Dysregulation of the IFN-I signaling pathway by Mycobacterium tuberculosis leads to exacerbation of HIV-1 infection of macrophages.
J Leukoc Biol
; 112(5): 1329-1342, 2022 11.
Article
em En
| MEDLINE
| ID: mdl-35588259
ABSTRACT
While tuberculosis (TB) is a risk factor in HIV-1-infected individuals, the mechanisms by which Mycobacterium tuberculosis (Mtb), the agent of TB in humans, worsens HIV-1 pathogenesis still need to be fully elucidated. Recently, we showed that HIV-1 infection and spread are exacerbated in macrophages exposed to TB-associated microenvironments. Transcriptomic analysis of macrophages conditioned with medium of Mtb-infected human macrophages (cmMTB) revealed an up-regulation of the typeI interferon (IFN-I) pathway, characterized by the overexpression of IFN-inducible genes. Historically, IFN-I are well known for their antiviral functions, but our previous work showed that this is not the case in the context of coinfection with HIV-1. Here, we show that the IFN-I response signature in cmMTB-treated macrophages matches the one observed in the blood of active TB patients, and depends on the timing of incubation with cmMTB. This suggests that the timing of macrophage's exposure to IFN-I can impact their capacity to control HIV-1 infection. Strikingly, we found that cmMTB-treated macrophages are hyporesponsive to extrastimulation with exogenous IFN-I, used to mimic HIV-1 infection. Yet, depleting STAT1 by gene silencing to block the IFN-I signaling pathway reduced TB-induced exacerbation of HIV-1 infection. Altogether, by aiming to understand why TB-derived IFN-I preexposure of macrophages did not induce antiviral immunity against HIV-1, we demonstrated that these cells are hyporesponsive to exogenous IFN-I, a phenomenon that prevents macrophage activation against HIV-1.
RESUMEN
Mycobacterium tuberculosis induces hyporesponsiveness of the IFN-I signaling pathway in macrophages, leading to the exacerbation of HIV-1 replication.
Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Tuberculose
/
Interferon Tipo I
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Infecções por HIV
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Coinfecção
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Macrófagos
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Mycobacterium tuberculosis
Tipo de estudo:
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
J Leukoc Biol
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
França