Interleukin-17 limits hypoxia-inducible factor 1α and development of hypoxic granulomas during tuberculosis

Domingo-Gonzalez, Racquel; Das, Shibali; Griffiths, Kristin; Ahmed, Mushtaq; Bambousková, Monika; Gopal, Radha; Gondi, Suhas; Muñoz-Torrico, Marcela; Salazar-Lezama, Miguel Ángel; Cruz‐Lagunas, Alfredo; Jiménez-Álvarez, Luis Armando; Ramírez-Martínez, Gustavo; Espinosa-Soto, Ramón; Sultana, Tamanna; Lyons‐Weiler, James; Reinhart, Todd A.; Arcos, Jesus; García-Hernández, María de la Luz; Mastrangelo, Michael A.; Al-Hammadi, Noor; Townsend, R. Reid; Balada-Llasat, Joan-Miquel; Torrelles, Jordi B.; Kaplan, Gilla; William, Horne; Kolls, Jay K.; Artyomov, Maxim N.; Rangel-Moreno, Javier; Zúñiga, Joaquı́n; Khader, Shabaana A.

doi:10.1172/jci.insight.92973

Cited by 50 publications

(53 citation statements)

References 58 publications

(67 reference statements)

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“…Accumulation of mycobacterial permissive and immunosuppressive polymorphonuclear and mononuclear MDSCs has also been reported in chronic Mtb infection in both mice and humans (32,33). These immunoregulatory cells localize to the perinecrotic regions of chronic granulomas in the lungs of murine and NHP TB models, signifying host failure of Mtb replication control (33)(34)(35). Although the presence of CD11b lo Gr-1 hi Ly6G hi Ly6C lo polymorphonuclear MDSCs (PMN-MDSCs) was not specifically investigated here, it is possible that the MDSCs are included in the CD11b + Gr-1 + gate used in the current study.…”

Section: Discussionmentioning

confidence: 97%

S100A8/A9 regulates CD11b expression and neutrophil recruitment during chronic tuberculosis

Scott¹,

Swanson²,

Al-Hammadi³

et al. 2020

Journal of Clinical Investigation

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110

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Section: Discussionmentioning

confidence: 97%

S100A8/A9 regulates CD11b expression and neutrophil recruitment during chronic tuberculosis

Scott¹,

Swanson²,

Al-Hammadi³

et al. 2020

Journal of Clinical Investigation

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110

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“…Contrary to the debatable PGL hypervirulence effects where M. tuberculosis PGL-deficient strains induce pro-inflammation (141), recent studies, using a necrotic M. tuberculosis mouse model, show that loss of M. tuberculosis PGLs decreases the Th17 response (e.g., IL-17A), where IL-17A production seems critical to limit the development of hypoxic necrotic granulomas and reduces disease severity in TB (142). Thus, indirectly, M. tuberculosis PGL may favor M. tuberculosis infection reducing tissue damage.…”

Section: The Pgl Familymentioning

confidence: 99%

Underestimated Manipulative Roles of Mycobacterium tuberculosis Cell Envelope Glycolipids During Infection

2019

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The Mycobacterium tuberculosis cell envelope has been evolving over time to make the bacterium transmissible and adaptable to the human host. In this context, the M. tuberculosis cell envelope contains a peripheral barrier full of lipids, some of them unique, which confer M. tuberculosis with a unique shield against the different host environments that the bacterium will encounter at the different stages of infection. This lipid barrier is mainly composed of glycolipids that can be characterized by three different subsets: trehalose-containing, mannose-containing, and 6-deoxy-pyranose-containing glycolipids. In this review, we explore the roles of these cell envelope glycolipids in M. tuberculosis virulence and pathogenesis, drug resistance, and further, how these glycolipids may dictate the M. tuberculosis cell envelope evolution from ancient to modern strains. Finally, we address how these M. tuberculosis cell envelope glycolipids are impacted by the host lung alveolar environment, their role in vaccination and masking host immunity, and subsequently the impact of these glycolipids in shaping how M. tuberculosis interacts with host cells, manipulating their immune response to favor the establishment of an infection.

