Advances on the Role and Applications of Interleukin-1 in Tuberculosis

Silvério, Diogo; Gonçalves, Rute; Appelberg, Rui; Saraiva, Margarida

doi:10.1128/mbio.03134-21

Cited by 30 publications

(18 citation statements)

References 113 publications

(191 reference statements)

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“…Here, we have revealed that meropenem induces an exacerbated IL-1β secretion by Mtb -infected THP-1 macrophages. This finding should be further explored since host-directed therapies that modulate this cytokine may influence TB progression (67,68). Overall, our outputs contribute to clarifying the placement of beta-lactams in alternative regimens against Mtb , in alignment with WHO requirements for this class (9).…”

Section: Discussionmentioning

confidence: 96%

Ethambutol and Meropenem/Clavulanate Synergy Promotes Enhanced Extracellular and Intracellular Killing ofMycobacterium tuberculosis

Olivença,

Pires,

Silveiro

et al. 2023

Preprint

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Increasing evidence supports the repositioning of beta-lactams for tuberculosis (TB) therapy. However, additional research on the interaction of these drugs with conventional anti-TB agents is still warranted. Since the complex cell envelope ofMycobacterium tuberculosis(Mtb) may pose an additional obstacle to the diffusion of beta-lactams, an improved activity upon combination with drugs that inhibit the synthesis of outer cell wall elements is particularly relevant. In this context, we aimed to determine potential synergies between beta-lactams and the antimycobacterial drugs ethambutol and isoniazid. This was followed by experiments that aimed to confirm if the increased antimicrobial effects remained within the intracellular milieu and if they promoted heightened immune responses. Results of checkerboard assays with H37Rv and eight clinical isolates, including four drug-resistantMtbstrains, exposed that only the treatments containing ethambutol and beta-lactams achieved synergistic effects, while the standard ethambutol and isoniazid association failed to produce synergy in any of the tested isolates. InMtb-infected THP-1 macrophages, combinations of ethambutol with increasing meropenem concentrations consistently displayed superior killing activities over the individual antibiotics. Flow cytometry with BODIPY FL vancomycin, which binds directly to the peptidoglycan, confirmed an increased exposure of this layer after co-treatment. This was reinforced by the high IL-1β secretion levels found in infected macrophages after incubation with concentrations of meropenem above 5 mg/L, which indicated an exposure of the host innate response sensors to pathogen-associated molecular patterns in the PG. Our findings show that the proposed impaired access of beta-lactams to periplasmic transpeptidases is counteracted by concomitant administration with ethambutol. The efficiency of this combination may be attributed to the synchronized inhibition of arabinogalactan and peptidoglycan synthesis, two key cell wall components. Given that beta-lactams exhibit a time-dependent bactericidal activity, a more effective pathogen recognition and killing prompted by this association may be highly beneficial to optimize TB regimens containing carbapenems.

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Section: Discussionmentioning

confidence: 96%

Ethambutol and Meropenem/Clavulanate Synergy Promotes Enhanced Extracellular and Intracellular Killing ofMycobacterium tuberculosis

Olivença,

Pires,

Silveiro

et al. 2023

Preprint

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“…Mtb infection upregulated MFN2 expression to enhance NLRP3 inflammasome formation (Xu et al, 2020). IL-1 is a key cytokine in the immune response against TB (Silveŕio et al, 2021). However, there is still curiosity about how Mtb actually induces inflammation.…”

Section: Inflammasome Activationmentioning

confidence: 99%

Mycobacterium tuberculosis-macrophage interaction: Molecular updates

Moure²,

Yang³

et al. 2023

Front. Cell. Infect. Microbiol.

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Mycobacterium tuberculosis (Mtb), the causative agent of Tuberculosis (TB), remains a pathogen of great interest on a global scale. This airborne pathogen affects the lungs, where it interacts with macrophages. Acidic pH, oxidative and nitrosative stressors, and food restrictions make the macrophage’s internal milieu unfriendly to foreign bodies. Mtb subverts the host immune system and causes infection due to its genetic arsenal and secreted effector proteins. In vivo and in vitro research have examined Mtb-host macrophage interaction. This interaction is a crucial stage in Mtb infection because lung macrophages are the first immune cells Mtb encounters in the host. This review summarizes Mtb effectors that interact with macrophages. It also examines how macrophages control and eliminate Mtb and how Mtb manipulates macrophage defense mechanisms for its own survival. Understanding these mechanisms is crucial for TB prevention, diagnosis, and treatment.

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“…of IL-1R signaling leads to expansion of pathologic lesions in the lung [79][80][81][82][83][84] . We observed that in the absence of IL-1R, mice failed to form organized intestinal pyogranulomas and had elevated intestinal Yp burdens, corroborating previous reports that IL-1R signaling promotes anti-Yersinia defense 48,65,66 .…”

Section: Il-1r Signaling Is Critical For Infection Control During Tub...mentioning

confidence: 99%

A TNF-IL-1 circuit controlsYersiniawithin intestinal granulomas

Matsuda

Sorobetea

Zhang

et al. 2023

Preprint

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Tumor necrosis factor (TNF) is a pleiotropic inflammatory cytokine that mediates antimicrobial defense and granuloma formation in response to infection by numerous pathogens. Yersinia pseudotuberculosis colonizes the intestinal mucosa and induces recruitment of neutrophils and inflammatory monocytes into organized immune structures termed pyogranulomas that control the bacterial infection. Inflammatory monocytes are essential for control and clearance of Yersinia within intestinal pyogranulomas, but how monocytes mediate Yersinia restriction is poorly understood. Here, we demonstrate that TNF signaling in monocytes is required for bacterial containment following enteric Yersinia infection. We further show that monocyte-intrinsic TNFR1 signaling drives production of monocyte-derived interleukin-1 (IL-1), which signals through IL-1 receptor on non-hematopoietic cells to enable pyogranuloma-mediated control of Yersinia infection. Altogether, our work reveals a monocyte-intrinsic TNF-IL-1 collaborative circuit as a crucial driver of intestinal granuloma function, and defines the cellular target of TNF signaling that restricts intestinal Yersinia infection.

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Advances on the Role and Applications of Interleukin-1 in Tuberculosis

Cited by 30 publications

References 113 publications

Ethambutol and Meropenem/Clavulanate Synergy Promotes Enhanced Extracellular and Intracellular Killing ofMycobacterium tuberculosis

Ethambutol and Meropenem/Clavulanate Synergy Promotes Enhanced Extracellular and Intracellular Killing ofMycobacterium tuberculosis

Mycobacterium tuberculosis-macrophage interaction: Molecular updates

A TNF-IL-1 circuit controlsYersiniawithin intestinal granulomas

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