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.

中性粒细胞代表活动性肺结核患者肺部的主要感染细胞群。需要有效去除感染和垂死的中性粒细胞，以保护周围组织免受生物活性中性粒细胞分子和随后的病理后遗症的侵害。同时清除凋亡的结核分枝杆菌被Mtb感染的坏死性中性粒细胞知之甚少（Mtb）感染的细胞或胞吞作用被认为对宿主防御有益。我们发现Mtb以ESX-1依赖的方式诱导人类嗜中性粒细胞坏死，而嗜中性粒细胞产生的活性氧（ROS）驱动这种坏死。人类巨噬细胞摄取感染的中性粒细胞后，Mtb生长需要中性粒细胞坏死。ROS产生的药理学抑制作用可以预防坏死并恢复巨噬细胞控制Mtb生长的能力，从而确定潜在的宿主定向治疗靶标。总之，坏死代表了恶性循环的起点，包括其他吞噬细胞摄取被感染的坏死细胞，其中的Mtb生长以及持续感染。