Host immunity increasesMycobacterium tuberculosisreliance on cytochromebdoxidase
Authors: Cai Yi , Jaecklein Eleni , Mackenzie Jared , Papavinasasundaram Kadamba , Olive Andrew J. , Chen Xinchun , Steyn Adrie , Sassetti Christopher 
Published: August 2020

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 ofMtbmetabolism, including a respiratory chain that consists of two distinct terminal cytochrome oxidase complexes. Under the conditions tested thus far, thebc1/aa3complex appears to play a dominant role, while the alternativebdoxidase is largely redundant. However, presence of two terminal oxidases in this obligate pathogen implies that respiratory requirements might change during infection. We report that the cytochromebdoxidase 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 thatΔcydAmutants were hypersusceptible to the low pH encountered in IFNγ-activated macrophages. Unlike wild typeMtb, cytochromebd-deficient bacteria were unable to sustain a maximal oxygen consumption rate (OCR) at low pH, indicating that the remaining cytochromebc1/aa3complex is preferentially inhibited under acidic conditions. Consistent with this model, the potency of the cytochromebc1/aa3inhibitor, 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.

Author Summary

Tuberculosis, caused byMycobacterium tuberculosis(Mtb) is a serious global health problem that is responsible for over one million deaths annually, more than any other single infectious agent. In the host,Mtbcan adapt to a wide variety of immunological and environmental pressures which is integral to its success as a pathogen. Accordingly, the respiratory capacity ofMtbis flexible. The electron transport chain ofMtbhas two terminal oxidases, the cytochromebc1/aa3super complex and cytochromebd, that contribute to the proton motive force and subsequent production of energy in the form of ATP. Thebc1/aa3super complex is required for optimal growth during infection but the role of cytochromebdis unclear. Here we report that the cytochromebdoxidase is required for resisting the adaptive immune response, in particular, acidification of the phagosome induced by lymphocyte-derived IFNγ. We found that the cytochromebdoxidase is specifically required under acidic conditions, where thebc1/aa3complex is preferentially inhibited. Additionally, we show that acidic conditions increased the potency of Q203, a cytochromebc1/aa3inhibitor and candidate tuberculosis therapy. This work defines a new link between the host immune response and the respiratory requirements ofMtbthat affects the potency of a potential new therapeutic.