Human NAIP/NLRC4 and NLRP3 inflammasomes detect Salmonella type III secretion system activities to restrict intracellular bacterial replication.
Human NAIP/NLRC4 and NLRP3 inflammasomes detect Salmonella type III secretion system activities to restrict intracellular bacterial replication.
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DOI：
10.1371/journal.ppat.1009718
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发表时间：
2022-01
期刊：
影响因子：
6.7
通讯作者：
Shin S
中科院分区：
文献类型：
--
作者：
Naseer N;Egan MS;Reyes Ruiz VM;Scott WP;Hunter EN;Demissie T;Rauch I;Brodsky IE;Shin S
鼠伤寒沙门氏菌（Salmonella enterica serovar Typhimurium）是一种革兰氏阴性病原体，其使用两种不同的III型分泌系统（T3 SS），称为沙门氏菌致病岛（SPI）-1和SPI-2，将毒力因子递送到宿主细胞中。SPI-1 T3 SS使沙门氏菌能够侵入宿主细胞，而SPI-2 T3 SS促进沙门氏菌的细胞内存活。在小鼠中，包括NAIP 1、NAIP 2和NAIP 5/6的胞质免疫传感器家族分别识别SPI-1 T3 SS针、内杆和鞭毛蛋白。配体识别触发NAIP/NLRC 4炎性体的组装，其介导半胱天冬酶-1活化、IL-1家族细胞因子分泌和感染细胞的焦亡。与小鼠相反，人类编码一个单一的NAIP，广泛识别所有三种配体。NAIP/NLRC 4或其他炎性小体在沙门氏菌感染人类巨噬细胞过程中的作用尚不清楚。我们发现，尽管NAIP/NLRC 4炎性小体对于检测人类巨噬细胞中的T3 SS配体是必不可少的，但它是对感染的反应所必需的，因为沙门氏菌也激活了NLRP 3和CASP 4/5炎性小体。重要的是，我们证明了组合NAIP/NLRC 4和NLRP 3炎性体激活限制了沙门氏菌在人巨噬细胞中的复制。与SPI-1相反，SPI-2 T3 SS内杆不被人或鼠NAIP感知，这被认为允许沙门氏菌逃避宿主识别并在细胞内复制。有趣的是，我们发现人NAIP检测SPI-2 T3 SS针蛋白。重要的是，在鞭毛蛋白和SPI-1 T3 SS两者都不存在的情况下，NAIP/NLRC 4炎性体仍然控制细胞内沙门氏菌负荷。这些发现揭示了沙门氏菌SPI-1和SPI-2 T3 SS的识别以及NAIP/NLRC 4和NLRP 3炎性体的参与控制了人巨噬细胞中的沙门氏菌感染。鼠伤寒沙门氏菌（Salmonella enterica serovar Typhimurium）是一种胃肠道细菌病原体，其引起胃肠疾病，并且是全世界发病率和死亡率的主要原因。沙门氏菌使用称为III型分泌系统（T3 SS）的分子生物学机器将毒力因子注入宿主细胞。这些T3 SS使沙门氏菌能够感染宿主细胞并在宿主细胞如巨噬细胞内存活。然而，宿主细胞含有一个称为NAIP的胞质免疫受体家族，其识别T3 SS和鞭毛蛋白组分。在检测到这些成分后，NAIP启动称为炎性小体的信号复合物的形成。炎性小体激活称为半胱天冬酶的宿主蛋白酶，这些蛋白酶对入侵的病原体产生强大的免疫反应。虽然小鼠编码多个NAIP已被广泛研究，但关于单个人NAIP在宿主对沙门氏菌的反应中的作用仍有很多未知。我们发现，虽然NAIP是必要的，以检测个别T3 SS配体，它只是部分所需的沙门氏菌感染在人类巨噬细胞的炎性反应。我们发现NLRP 3和CASP 4/5炎性小体也被激活，NAIP和NLRP 3介导的反应的组合限制了人类巨噬细胞中的细胞内沙门氏菌复制。我们的研究结果表明，人类巨噬细胞采用多种炎性小体安装强大的宿主防御沙门氏菌感染。
Salmonella enterica serovar Typhimurium is a Gram-negative pathogen that uses two distinct type III secretion systems (T3SSs), termed Salmonella pathogenicity island (SPI)-1 and SPI-2, to deliver virulence factors into the host cell. The SPI-1 T3SS enables Salmonella to invade host cells, while the SPI-2 T3SS facilitates Salmonella’s intracellular survival. In mice, a family of cytosolic immune sensors, including NAIP1, NAIP2, and NAIP5/6, recognizes the SPI-1 T3SS needle, inner rod, and flagellin proteins, respectively. Ligand recognition triggers assembly of the NAIP/NLRC4 inflammasome, which mediates caspase-1 activation, IL-1 family cytokine secretion, and pyroptosis of infected cells. In contrast to mice, humans encode a single NAIP that broadly recognizes all three ligands. The role of NAIP/NLRC4 or other inflammasomes during Salmonella infection of human macrophages is unclear. We find that although the NAIP/NLRC4 inflammasome is essential for detecting T3SS ligands in human macrophages, it