Mycobacterium tuberculosis Induces an Atypical Cell Death Mode to Escape from Infected Macrophages

Lee, Jin‐Hee; Repasy, Teresa; Papavinasasundaram, Kadamba; Sassetti, Christopher M.; Kornfeld, Hardy

doi:10.1371/journal.pone.0018367

Cited by 107 publications

(130 citation statements)

References 43 publications

Supporting

Mentioning

120

Contrasting

Unclassified

Order By: Relevance

“…After the publication of our paper, a similar study was published also showing that this atypical necrosis is independent of caspase-1 and cathepsin B, indicating that pyroptosis or pyronecrosis are not induced. This study did however find an increase in lysosomal membrane permeability early during cell death induced by virulent bacteria, implicating a lysosomal death pathway (373). Though our results do not point towards the previously described inflammasome-mediated pyronecrosis, which is dependent on cathepsin B, another subsequent study have suggested that the ESAT-6-dependent necrosis is in fact mediated through NLRP3 without involvement of cathepsin B.…”

Section: Paper IIcontrasting

confidence: 98%

“…Subsequent studies have indicated that when this critical threshold is reached, ESAT-6 through ESX-1 secretion damages phagosomal and lysosomal membranes and translocates into the cytosol where ESX-5 activates NLRP3, leading to both IL-1β production and necrosis. Though we together with other groups were unable to show any involvement of cathepsin B in this type of cell death (218,373), some studies suggest that cathepsin B might play a role (42,217). Nevertheless, necrosis induced in macrophages by M. tuberculosis coincides with inflammasome activation without showing features of either pyroptosis or pyronecrosis.…”

Section: Paper IImentioning

confidence: 55%

See 1 more Smart Citation

Mycobacterium tuberculosis and the human macrophage : shifting the balance through inflammasome activation

Eklund¹

2013

View full text Add to dashboard Cite

Mycobacterium tuberculosis is a very successful pathogen and tuberculosis constitutes a major threat to global health worldwide. The World Health Organization (WHO) estimates that almost nine million new cases and 1.5 million deaths occur annually and the situation is worsened by increased antibiotic resistance and an extreme synergism with the HIV pandemic. M. tuberculosis primarily affects the lungs where the infection can lead to either eradication of the bacteria or the initiation of an immune response that culminates in the formation of a large cluster of immune cells termed granulomas. In these granulomas, the bacteria can either replicate and cause disease with the ultimate goal of spreading to new hosts or cause latent tuberculosis, which can persist for decades. The tools available to manage the disease are currently suboptimal and include lengthy antibiotic treatments and an inefficient vaccine resulting in poor protection. On a cellular level, M. tuberculosis primarily infects the cell designed to recognize, ingest and eradicate bacteria, namely the human macrophage. Following recognition, the macrophage phagocytoses the bacterium and tries to kill it using an array of different effector mechanisms including acidification of the bacterium-containing vacuole, different degradative enzymes and the generation of radicals. However, the bacterium is able to circumvent many of these harmful effects, leading to a tug-of-war between the bacterium and host macrophage. This thesis aims at studying the interaction between the human macrophage and M. tuberculosis to identify host factors critical for controlling growth of the bacteria. More specifically, it focuses on the role of an intracellular receptor protein called NLRP3 and its downstream effects. NLRP3 is activated in human macrophages infected by M. tuberculosis and upon activation it forms a multi-protein complex known as the inflammasome. This protein complex is known to induce the production of the proinflammatory cytokine IL-1β and specialized forms of macrophage cell death. We hypothesized that stimulating this pathway would have a beneficial effect for the host macrophage during infection with M. tuberculosis. To allow us to follow interaction between M. tuberculosis and the human macrophage, we first developed a luminometry-based method of measuring bacterial numbers and following bacterial growth over several days in infected cells. With this new assay we showed that low numbers of bacteria induced very low levels of IL-1β and failed to induce any type of cell death in the macrophage. However, when a critical number of bacteria were reached, the infected macrophages underwent necrosis, which was accompanied by high levels of IL-1β. We were also able to show that addition of vitamin D, which has been implicated as an important factor for increased killing capacity of infected macrophages, increased the production of IL-1β, which coincided with increased killing of M. tuberculosis. This effect was seen specifically in cells from patients with active...

show abstract

Section: Paper IIcontrasting

confidence: 98%

Section: Paper IImentioning

confidence: 55%

Mycobacterium tuberculosis and the human macrophage : shifting the balance through inflammasome activation

Eklund¹

2013

View full text Add to dashboard Cite

show abstract

“…2,3 While apoptosis of infected macrophages is considered beneficial for controlling bacterial growth and stimulating the adaptive immune response, necrosis of macrophages helps disseminate bacteria. 3,34 Virulent Mycobacterium tuberculosis manipulates host cell death mechanisms by inducing the expression of Mcl-1. 19 We used PPD treatment and BCG infection to study the involvement of Notch signaling and Mcl-1 in macrophages.…”

Section: Discussionmentioning

confidence: 99%

Notch signaling regulates expression of Mcl-1 and apoptosis in PPD-treated macrophages

et al. 2013

View full text Add to dashboard Cite

“…By contrast, apoptosis of the infected macrophages helps the host to control the bacterial infection (11). Virulent M. tuberculosis strains induce a necrosislike cell death and concomitantly suppress apoptosis of macrophages (12). Although M. tuberculosis is known to secrete virulence factors that interfere with phagosome maturation (9), it is unknown how M. tuberculosis kills macrophages.…”

mentioning

confidence: 99%

An outer membrane channel protein of Mycobacterium tuberculosis with exotoxin activity

Danilchanka¹,

Sun²,

Pavlenok³

et al. 2014

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

108

136

View full text Add to dashboard Cite

The ability to control the timing and mode of host cell death plays a pivotal role in microbial infections. Many bacteria use toxins to kill host cells and evade immune responses. Such toxins are unknown in Mycobacterium tuberculosis. Virulent M. tuberculosis strains induce necrotic cell death in macrophages by an obscure molecular mechanism. Here we show that the M. tuberculosis protein Rv3903c (channel protein with necrosis-inducing toxin, CpnT) consists of an N-terminal channel domain that is used for uptake of nutrients across the outer membrane and a secreted toxic C-terminal domain. Infection experiments revealed that CpnT is required for survival and cytotoxicity of M. tuberculosis in macrophages. Furthermore, we demonstrate that the C-terminal domain of CpnT causes necrotic cell death in eukaryotic cells. Thus, CpnT has a dual function in uptake of nutrients and induction of host cell death by M. tuberculosis.transport | pore | secretion

show abstract

Mycobacterium tuberculosis Induces an Atypical Cell Death Mode to Escape from Infected Macrophages

Cited by 107 publications

References 43 publications

Mycobacterium tuberculosis and the human macrophage : shifting the balance through inflammasome activation

Mycobacterium tuberculosis and the human macrophage : shifting the balance through inflammasome activation

Notch signaling regulates expression of Mcl-1 and apoptosis in PPD-treated macrophages

An outer membrane channel protein of Mycobacterium tuberculosis with exotoxin activity

Contact Info

Product

Resources

About