Serine protease activity contributes to control of Mycobacterium tuberculosis in hypoxic lung granulomas in mice

Reece, Stephen T.; Loddenkemper, Christoph; Askew, David J.; Zedler, Ulrike; Schommer-Leitner, Sandra; Stein, Maik; Mir, Fayaz Ahmad; Dorhoi, Anca; Mollenkopf, Hans-Joachim; Silverman, Gary A.; Kaufmann, Stefan H. E.

doi:10.1172/jci42796

Cited by 82 publications

(82 citation statements)

References 59 publications

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“…S1), they showed significantly increased bacterial burden and numbers of granulomas in the lungs at day 56 p.i., with a greater proportion demonstrating hypoxia and central caseation, classical features of human granuloma pathology ( Fig. 1 A-C) (37). We investigated whether Arg1 was expressed in lung granulomas in this model.…”

Section: Resultsmentioning

confidence: 95%

“…(Fig. 1 A-C) (37). When infected Nos2 −/− mice were subjected to temporary antibody-mediated blocking of IFN-γ at days 14 and 21 p.i.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, we described the formation of human-like TB granulomas in Nos2 −/− mice when Mtb bacilli disseminated to the lung via hematogenous spread from a primarily lymphatic focus after infection of the ear dermis (Fig. S1A) (37). Dermally Mtbinfected (hereafter referred to simply as "infected") Nos2 −/− mice, but not WT mice, demonstrated culturable Mtb and mainly nonnecrotizing granulomas, but also occasional necrotic granulomas, in the lungs at day 56 postinfection (p.i.)…”

Section: Resultsmentioning

confidence: 99%

“…This observation contrasts with the recent finding that in aerosol Mtb-infected Nos2 −/− mice CD11b + myeloid-derived suppressor cells (MDSCs) expressing high levels of Arg1 are located at the edges of necrotic lung lesions in which neutrophils and MDSCs are thought to be the main drivers of lung necrosis (50). Differences in bacterial burden in the lung upon aerosol and dermal infection would affect the kinetics of inflammatory cellular influx into the lung, which subsequently determines the ultimate architecture and structure of the lesions (37,50). More specifically, the lower bacterial counts (10 4 cfus) at early time points (day 30 p.i.)…”

Section: Discussionmentioning

confidence: 99%

“…Nos2 −/− mice dermally infected with Mtb, but not aerosol Mtb-infected Nos2 −/− mice, recapitulate several features of TB granuloma pathology in humans, including hypoxia and caseation in the central regions of lung granulomas (37). We identified Arg1-expressing macrophages in hypoxic TB granulomas in the lungs of dermally Mtb-infected Nos2 −/− mice that were analogous to TB lung granulomas in humans and nonhuman primates (NHPs) (11,38).…”

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confidence: 91%

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Macrophage arginase-1 controls bacterial growth and pathology in hypoxic tuberculosis granulomas

Duque-Correa¹,

Kühl

Rodríguez

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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110

109

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Lung granulomas develop upon Mycobacterium tuberculosis (Mtb) infection as a hallmark of human tuberculosis (TB). They are structured aggregates consisting mainly of Mtb-infected and -uninfected macrophages and Mtb-specific T cells. The production of NO by granuloma macrophages expressing nitric oxide synthase-2 (NOS2) via L-arginine and oxygen is a key protective mechanism against mycobacteria. Despite this protection, TB granulomas are often hypoxic, and bacterial killing via NOS2 in these conditions is likely suboptimal. Arginase-1 (Arg1) also metabolizes L-arginine but does not require oxygen as a substrate and has been shown to regulate NOS2 via substrate competition. However, in other infectious diseases in which granulomas occur, such as leishmaniasis and schistosomiasis, Arg1 plays additional roles such as T-cell regulation and tissue repair that are independent of NOS2 suppression. To address whether Arg1 could perform similar functions in hypoxic regions of TB granulomas, we used a TB murine granuloma model in which NOS2 is absent. Abrogation of Arg1 expression in macrophages in this setting resulted in exacerbated lung granuloma pathology and bacterial burden. Arg1 expression in hypoxic granuloma regions correlated with decreased T-cell proliferation, suggesting that Arg1 regulation of T-cell immunity is involved in disease control. Our data argue that Arg1 plays a central role in the control of TB when NOS2 is rendered ineffective by hypoxia.

