M. tuberculosis-Induced Necrosis of Infected Neutrophils Promotes Bacterial Growth Following Phagocytosis by Macrophages

Neutrophils represent the main infected cell population in the lungs of active tuberculosis patients. Efficient removal of infected and dying neutrophils is required to protect the surrounding tissue from bioactive neutrophil molecules and subsequent pathological sequelae. While the removal of apopt...

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Bibliographic Details
Published in:	Cell host & microbe 2017-10, Vol.22 (4), p.519-530.e3
Main Authors:	Dallenga, Tobias, Repnik, Urska, Corleis, Björn, Eich, Jacqueline, Reimer, Rudolph, Griffiths, Gareth W., Schaible, Ulrich E.
Format:	Article
Language:	eng
Subjects:	Adolescent Adult Aged Antigens, Bacterial - genetics Antigens, Bacterial - metabolism Apoptosis Bacterial Proteins - genetics Bacterial Proteins - metabolism cell death Coculture Techniques efferocytosis ESAT-6 host-directed therapy Humans macrophages Macrophages - metabolism Macrophages - microbiology Middle Aged Mycobacterium tuberculosis Mycobacterium tuberculosis - genetics Mycobacterium tuberculosis - growth & development Mycobacterium tuberculosis - pathogenicity necrosis Necrosis - microbiology Necrosis - pathology neutrophils Neutrophils - microbiology Neutrophils - pathology Phagocytosis Primary Cell Culture Reactive Oxygen Species - metabolism respiratory burst Single-Cell Analysis tuberculosis
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Summary:	Neutrophils represent the main infected cell population in the lungs of active tuberculosis patients. Efficient removal of infected and dying neutrophils is required to protect the surrounding tissue from bioactive neutrophil molecules and subsequent pathological sequelae. While the removal of apoptotic M. tuberculosis (Mtb)-infected cells, or efferocytosis, is considered beneficial for host defense, little is known about Mtb-infected necrotic neutrophils. We found that Mtb induces necrosis of human neutrophils in an ESX-1-dependent manner, and neutrophil-produced reactive oxygen species (ROS) drive this necrosis. Neutrophil necrosis was required for Mtb growth after uptake of infected neutrophils by human macrophages. Pharmacological inhibition of ROS production could prevent necrosis and restore the capability of macrophages to control Mtb growth, thereby identifying a potential host-directed therapy target. Taken together, necrosis represents the starting point for a vicious cycle including the uptake of infected necrotic cells by other phagocytes, Mtb growth therein, and sustained infection. [Display omitted] •M. tuberculosis induces necrosis of infected neutrophils in an ESX-1-dependent manner•Neutrophil-produced reactive oxygen species (ROS) drive M. tuberculosis-induced necrosis•Uptake of necrotic infected neutrophils by macrophages promotes M. tuberculosis growth•Inhibiting ROS and necrosis restores the ability of macrophages to control Mtb growth The role of necrosis in M. tuberculosis (Mtb) infection is not explored. Dallenga et al. find that Mtb infection of neutrophils induces necrosis in an ESX-1- and ROS-dependent manner, which promotes bacterial growth when engulfed by macrophages. Pharmacological inhibition of ROS and necrosis restored control of M. tuberculosis by macrophages.
ISSN:	1931-3128 1934-6069