Journal Article

Host immunity increases Mycobacterium tuberculosis reliance on cytochrome bd oxidase

Sassetti, Christopher M., Papavinasasundaram, Kadamba, Steyn, Adrie J. C., Olive, Andrew J., Cai, Yi, Jaecklein, Eleni, Chen, Xinchun, Mackenzie, Jared S.

2021

Overview

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 bc 1 /aa 3 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 (IFNγ), but did not involve nitrogen and oxygen radicals that are known to inhibit respiration in other contexts. Instead, we found that ΔcydA mutants were hypersusceptible to the low pH encountered in IFNγ-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 bc 1 /aa 3 complex is preferentially inhibited under acidic conditions. Consistent with this model, the potency of the cytochrome bc 1 /aa 3 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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adaptation, Physiological - physiology / Adaptive immunity / Animals / Antimicrobial agents / Bacteria / Biology and Life Sciences / Changing environments / Cytochrome / Cytochrome bc1 / Cytochrome bd / Cytochrome oxidase / Cytochromes / Cytokines / Development and progression / Electron transport / Electron Transport Complex IV - metabolism / Environmental changes / Flow cytometry / Free radicals / Health aspects / Host-bacteria relationships / Humans / Hypoxia / Immune Evasion - physiology / Immune response / Immune system / Immunity / Immunological research / Immunosuppressive agents / Infections / Interferon / Lymphocytes / Macrophages / Macrophages - immunology / Macrophages - metabolism / Macrophages - microbiology / Medicine and Health Sciences / Metabolism / Mice / Microbial metabolism / Mycobacterium tuberculosis / Mycobacterium tuberculosis - enzymology / Mycobacterium tuberculosis - immunology / Oxidase / Oxygen consumption / Pathogens / pH effects / Physical Sciences / Physiological aspects / Research and Analysis Methods / Respiration / Tuberculosis / Tuberculosis - immunology / γ-Interferon