is partially required for responses to infection, as Salmonella also activated the NLRP3 and CASP4/5 inflammasomes. Importantly, we demonstrate that combinatorial NAIP/NLRC4 and NLRP3 inflammasome activation restricts Salmonella replication in human macrophages. In contrast to SPI-1, the SPI-2 T3SS inner rod is not sensed by human or murine NAIPs, which is thought to allow Salmonella to evade host recognition and replicate intracellularly. Intriguingly, we find that human NAIP detects the SPI-2 T3SS needle protein. Critically, in the absence of both flagellin and the SPI-1 T3SS, the NAIP/NLRC4 inflammasome still controlled intracellular Salmonella burden. These findings reveal that recognition of Salmonella SPI-1 and SPI-2 T3SSs and engagement of both the NAIP/NLRC4 and NLRP3 inflammasomes control Salmonella infection in human macrophages. Salmonella enterica serovar Typhimurium is a gastrointestinal bacterial pathogen that causes diarrheal disease and is a major cause of morbidity and mortality worldwide. Salmonella uses molecular syringe-like machines called type III secretion systems (T3SSs) to inject virulence factors into host cells. These T3SSs enable Salmonella to infect and survive within host cells such as macrophages. However, host cells contain a family of cytosolic immune receptors, termed NAIPs, that recognize T3SS and flagellin components. Upon detecting these components, NAIPs initiate formation of signaling complexes called inflammasomes. Inflammasomes activate host proteases called caspases that mount robust immune responses against the invading pathogen. While mice encode multiple NAIPs that have been extensively studied, much remains unknown about the role of the single human NAIP in host responses to Salmonella. We find that while NAIP is necessary to detect individual T3SS ligands, it is only partially required for inflammasome responses to Salmonella infection in human macrophages. We found that the NLRP3 and CASP4/5 inflammasomes are also activated, and the combination of NAIP- and NLRP3-mediated responses limits intracellular Salmonella replication in human macrophages. Our results demonstrate that human macrophages employ multiple inflammasomes to mount robust host defense against Salmonella infection.
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影响因子：
30.5
作者：
Franchi, Luigi;Amer, Amal;Nunez, Gabriel
通讯作者：
Nunez, Gabriel
影响因子：
4.4
作者：
Cummings, LA;Barrett, SLR;Cookson, BT
通讯作者：
Cookson, BT
DOI：
10.1073/pnas.120163297
发表时间：
2000-06-06
影响因子：
11.1
作者：
Datsenko, KA;Wanner, BL
通讯作者：
Wanner, BL
影响因子：
5.5
作者：
Bierschenk, Damien;Monteleone, Mercedes;Schroder, Kate
通讯作者：
Schroder, Kate
DOI：
10.1084/jem.20100257
发表时间：
2010-08-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Broz P;Newton K;Lamkanfi M;Mariathasan S;Dixit VM;Monack DM
通讯作者：
Monack DM