Interaction of Mycobacterium tuberculosis with Host Cell Death Pathways

Srinivasan, Lalitha; Ahlbrand, Sarah E.; Briken, Volker

doi:10.1101/cshperspect.a022459

Cited by 72 publications

(59 citation statements)

References 92 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…When such immune evasive strategies are employed, MTB is successfully able to replicate within macrophages . Macrophages infected with MTB may undergo apoptosis, which has been shown to enhance killing of MTB as well as facilitate antigen presentation to T cells through either MHC class I or CD1 molecules . Thus, any increase in apoptosis of MTB ‐infected macrophages is likely to enhance host immunity against MTB .…”

Section: Introductionmentioning

confidence: 99%

Curcumin enhances human macrophage control of Mycobacterium tuberculosis infection

Bai

Oberley‐Deegan

Bai³

et al. 2016

Respirology

View full text Add to dashboard Cite

Background and objective: With the worldwide emergence of highly drug-resistant tuberculosis (TB), novel agents that have direct antimycobacterial effects or that enhance host immunity are urgently needed. Curcumin is a polyphenol responsible for the bright yellow-orange colour of turmeric, a spice derived from the root of the perennial herb Curcuma longa. Curcumin is a potent inducer of apoptosis-an effector mechanism used by macrophages to kill intracellular Mycobacterium tuberculosis (MTB). Methods: An in vitro human macrophage infection model was used to determine the effects of curcumin on MTB survival. Results: We found that curcumin enhanced the clearance of MTB in differentiated THP-1 human monocytes and in primary human alveolar macrophages. We also found that curcumin was an inducer of caspase-3-dependent apoptosis and autophagy. Curcumin mediated these anti-MTB cellular functions, in part, via inhibition of nuclear factor-kappa B (NFκB) activation. Conclusion: Curcumin protects against MTB infection in human macrophages. The host-protective role of curcumin against MTB in macrophages needs confirmation in an animal model; if validated, the immunomodulatory anti-TB effects of curcumin would be less prone to drug resistance development.

show abstract

Section: Introductionmentioning

confidence: 99%

Curcumin enhances human macrophage control of Mycobacterium tuberculosis infection

Bai

Oberley‐Deegan

Bai³

et al. 2016

Respirology

View full text Add to dashboard Cite

show abstract

“…Consequently, host innate immune mechanisms have co-evolved to better counter mycobacterial infections (Aldwell et al, 1996). Host macrophages also induce an apoptotic signal to control bacterial infection (Rodrigues et al, 2013; Srinivasan et al, 2014). Understanding the mechanism of apoptosis induced by M. bovis infection will lead to better delineate host immune responses that could be exploited to control infection.…”

Section: Introductionmentioning

confidence: 99%

Mycobacterium bovis Induces Endoplasmic Reticulum Stress Mediated-Apoptosis by Activating IRF3 in a Murine Macrophage Cell Line

Cui

Zhao

Sreevatsan

et al. 2016

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

Mycobacterium bovis (M. bovis) is highly adapted to macrophages and has developed multiple mechanisms to resist intracellular assaults. However, the host cells in turn deploy a multipronged defense mechanism to control bacterial infection. Endoplasmic reticulum (ER) stress-mediated apoptosis is one such primary defense mechanism. However, the role of interferon regulatory factor 3 (IRF3) between ER stress and apoptosis during M. bovis infection is unknown. Here, we demonstrate that M. bovis effectively induced apoptosis in murine macrophages. Caspase-12, caspase-9, and caspase-3 were activated over a 48 h infection period. The splicing of XBP-1 mRNA and the level of phosphorylation of eIF2α, indicators of ER stress, significantly increased at early time points after M. bovis infection. The expansion of the ER compartment, a morphological hallmark of ER stress, was observed at 6 h. Pre-treatment of Raw 264.7 cells with 4-PBA (an ER stress-inhibitor) reduced the activation of the ER stress indicators, caspase activation and its downstream poly (ADP-ribose) polymerase (PARP) cleavage, phosphorylation of TBK1 and IRF3 and cytoplasmic co-localization of STING and TBK1. M. bovis infection led to the interaction of activated IRF3 and cytoplasmic Bax leading to mitochondrial damage. Role of IRF3 in apoptosis was further confirmed by blocking this molecule with BX-795 that showed significant reduction expression of caspase-8 and caspase-3. Intracellular survival of M. bovis increased in response to 4-PBA and BX-795. These findings indicate that STING-TBK1-IRF3 pathway mediates a crosstalk between ER stress and apoptosis during M. bovis infection, which can effectively control intracellular bacteria.

