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1.
PLoS Pathog ; 17(7): e1008911, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34320028

RESUMEN

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 (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.


Asunto(s)
Complejo IV de Transporte de Electrones/metabolismo , Evasión Inmune/fisiología , Mycobacterium tuberculosis/inmunología , Tuberculosis/inmunología , Adaptación Fisiológica/fisiología , Animales , Humanos , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/microbiología , Ratones , Mycobacterium tuberculosis/enzimología
2.
bioRxiv ; 2024 Oct 11.
Artículo en Inglés | MEDLINE | ID: mdl-39091727

RESUMEN

Mycobacterium tuberculosis (Mtb) infection of macrophages reprograms cellular metabolism to promote lipid retention. While it is clearly known that intracellular Mtb utilize host derived lipids to maintain infection, the role of macrophage lipid processing on the bacteria's ability to access the intracellular lipid pool remains undefined. We utilized a CRISPR-Cas9 genetic approach to assess the impact of sequential steps in fatty acid metabolism on the growth of intracellular Mtb. Our analyzes demonstrate that mutated macrophages that cannot either import, store or catabolize fatty acids restrict Mtb growth by both common and divergent anti-microbial mechanisms, including increased glycolysis, increased oxidative stress, production of pro-inflammatory cytokines, enhanced autophagy and nutrient limitation. We also show that impaired macrophage lipid droplet biogenesis is restrictive to Mtb replication, but increased induction fails to rescue Mtb growth. Our work expands our understanding of how host fatty acid homeostasis impacts Mtb growth in the macrophage.

3.
bioRxiv ; 2024 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-38766174

RESUMEN

The eukaryotic GID/CTLH complex is a highly conserved E3 ubiquitin ligase involved in a broad range of biological processes. However, a role of this complex in host antimicrobial defenses has not been described. We exploited Mycobacterium tuberculosis ( Mtb ) induced cytotoxicity in macrophages in a FACS based CRISPR genetic screen to identify host determinants of intracellular Mtb growth restriction. Our screen identified 5 ( GID8 , YPEL5 , WDR26 , UBE2H , MAEA ) of the 10 predicted members of the GID/CTLH complex as determinants of intracellular growth of both Mtb and Salmonella serovar Typhimurium. We show that the antimicrobial properties of the GID/CTLH complex knockdown macrophages are mediated by enhanced GABAergic signaling, activated AMPK, increased autophagic flux and resistance to cell death. Meanwhile, Mtb isolated from GID/CTLH knockdown macrophages are nutritionally starved and oxidatively stressed. Our study identifies the GID/CTLH complex activity as broadly suppressive of host antimicrobial responses against intracellular bacterial infections.

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