IFNG-mediated immune responses enhance autophagy against<i>Mycobacterium tuberculosis</i>antigens in patients with active tuberculosis

Rovetta, Ana Inés; Peña, Delfina; Pino, Rodrigo Emanuel Hernández Del; Recalde, Gabriela; Pellegrini, Joaquín Miguel; Bigi, Fabiana; Musella, Rosa M.; Palmero, Domingo; Gutierrez, Marisa; Colombo, María Isabel; García, Verónica

doi:10.4161/15548627.2014.981791

Cited by 62 publications

(58 citation statements)

References 51 publications

(87 reference statements)

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“…4.8.2.0 software (Carl Zeiss). The number of fluorescent LC3 puncta was quantified using the Particle Analyzer plugin of ImageJ software after image thresholding [14,32]. ImageJ was also used for colocalization analysis.…”

Section: Methodsmentioning

confidence: 99%

Autophagy Is an Innate Mechanism Associated with Leprosy Polarization

et al. 2017

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Leprosy is a chronic infectious disease that may present different clinical forms according to the immune response of the host. Levels of IFN-γ are significantly raised in paucibacillary tuberculoid (T-lep) when compared with multibacillary lepromatous (L-lep) patients. IFN-γ primes macrophages for inflammatory activation and induces the autophagy antimicrobial mechanism. The involvement of autophagy in the immune response against Mycobacterium leprae remains unexplored. Here, we demonstrated by different autophagic assays that LC3-positive autophagosomes were predominantly observed in T-lep when compared with L-lep lesions and skin-derived macrophages. Accumulation of the autophagic receptors SQSTM1/p62 and NBR1, expression of lysosomal antimicrobial peptides and colocalization analysis of autolysosomes revealed an impairment of the autophagic flux in L-lep cells, which was restored by IFN-γ or rapamycin treatment. Autophagy PCR array gene-expression analysis revealed a significantly upregulation of autophagy genes (BECN1, GPSM3, ATG14, APOL1, and TPR) in T-lep cells. Furthermore, an upregulation of autophagy genes (TPR, GFI1B and GNAI3) as well as LC3 levels was observed in cells of L-lep patients that developed type 1 reaction (T1R) episodes, an acute inflammatory condition associated with increased IFN-γ levels. Finally, we observed increased BCL2 expression in L-lep cells that could be responsible for the blockage of BECN1-mediated autophagy. In addition, in vitro studies demonstrated that dead, but not live M. leprae can induce autophagy in primary and lineage human monocytes, and that live mycobacteria can reduce the autophagy activation triggered by dead mycobacteria, suggesting that M. leprae may hamper the autophagic machinery as an immune escape mechanism. Together, these results indicate that autophagy is an important innate mechanism associated with the M. leprae control in skin macrophages.

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Section: Methodsmentioning

confidence: 99%

Autophagy Is an Innate Mechanism Associated with Leprosy Polarization

et al. 2017

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“…IFN‐γ induces autophagy in response to Mtb antigens in patients with active TB (Rovetta et al ., 2014). In human primary macrophages, the protective effect of IFN‐γ depends on the timing of addition, concentration and magnitude of the ensuing microbial challenge (Vogt and Nathan, 2011).…”

Section: Autophagy In the Immune Response To Tbmentioning

confidence: 99%

“…In primary human macrophages and THP-1 macrophages, active vitamin D3 also induces the localization of Mtb in autophagosomes in a cathelicidin-dependent manner (Yuk et al, 2009). IFN-γ induces autophagy in response to Mtb antigens in patients with active TB (Rovetta et al, 2014). In human primary macrophages, the protective effect of IFN-γ depends on the timing of addition, concentration and magnitude of the ensuing microbial challenge (Vogt and Nathan, 2011).…”

Section: Autophagy In the Immune Response To Tbmentioning

confidence: 99%

The innate immune response in human tuberculosis

2015

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Summary M ycobacterium tuberculosis (Mtb) infection can be cleared by the innate immune system before the initiation of an adaptive immune response. This innate protection requires a variety of robust cell autonomous responses from many different host immune cell types. However, Mtb has evolved strategies to circumvent some of these defences. In this mini‐review, we discuss these host–pathogen interactions with a focus on studies performed in human cells and/or supported by human genetics studies (such as genome‐wide association studies).

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“…This statement is supported by studies conducted by Gutierrez and co-workers who reported that stimulation of autophagy in macrophages promotes phago-lysosome maturation and impacts mycobacterial survival [8]. More recent investigations revealed increased susceptibility to TB in mice defective in autophagy pathways [9] and a positive interplay between autophagy and interferon-gamma (IFN-γ) in TB patients [10].…”

Section: Promoting Phagosome Maturation and Enhancing Autophagymentioning

confidence: 85%

Host-Directed Therapies and Anti-Virulence Compounds to Address Anti-Microbial Resistant Tuberculosis Infection

2020

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Despite global efforts to contain tuberculosis (TB), the disease remains a leading cause of morbidity and mortality worldwide, further exacerbated by the increased resistance to antibiotics displayed by the tubercle bacillus Mycobacterium tuberculosis. In order to treat drug-resistant TB, alternative or complementary approaches to standard anti-TB regimens are being explored. An area of active research is represented by host-directed therapies which aim to modulate the host immune response by mitigating inflammation and by promoting the antimicrobial activity of immune cells. Additionally, compounds that reduce the virulence of M. tuberculosis, for instance by targeting the major virulence factor ESX-1, are being given increased attention by the TB research community. This review article summarizes the current state of the art in the development of these emerging therapies against TB.

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IFNG-mediated immune responses enhance autophagy againstMycobacterium tuberculosisantigens in patients with active tuberculosis

Cited by 62 publications

References 51 publications

Autophagy Is an Innate Mechanism Associated with Leprosy Polarization

Autophagy Is an Innate Mechanism Associated with Leprosy Polarization

The innate immune response in human tuberculosis

Host-Directed Therapies and Anti-Virulence Compounds to Address Anti-Microbial Resistant Tuberculosis Infection

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