunology and Infectious Disease | Microbiology
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.
Mycobacterium tuberculosis, Macrophages, Respiratory infections, Mouse models, Operons, Phagosomes, Immunity, Protons
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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.
DOI of Published Version
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
Cai Y, Jaecklein E, Mackenzie JS, Papavinasasundaram K, Olive AJ, Chen X, Steyn AJ, Sassetti CM. (2021). Host immunity increases Mycobacterium tuberculosis reliance on cytochrome bd oxidase. Open Access Publications by UMass Chan Authors. https://doi.org/10.1371/journal.ppat.1008911. Retrieved from https://escholarship.umassmed.edu/oapubs/4861
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