Unique role for ATG5 in neutrophil-mediated immunopathology during

M. tuberculosis infection

  Kimmey, J.M., et al. Nature 528, 565–569 (24 December 2015)

Speaker: Chu-Yi Hsieh(謝筑伊)                                           Time: 15:00~16:00, May. 11, 2016

Commentator: Professor Chih-Peng Chang (張志鵬老師)

Time: 15:00~16:00, May. 11, 2016

Place: Room 601

Abstract:

Mycobacterium tuberculosis is a major threat to public health. Recent reports estimate that a third of the world's population is infected with M. tuberculosis, the causative agent of tuberculosis (TB). M. tuberculosis replicates in macrophages in part by inhibiting phagosome–lysosome fusion, while interferon-γ (IFNγ) from NK and T helper cells enhances phagosome–lysosome fusion in macrophages to eliminate M. tuberculosis. Recent evidence also indicates that IFNγ triggers autophagy-mediated bacterial killing in macrophages. However, the underlying mechanisms for autophagy clearance of M. tuberculosis still remain to be further investigated. In this study, the author used a genetic approach to elucidate the role for multiple autophagy-related genes and the requirement for autophagy in resistance to  M. tuberculosis  infection  in vivo. Consistent with previous publications, they observed that Atg5-deficientmice succumbed to M. tuberculosis infection. However, the mice with deletion of other essential autophagy genes  were all survived and able to control M. tuberculosis infection. Moreover, the induction of pro-inflammatory cytokines in Atg5-deficient mice was apparently increased. Further analyses showed that Atg5-deficient mice contained a significantly greater frequency of PMNs (polymorponuclear cells) in lungs compared to  Atg5^fl/fl or C57Bl/6 mice.  Depletion of PMNs in Atg5-deficient mice led to the resistance to of M. tuberculosis tuberculosis infection.  In addition, the author used different conditional knockout mice to determine in which cell type(s)  Atg5  is required to control  M. tuberculosis infection and found that loss of Atg5 in PMNs caused mice susceptible to M. tuberculosis infection. Together, this work reveals that, in contrary to the original idea, autophagic capacity is not correlated with the outcome of M. tuberculosis  infection. Instead, ATG5 plays a unique role in protection against  M. tuberculosis  by preventing PMN-mediated immunopathology. 

References:

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