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“…Besides, HIF-1α is not only a transcriptional regulator of LDHA, but also coordinates IFN-γ-dependent adaptive immunity to M. tuberculosis (10). It has been reported that IL-17 limits HIF1α expression (and lactate accumulation) and hypoxic necrotic granuloma development in C3HeB/FeJ mice infected with an M. tuberculosis clinical isolate (12). Thus, LDHA inhibition resulting in heightened IL-17 activity and/or reduced IFN-γ-dependent exacerbated inflammation could explain the FX11-limited necrotic granuloma progression in the Nos2 −/− mouse model.…”

Section: Resultsmentioning

confidence: 99%

“…Generation of lactate from pyruvate, a terminal glycolytic step, is catalyzed by lactate dehydrogenase A (LDHA), whose functions depend on hypoxia-inducible factors (HIFs) (10). Both LDHA and HIF1-α transcripts have been found to be significantly induced in M. tuberculosis -infected mouse lungs (11, 12), and the essential function of HIF1-α in controlling TB progression has already been recognized (10). Although metabolic phenotypes of malignant and immune cells show some critical differences, they present many similarities (13).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of host Lactate dehydrogenase A by a small-molecule limitsMycobacterium tuberculosisgrowth and potentiates bactericidal activity of isoniazid

Gopinath

Kaiser

Abed

et al. 2019

Preprint

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13Lactate dehydrogenase A (LDHA) mediates interconversion of pyruvate and lactate. Increased 14 lactate turnover is shared by malignant and immune cells. Hypoxic lung granuloma in 15 Mycobacterium tuberculosis-infected animals present elevated levels of Ldha and lactate. Such 16 alteration in metabolic milieu could influence the outcome of interactions between M. 17 tuberculosis and its infected immune cells. Given the central role of LDHA for tumorigenicity, 18 targeting lactate metabolism is a promising approach for cancer therapy. Here, we sought to 19 determine the importance of LDHA for Tuberculosis (TB) disease progression and its potential as 20 a host-directed therapeutic target. To this end, we administered FX11, a small-molecule NADH-21 competitive LDHA inhibitor, to M. tuberculosis infected C57BL/6J mice and Nos2 -/mice with 22 hypoxic necrotizing lung TB lesions mimicking human pathology more closely. FX11 did not 23 inhibit M. tuberculosis growth in aerobic/hypoxic liquid culture, but modestly reduced the 24 pulmonary bacterial burden in C57BL/6J mice. Intriguingly, FX11 administration limited M. 25 tuberculosis replication and onset of necrotic lesions in Nos2 -/mice. In this model, Isoniazid 26 (INH) monotherapy has been known to exhibit biphasic killing kinetics owing to the probable 27 selection of an INH-tolerant subpopulation. This adverse effect was corrected by adjunct FX11 28 treatment and augmented the INH-derived bactericidal effect against M. tuberculosis. Our 29findings therefore support LDHA as a potential target for host-directed adjunctive TB therapy 30 and encourage further investigations into the underlying mechanism. 31 IMPORTANCE 32Tuberculosis (TB) continues to be a global health threat of critical dimension. 33Standard TB drug treatment is prolonged and cumbersome. Inappropriate treatment or non-34 compliance results in emergence of drug-resistant Mycobacterium tuberculosis strains (MDR-35 3 TB) that render current treatment options ineffective. Targeting the host immune system as 36 adjunct therapy to augment bacterial clearance is attractive as it is also expected to be effective 37 against MDR-TB. Here, we provide evidence that pharmaceutical blockade of host lactate 38 dehydrogenase A (LDHA) by a small-molecule limits M. tuberculosis growth and reduces 39 pathology. Notably, LDHA inhibition potentiates the effect of Isoniazid, a first-line anti-TB 40 drug. Hence, its implications of our findings for short-term TB treatment are profound. In sum, 41 our findings establish murine LDHA as a potential target for host-directed TB therapy. 42Untargeted metabolite analysis has identified elevated levels of lactate in necrotic 59 granuloma of M. tuberculosis-infected guinea pigs (9). Generation of lactate from pyruvate, a 60 terminal glycolytic step, is catalyzed by lactate dehydrogenase A (LDHA), whose functions 61 depend on hypoxia-inducible factors (HIFs) (10). Both LDHA and HIF1-α transcripts have been 62 found to be significantly induced in M. tuberculosis-infected m...

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Interleukin-17 limits hypoxia-inducible factor 1α and development of hypoxic granulomas during tuberculosis

Cited by 50 publications

References 58 publications

S100A8/A9 regulates CD11b expression and neutrophil recruitment during chronic tuberculosis

S100A8/A9 regulates CD11b expression and neutrophil recruitment during chronic tuberculosis

Underestimated Manipulative Roles of Mycobacterium tuberculosis Cell Envelope Glycolipids During Infection

Inhibition of host Lactate dehydrogenase A by a small-molecule limitsMycobacterium tuberculosisgrowth and potentiates bactericidal activity of isoniazid

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