A genome-wide screen in macrophages identifies PTEN as required for myeloid restriction of Listeria monocytogenes infection.
A genome-wide screen in macrophages identifies PTEN as required for myeloid restriction of Listeria monocytogenes infection.
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DOI：
10.1371/journal.ppat.1011058
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发表时间：
2023-05
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影响因子：
6.7
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中科院分区：
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单核细胞增生李斯特菌（Listeria monocytogenes，Lm）是一种胞内食源性致病菌，可引起免疫功能低下者严重的单核细胞增生症.巨噬细胞在Lm感染期间通过促进Lm从胃肠道的传播和在免疫激活时限制细菌生长而发挥双重作用。尽管巨噬细胞与Lm感染相关，但巨噬细胞吞噬Lm的机制尚未完全了解。为了鉴定对巨噬细胞的Lm感染重要的宿主因素，我们进行了无偏倚的CRISPR/Cas9筛选，其揭示了对Lm的吞噬作用特异性的途径以及通常细菌内化所需的途径。具体地说，我们发现肿瘤抑制因子PTEN促进巨噬细胞吞噬Lm和L。ivanovii，而不是其他革兰氏阳性菌。此外，我们发现PTEN通过其脂质磷酸酶活性促进对巨噬细胞的粘附来增强Lm的吞噬作用。使用条件敲除小鼠缺乏Pten在骨髓细胞中，我们表明，PTEN依赖的吞噬作用是重要的宿主保护在口服Lm感染。总体而言，这项研究提供了一个全面的识别参与调节Lm摄取的巨噬细胞因子，并表征了一个因子，PTEN，在体外和体内Lm感染过程中的功能。重要的是，这些结果证明了调理素独立的吞噬作用在Lm发病机制中的作用，并表明巨噬细胞在食源性弧菌病中起主要的保护作用。单核细胞增生李斯特菌（Listeria monocytogenes，Lm）是一种细菌病原体，主要在免疫功能低下的老年人和孕妇中引起食源性疾病李斯特菌病。李斯特菌病是已知最致命的细菌感染之一，即使用抗生素治疗，死亡率也高达30%。结核菌病的高死亡率是由于免疫系统对Lm的无效限制，以及随后细菌越过胃肠道传播到内脏器官，如肝脏和大脑。巨噬细胞对Lm的免疫清除很重要，但也被假设促进细胞内Lm的传播;因此，Lm-巨噬细胞相互作用的研究对于理解细菌生长和这些吞噬细胞的限制之间的平衡至关重要。我们在巨噬细胞中进行了正向遗传筛选，发现肿瘤抑制因子PTEN通过增强对巨噬细胞的粘附来促进Lm的吞噬作用。这些结果证明了巨噬细胞PTEN的一种新功能，其典型地充当吞噬作用的抑制物。此外，我们发现，PTEN保护小鼠免受严重疾病，并降低口服接种Lm后的细菌负荷。我们的研究结果表明，第一次，巨噬细胞吞噬作用是一个重要的免疫防御入侵Lm在食源性感染途径。
Listeria monocytogenes (Lm) is an intracellular foodborne pathogen which causes the severe disease listeriosis in immunocompromised individuals. Macrophages play a dual role during Lm infection by both promoting dissemination of Lm from the gastrointestinal tract and limiting bacterial growth upon immune activation. Despite the relevance of macrophages to Lm infection, the mechanisms underlying phagocytosis of Lm by macrophages are not well understood. To identify host factors important for Lm infection of macrophages, we performed an unbiased CRISPR/Cas9 screen which revealed pathways that are specific to phagocytosis of Lm and those that are required for internalization of bacteria generally. Specifically, we discovered the tumor suppressor PTEN promotes macrophage phagocytosis of Lm and L. ivanovii, but not other Gram-positive bacteria. Additionally, we found that PTEN enhances phagocytosis of Lm via its lipid phosphatase activity by promoting adherence to macrophages. Using conditional knockout mice lacking Pten in myeloid cells, we show that PTEN-dependent phagocytosis is important for host protection during oral Lm infection. Overall, this study provides a comprehensive identification of macrophage factors involved in regulating Lm uptake and characterizes the function of one factor, PTEN, during Lm infection in vitro and in vivo. Importantly, these results demonstrate a role for opsonin-independent phagocytosis in Lm pathogenesis and suggest that macrophages play a primarily protective role during foodborne listeriosis. Listeria monocytogenes (Lm) is a bacterial pathogen that causes the foodborne illness listeriosis primarily in immunocompromised, elderly, and pregnant individuals. Listeriosis is one of the deadliest bacterial infections known, with a mortality rate of ~30% even when treated with antibiotics. The high mortality rate of listeriosis is due to inefficient restriction of Lm by the immune system, and subsequent spread of bacteria beyond the gastrointestinal tract to internal organs such as the liver and brain. Macrophages are important for immune clearance of Lm but are also hypothesized to promote dissemination of intracellular Lm; thus, studies of Lm-macrophage interactions are critical for understanding the balance between bacterial growth and restriction by these phagocytes. We performed a forward genetic screen in macrophages and discovered that the tumor suppressor PTEN promotes phagocytosis of Lm by enhancing adherence to macrophages. These results demonstrate a novel function of macrophage PTEN, which canonically acts as a repressor of phagocytosis. In addition, we found that PTEN protects mice from severe disease and lowers bacterial burdens following oral inoculation of Lm. Our results demonstrate for the first time that macrophage phagocytosis is an important immune defense against invasive Lm during the foodborne route of infection.
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影响因子：
46.9
作者：
Doench JG;Fusi N;Sullender M;Hegde M;Vaimberg EW;Donovan KF;Smith I;Tothova Z;Wilen C;Orchard R;Virgin HW;Listgarten J;Root DE
通讯作者：
Root DE
转录调节因子 SpxA1 影响单核细胞增生李斯特氏菌的形态和毒力。
影响因子：
3.1
作者：
通讯作者：
--
影响因子：
30.5
作者：
Arbibe, L;Mira, JP;Knaus, UG
通讯作者：
Knaus, UG
影响因子：
4.1
作者：
Currie, RA;Walker, KS;Lucocq, J
通讯作者：
Lucocq, J
DOI：
10.1084/jem.20181210
发表时间：
2018-11-05
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Disson O;Blériot C;Jacob JM;Serafini N;Dulauroy S;Jouvion G;Fevre C;Gessain G;Thouvenot P;Eberl G;Di Santo JP;Peduto L;Lecuit M
通讯作者：
Lecuit M