IL-17A Promotes Intracellular Growth of Mycobacterium by Inhibiting Apoptosis of Infected Macrophages

Cruz, Andrea; Ludovico, Paula; Torrado, Egídio; Gama, José B.; Sousa, Jeremy; Gaifem, Joana; Appelberg, Rui; Rodrigues, Fernando; Cooper, Andrea M.; Pedrosa, Jorge; Saraiva, Margarida

doi:10.3389/fimmu.2015.00498

Cited by 29 publications

(29 citation statements)

References 31 publications

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“…Lombard also highlights that the IL-17A-driven exacerbation of inflammation observed in several circumstances may lead to tissue destruction. IL-17A is overproduced in response to high mycobacterial loads in the mouse [35] or in humans infected with multidrug-resistant Mtb strains resulting in high antigen loads [36], leading to an unfavorable clinical outcome.…”

Section: Discussionmentioning

confidence: 99%

Cording Mycobacterium tuberculosis Bacilli Have a Key Role in the Progression towards Active Tuberculosis, Which is Stopped by Previous Immune Response

Arias

Cardona

Català³

et al. 2020

Microorganisms

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Cording was the first virulence factor identified in Mycobacterium tuberculosis (Mtb). We aimed to ascertain its role in the induction of active tuberculosis (TB) in the mouse strain C3HeB/FeJ by testing the immunopathogenic capacity of the H37Rv strain. We have obtained two batches of the same strain by stopping their growth in Proskauer Beck liquid medium once the mid-log phase was reached, in the noncording Mtb (NCMtb) batch, and two days later in the cording Mtb (CMtb) batch, when cording could be detected by microscopic analysis. Mice were challenged with each batch intravenously and followed-up for 24 days. CMtb caused a significant increase in the bacillary load at an early stage post-challenge (day 17), when a granulomatous response started, generating exudative lesions characterized by neutrophilic infiltration, which promoted extracellular bacillary growth together with cording formation, as shown for the first time in vivo. In contrast, NCMtb experienced slight or no bacillary growth and lesions could barely be detected. Previous Bacillus Calmette-Guérin (BCG) vaccination or low dose aerosol (LDA) Mtb infection were able to delay the progression towards active TB after CMtb challenge. While BCG vaccination also reduced bacillary load when NCMtb was challenged, LDA did not, and its proliferative lesions experienced neutrophil infiltration. Analysis of lung cytokine and chemokine profiles points to their capacity to block the production of CXCL-1 and further amplification of IL-1β, IL-17 and neutrophilic extracellular trap formation, all of which are essential for TB progression. These data highlight the key role of cording formation in the induction of active TB.

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Section: Discussionmentioning

confidence: 99%

Cording Mycobacterium tuberculosis Bacilli Have a Key Role in the Progression towards Active Tuberculosis, Which is Stopped by Previous Immune Response

Arias

Cardona

Català³

et al. 2020

Microorganisms

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“…Importantly, in anti-IL-17A-antibody-treated mice gene expression patterns associated with macrophage polarization and pro- and anti-apoptotic responses were not affected. In fact, a recent study showed that IL-17A actually promotes intracellular growth of M. tuberculosis by inhibiting apoptosis of infected macrophages68. Thus, while anti-TNFα antibody treatment prevents apoptosis of mycobacterially infected macrophages enabling bacterial growth, anti-IL-17A treatment may actually limit intracellular growth of M. tuberculosis by enhancing apoptosis of infected macrophages.…”

Section: Discussionmentioning

confidence: 99%

Controlled Mycobacterium tuberculosis infection in mice under treatment with anti-IL-17A or IL-17F antibodies, in contrast to TNFα neutralization

