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dc.contributor.authorCai, Yi
dc.contributor.authorJaecklein, Eleni
dc.contributor.authorMackenzie, Jared
dc.contributor.authorPapavinasasundaram, Kadamba
dc.contributor.authorMichigan State University
dc.contributor.authorChen, Xinchun
dc.contributor.authorAfrica Health Research Institute
dc.contributor.authorSassetti, Christopher M.
dc.date2022-08-11T08:08:25.000
dc.date.accessioned2022-08-23T15:54:25Z
dc.date.available2022-08-23T15:54:25Z
dc.date.issued2020-08-21
dc.date.submitted2020-09-03
dc.identifier.citation<p>bioRxiv 2020.08.21.260737; doi: https://doi.org/10.1101/2020.08.21.260737. <a href="https://doi.org/10.1101/2020.08.21.260737" target="_blank" title="View preprint on bioRxiv">Link to preprint on bioRxiv service</a>.</p>
dc.identifier.doi10.1101/2020.08.21.260737
dc.identifier.urihttp://hdl.handle.net/20.500.14038/29550
dc.description.abstractIn 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, 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 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.
dc.language.isoen_US
dc.relationNow published in PLOS Pathogens doi: 10.1371/journal.ppat.1008911
dc.rightsThe copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY 4.0 International license.
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectMicrobiology
dc.subjectMycobacterium tuberculosis
dc.subjectcytochrome bd oxidase
dc.subjectimmunity
dc.subjectAmino Acids, Peptides, and Proteins
dc.subjectBacteria
dc.subjectBacterial Infections and Mycoses
dc.subjectEnzymes and Coenzymes
dc.subjectImmunity
dc.subjectImmunology of Infectious Disease
dc.subjectImmunopathology
dc.subjectMicrobiology
dc.titleHost immunity increases Mycobacterium tuberculosis reliance on cytochrome bd oxidase [preprint]
dc.typePreprint
dc.source.journaltitlebioRxiv
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=2788&amp;context=faculty_pubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/faculty_pubs/1771
dc.identifier.contextkey19232026
refterms.dateFOA2022-08-23T15:54:25Z
html.description.abstract<p><p id="x-x-x-p-3">In order to sustain a persistent infection, <em>Mycobacterium tuberculosis</em> (<em>Mtb</em>) 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 <em>Mtb</em> metabolism, including a respiratory chain that consists of two distinct terminal cytochrome oxidase complexes. Under the conditions tested thus far, the <em>bc</em><sub><em>1</em></sub><em>/aa</em><sub><em>3</em></sub> complex appears to play a dominant role, while the alternative <em>bd</em> 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 <em>bd</em> 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 <em>ΔcydA</em> mutants were hypersusceptible to the low pH encountered in IFNγ-activated macrophages. Unlike wild type <em>Mtb</em>, cytochrome <em>bd</em>-deficient bacteria were unable to sustain a maximal oxygen consumption rate (OCR) at low pH, indicating that the remaining cytochrome <em>bc</em><sub><em>1</em></sub><em>/aa</em><sub><em>3</em></sub> complex is preferentially inhibited under acidic conditions. Consistent with this model, the potency of the cytochrome <em>bc</em><sub><em>1</em></sub><em>/aa</em><sub><em>3</em></sub> 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.</p>
dc.identifier.submissionpathfaculty_pubs/1771
dc.contributor.departmentGraduate School of Biomedical Sciences
dc.contributor.departmentDepartment of Microbiology and Physiological Systems


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The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a  CC-BY 4.0 International license.
Except where otherwise noted, this item's license is described as The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY 4.0 International license.