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Section: Resultsmentioning

confidence: 95%

“…(Fig. 1 A-C) (37). When infected Nos2 −/− mice were subjected to temporary antibody-mediated blocking of IFN-γ at days 14 and 21 p.i.…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 91%

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Macrophage arginase-1 controls bacterial growth and pathology in hypoxic tuberculosis granulomas

Duque-Correa¹,

Kühl

Rodríguez

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

110

109

View full text Add to dashboard Cite

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Activation of the NLRP3 inflammasome by Mycobacterium tuberculosis is uncoupled from susceptibility to active tuberculosis

et al. 2011

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As a hallmark of tuberculosis (TB), Mycobacterium tuberculosis (MTB) induces granulomatous lung lesions and systemic inflammatory responses during active disease. Molecular regulation of inflammation is associated with inflammasome assembly. We determined the extent to which MTB triggers inflammasome activation and how this impacts on the severity of TB in a mouse model. MTB stimulated release of mature IL-1b in macrophages while attenuated M. bovis BCG failed to do so. Tubercle bacilli specifically activated the NLRP3 inflammasome and this propensity was strictly controlled by the virulenceassociated RD1 locus of MTB. However, Nlrp3-deficient mice controlled pulmonary TB, a feature correlated with NLRP3-independent production of IL-1b in infected lungs. Our studies demonstrate that MTB activates the NLRP3 inflammasome in macrophages in an ESX-1-dependent manner. However, during TB, MTB promotes NLRP3-and caspase-1-independent IL-1b release in myeloid cells recruited to lung parenchyma and thus overcomes NLRP3 deficiency in vivo in experimental models.

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Frequency and co‐occurrence of porous skeletal lesions in identified non‐adults from Portugal (19th to 20th centuries) and its association with respiratory infections as cause of death

Gomes

Petit

Dutour

et al. 2022

Intl J of Osteoarchaeology

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Porous skeletal lesions (PSL) have been reported in scientific literature since the 19th century, yet their etiology(ies) remains a complex issue under debate. The aim of this study is twofold: evaluate the frequency, co-occurrence, and association of PSL with biological sex and age at death and examine possible relationships between the presence/absence of PSL with the known cause of death (COD). Fifty-six non-adult skeletons from the Coimbra Identified Skeletal Collection (19th to 20th centuries) were evaluated. Lesion presence/absence was recorded macroscopically without previous knowledge of the biographic data. Forty-nine individuals (87.5%) presented at least one type of PSL, and cribra femoralis was the most frequent (n = 39), followed by orbitalia (n = 26), humeralis (n = 15), and cranii (n = 6). Porous skeletal lesions affected males and females equally, and younger individuals presented a significantly higher frequency of cribra femoralis. Even without statistical significance, the cooccurrence of cribra orbitalia, humeralis, and femoralis was common, as described in the "cribrous syndrome" where it is advocated a shared etiology for these lesions, based on macroscopic, microscopic, and radiological features. Individuals with a COD as respiratory infection, particularly pulmonary tuberculosis, exhibited a higher risk of expressing cribra orbitalia. The results of this investigation suggest an influence of age and infectious diseases in the expression of PSL, impacting the bioarchaeological interpretations. There is a need for further research in clinical, autopsy, and identified skeletal collection samples to further understand co-occurrence, comorbidity, and possible frailty related to PSL.

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Serine protease activity contributes to control of Mycobacterium tuberculosis in hypoxic lung granulomas in mice

Cited by 82 publications

References 59 publications

Macrophage arginase-1 controls bacterial growth and pathology in hypoxic tuberculosis granulomas

Macrophage arginase-1 controls bacterial growth and pathology in hypoxic tuberculosis granulomas

Activation of the NLRP3 inflammasome by Mycobacterium tuberculosis is uncoupled from susceptibility to active tuberculosis

Frequency and co‐occurrence of porous skeletal lesions in identified non‐adults from Portugal (19th to 20th centuries) and its association with respiratory infections as cause of death

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