show abstract

“…The fate of individual infected macrophages is therefore a major determinant of whether granulomas can contain the infection or facilitate dissemination of the infection. It has been previously shown that mycobacteriainfected macrophages can undergo several types of regulated cell death, like apoptosis, necroptosis, and pyroptosis, resulting in different infection outcomes (21). Apoptosis of infected cells is generally regarded as a host-protective defence mechanism against mycobacterial infection, and virulent Mtb therefore actively inhibit apoptosis (20,22,23).…”

mentioning

confidence: 99%

Deficiency in the autophagy modulator Dram1 exacerbates pyroptotic cell death of Mycobacteria-infected macrophages

Zhang

Varela

Forn-Cuní

et al. 2019

Preprint

View full text Add to dashboard Cite

AbstractDNA Damage Regulated Autophagy Modulator 1 (DRAM1) is a stress-inducible regulator of autophagy and cell death. DRAM1 has been implicated in cancer, myocardial infarction, and infectious diseases, but the molecular and cellular functions of this transmembrane protein remain poorly understood. Previously, we have proposed DRAM1 as a host resistance factor for tuberculosis (TB) and a potential target for host-directed anti-infective therapies. In this study, we generated a zebrafish dram1 mutant and investigated its loss-of-function effects during Mycobacterium marinum (Mm) infection, a widely used model in TB research. In agreement with previous knockdown analysis, dram1 mutation increased the susceptibility of zebrafish larvae to Mm infection. RNA sequencing revealed major effects of Dram1 deficiency on metabolic, immune response, and cell death pathways during Mm infection, whereas only minor effects on proteinase and metabolic pathways were found under uninfected conditions. Furthermore, unchallenged dram1 mutants did not display overt autophagic defects, but autophagic targeting of Mm was reduced in absence of Dram1. The phagocytic ability of macrophages in dram1 mutants was unaffected, but acidification of Mm-containing vesicles was strongly reduced, indicating that Dram1 is required for phagosome maturation. By in vivo imaging we observed that Dram1-deficient macrophages fail to restrict Mm during early stages of infection. The resulting increase in bacterial burden could be reverted by knockdown of inflammatory caspase a (caspa) and gasdermin Eb (gsdmeb), demonstrating pyroptosis as the mechanism underlying premature cell death of Mm-infected macrophages in dram1 mutants. Collectively, these data demonstrate that dissemination of mycobacterial infection in zebrafish larvae is promoted in absence of Dram1 due to reduced maturation of mycobacteria-containing vesicles, failed intracellular containment, and consequent pyroptotic cell death of infected macrophages. These results provide new evidence that Dram1 plays a central role in host resistance to intracellular infection, acting at the crossroad of autophagy and cell death.

show abstract

Interaction of Mycobacterium tuberculosis with Host Cell Death Pathways

Cited by 72 publications

References 92 publications

Curcumin enhances human macrophage control of Mycobacterium tuberculosis infection

Curcumin enhances human macrophage control of Mycobacterium tuberculosis infection

Mycobacterium bovis Induces Endoplasmic Reticulum Stress Mediated-Apoptosis by Activating IRF3 in a Murine Macrophage Cell Line

Deficiency in the autophagy modulator Dram1 exacerbates pyroptotic cell death of Mycobacteria-infected macrophages

Contact Info

Product

Resources

About