Segueni¹,

Tritto²,

Bourigault³

et al. 2016

Sci Rep

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Antibodies targeting IL-17A or its receptor IL-17RA show unprecedented efficacy in the treatment of autoimmune diseases such as psoriasis. These therapies, by neutralizing critical mediators of immunity, may increase susceptibility to infections. Here, we compared the effect of antibodies neutralizing IL-17A, IL-17F or TNFα on murine host responses to Mycobacterium tuberculosis infection by evaluating lung transcriptomic, microbiological and histological analyses. Coinciding with a significant increase of mycobacterial burden and pathological changes following TNFα blockade, gene array analyses of infected lungs revealed major changes of inflammatory and immune gene expression signatures 4 weeks post-infection. Specifically, gene expression associated with host-pathogen interactions, macrophage recruitment, activation and polarization, host-antimycobacterial activities, immunomodulatory responses, as well as extracellular matrix metallopeptidases, were markedly modulated by TNFα blockade. IL-17A or IL-17F neutralization elicited only mild changes of few genes without impaired host resistance four weeks after M. tuberculosis infection. Further, the absence of both IL-17RA and IL-22 pathways in genetically deficient mice did not profoundly compromise host control of M. tuberculosis over a 6-months period, ruling out potential compensation between these two pathways, while TNFα-deficient mice succumbed rapidly. These data provide experimental confirmation of the low clinical risk of mycobacterial infection under anti-IL-17A therapy, in contrast to anti-TNFα treatment.

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“…Further mechanistic investigations into the host–pathogen interactions during transition from dormant to reactivated pathogen states utilizing the in vitro human M. tuberculosis microgranuloma model are ongoing to address the obvious limitations of this observational study. Whereas anti‐TNFα antibody treatment may prevent apoptosis of M. tuberculosis ‐infected macrophages enabling bacterial growth, 13 a recent study showed that IL‐17A actually promotes intracellular growth of M. tuberculosis by inhibiting apoptosis of infected macrophages 60 . Hence, anti‐IL‐17A treatment may limit intracellular growth of M. tuberculosis by enhancing apoptosis of infected macrophages.…”

Section: Discussionmentioning

confidence: 99%

“…Whereas anti-TNFα antibody treatment may prevent apoptosis of M. tuberculosis-infected macrophages enabling bacterial growth, 13 a recent study showed that IL-17A actually promotes intracellular growth of M. tuberculosis by inhibiting apoptosis of infected macrophages. 60 Hence, anti-IL-17A treatment may limit intracellular growth of M. tuberculosis by enhancing apoptosis of infected macrophages.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of IL‐17A by secukinumab shows no evidence of increased Mycobacterium tuberculosis infections

et al. 2017

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Secukinumab, a fully human monoclonal antibody that selectively neutralizes interleukin-17A (IL-17A), has been shown to have significant efficacy in the treatment of moderate to severe psoriasis, psoriatic arthritis and ankylosing spondylitis. Blocking critical mediators of immunity may carry a risk of increased opportunistic infections. Here we present clinical and in vitro findings examining the effect of secukinumab on Mycobacterium tuberculosis infection. We re-assessed the effect of secukinumab on the incidence of acute tuberculosis (TB) and reactivation of latent TB infection (LTBI) in pooled safety data from five randomized, double-blind, placebo-controlled, phase 3 clinical trials in subjects with moderate to severe plaque psoriasis. No cases of TB were observed after 1 year. Importantly, in subjects with a history of pulmonary TB (but negative for interferon-γ release and receiving no anti-TB medication) or positive for latent TB (screened by interferon-γ release assay and receiving anti-TB medication), no cases of active TB were reported. Moreover, an in vitro study examined the effect of the anti-tumor necrosis factor-α (TNFα) antibody adalimumab and secukinumab on dormant M. tuberculosis H37Rv in a novel human three-dimensional microgranuloma model. Auramine-O, Nile red staining and rifampicin resistance of M. tuberculosis were measured. In vitro, anti-TNFα treatment showed increased staining for Auramine-O, decreased Nile red staining and decreased rifampicin resistance, indicative of mycobacterial reactivation. In contrast, secukinumab treatment was comparable to control indicating a lack of effect on M. tuberculosis dormancy. To date, clinical and preclinical investigations with secukinumab found no evidence of increased M. tuberculosis infections.

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IL-17A Promotes Intracellular Growth of Mycobacterium by Inhibiting Apoptosis of Infected Macrophages

Cited by 29 publications

References 31 publications

Cording Mycobacterium tuberculosis Bacilli Have a Key Role in the Progression towards Active Tuberculosis, Which is Stopped by Previous Immune Response

Cording Mycobacterium tuberculosis Bacilli Have a Key Role in the Progression towards Active Tuberculosis, Which is Stopped by Previous Immune Response

Controlled Mycobacterium tuberculosis infection in mice under treatment with anti-IL-17A or IL-17F antibodies, in contrast to TNFα neutralization

Inhibition of IL‐17A by secukinumab shows no evidence of increased Mycobacterium tuberculosis infections

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