LAG-3 potentiates the survival of Mycobacterium tuberculosis in host phagocytes by modulating mitochondrial signaling in an in-vitro granuloma model

Phillips, Bonnie; Gautam, Uma S.; Bucşan, Allison N.; Foreman, Taylor W.; Golden, Nadia; Niu, Tianhua; Kaushal, Deepak; Mehra, Smriti

doi:10.1371/journal.pone.0180413

Cited by 21 publications

(11 citation statements)

References 60 publications

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“…Activated pDCs have a ~70-fold increase of LAG3 mRNA expression when compared with activated T cells (Workman et al, 2009), suggesting they could be primary mediators of an immunosuppressive environment (Graydon et al, 2019). We also showed that LAG3 expression is induced significantly in the lungs of macaques with PTB and correlates with increased bacterial burden, and LAG3 overproduction can diminish T cell responses (Phillips et al, 2017). Together, these results project pDCs as a key immune cell in the lungs of PTB macaques where they are primed for rapid ll Article type I IFN production, prolonged survival, and may contribute to suppression and exhaustion of T cell responses.…”

Section: Discussionmentioning

confidence: 51%

The immune landscape in tuberculosis reveals populations linked to disease and latency

Esaulova

Das

Singh

et al. 2021

Cell Host & Microbe

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131

126

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Section: Discussionmentioning

confidence: 51%

The immune landscape in tuberculosis reveals populations linked to disease and latency

Esaulova

Das

Singh

et al. 2021

Cell Host & Microbe

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131

126

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“…Monocyte derived macrophages (MDMs) were generated from macaque blood and cocultured with CD4 + s, as described previously ( 73 ). A subset of MDMs was treated with IDO1-specific siRNA 24 h before M. tuberculosis -infection (multiplicity of infection = 10:1) ( Table S1 ) to inhibit IDO1 expression, as described previously ( 71 ).…”

Section: Methodsmentioning

confidence: 99%

In vivo inhibition of tryptophan catabolism reorganizes the tuberculoma and augments immune-mediated control ofMycobacterium tuberculosis

Gautam

Foreman

Bucşan

et al. 2017

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

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198

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SignificanceMycobacterium tuberculosis induces the expression of the indoleamine 2,3-dioxygenase (IDO) enzyme, which catabolizes tryptophan. Tryptophan metabolites potently suppress host immunity. The present study demonstrates that blockade of IDO activity reduces both clinical manifestations of tuberculosis (TB) as well as microbial and pathological correlates of the human TB syndrome in macaques. In granulomas, T cells localize in the periphery, and are unable to access the core, where bacilli persist. Inhibiting IDO activity altered granuloma organization such that more T cells translocated to the lesion core and exhibited highly proliferative signatures. Our results identify a highly efficient immunosuppressive mechanism at play in the granuloma environment that aids in M. tuberculosis persistence. The ability to modulate this pathway with safe and approved compounds could, however, facilitate chemotherapy-adjunctive host-directed therapy approaches for the control of TB.

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“…LAG-3 favors M. tb survival by interfering with the mitochondrial apoptosis pathway. Thus, the silencing/down-regulation of LAG-3 in CD4 + T cell leads to an increase in M. tb killing, IFN-γ expression and decrease in mitochondrial electron transport (Phillips et al, 2017).…”

Section: Modulation Of Innate Immunitymentioning

confidence: 98%

Stealth Strategies of Mycobacterium tuberculosis for Immune Evasion

Naeem¹,

Ahmad²,

Tyagi³

et al. 2021

Current Issues in Molecular Biology

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Tuberculosis is a devastating disease causing high mortality all over the world, especially in the developing countries. Mycobacterium tuberculosis (M. tb) is the causative agent of tuberculosis which replicates in the intracellular environment of host macrophages. Although the host immune system is capable of completely eliminating the pathogen, co-evolution of M. tb with humans has resulted in its ability to hijack the host innate and adaptive immune systems in numerous ways. Limited recent progress has been made in the understanding of M. tb immune escape mechanisms, hence exploration of survival strategies of M. tb has been critically reviewed with an insight into understanding its pathogenesis. We summarized the recent studies regarding the modulation of innate immune response, adaptive immune response, epigenetics and the role of miRNA. All of these advancements suggest that M. tb is well-familiarize with the host immune system and possess the ability to hijack it for intracellular survival. ! 597 Curr. Issues Mol. Biol. (2021) 41: 597-616. caister.com/cimb Stealth Strategies of Mycobacterium tuberculosis for Immune Evasion 2010). It further inhibits the major histocompatibity complex class-II (MHC-II)mediated antigen presentation to adaptive immune cells, i.e. CD4 + T cells (Harding and Boom , 2010). To survive in the hostile cellular environment, pathogenic mycobacteria employ various strategies, such as: phago-lysosome maturation inhibition, autophagy suppression, cytokine activation and production, reactive oxygen (ROS) and nitrogen species (RNS) inhibition, manipulation of antigen presentation to T cells, and epigenetics (Cambier et al., 2014;Harding and Boom, 2010). M. tb is recognized by macrophages through pattern recognition receptors (PRRs) which include; Toll-like receptors (TLR-2, TLR-4, TLR-9), NOD-like receptors (NLR), and C-type lectin receptor (CLR) (Mortaz et al., 2015). Recognition activates intracellular signaling cascades, such as IL-1 receptor-associated kinases (IRAK), TNF receptor-associated factor 6 (TRAF-6), TGF-ß-activated protein kinase 1 (TAK1), and mitogen-activated protein kinases (MAPK) (Ernst, 1998;Mortaz et al., 2015). TLR signaling leads to the release of pro-inflammatory cytokines, such as tumor necrosis factor (TNF), interleukin-12 (IL-12), and IL-1β. These cytokines recruit adaptive immune cells, T-cells, which can aid in the mycobactericidal response by their interferon-gamma (IFN-γ) release (Mortaz et al., 2015). IFN-γ increases the microbicidal capacity of macrophages by enhancing trafficking of the phagocytosed bacteria to lysosomes. Moreover, IFN-γ triggers macrophages to produce damaging radical species, such as ROS and RNS (Mortaz et al., 2015). How M. tb successfully manipulate these responses of the innate and adaptive immune system of host for its persistence is questionable till date? Similar to our present study on M. tb, Ahmed et al., (Ahmed et al., 2016) has described the similar stealing strategies of another notorious intracellular organism, Brucella. The...

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LAG-3 potentiates the survival of Mycobacterium tuberculosis in host phagocytes by modulating mitochondrial signaling in an in-vitro granuloma model

Cited by 21 publications

References 60 publications

The immune landscape in tuberculosis reveals populations linked to disease and latency

The immune landscape in tuberculosis reveals populations linked to disease and latency

In vivo inhibition of tryptophan catabolism reorganizes the tuberculoma and augments immune-mediated control ofMycobacterium tuberculosis

Stealth Strategies of Mycobacterium tuberculosis for Immune Evasion

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