Host immunity increases Mycobacterium tuberculosis reliance on cytochrome bd oxidase

Abstract

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, 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.

Cytochrome bd‐I from Escherichia coli is catalytically active in the absence of the CydH subunit

“…It has been shown that cytochrome bd ‐I can detoxify various reactive oxygen and nitrogen species [10–13]. In line with these molecular features, cytochrome bd‐ I is important for biofilm formation [14,15] and for host infection by pathogenic E. coli strains [16] and various other pathogenic bacteria [17–20].…”