期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2103526118
关键词
type VI secretion system (T6SS); micropeptide; manganese; innate; immunity; STING
资金
- National Natural Science Foundation of China [31725003, 31670053, 31970114, 32170130, 31800113]
- National Key R&D Program of China [2018YFA0901200]
- Open Project Program of the State Key Laboratory of Pathogen and Biosecurity [SKLPBS1825]
- China Postdoctoral Science Foundation [2018M631201, 2020M673501]
- Chinese Universities Scientific Fund (the Starting Research Fund from the Northwest AF University) [2452018045]
- Shaanxi Postdoctoral Science Foundation [2018BSHTDZZ20]
- Natural Science Basis Research Plan in Shaanxi Province of China [2020JQ-245]
This study reveals a unique virulence strategy of Yersinia pseudotuberculosis (Yptb) involving modulating the availability of the immunostimulatory metal ion Mn2+ in host cells. The Yptb T6SS delivers a micropeptide TssS into host cells to enhance virulence, but mutant strains lacking TssS show reduced virulence and stronger host innate immune responses. Furthermore, TssS functions as a Mn2+-chelating protein and inhibits the STING-mediated immune response by sequestering Mn2+, leading to bacterial immune evasion and sabotaged bacterial clearance in vivo.
Cellular ionic concentrations are a central factor orchestrating host innate immunity, but no pathogenic mechanism that perturbs host innate immunity by directly targeting metal ions has yet been described. Here, we report a unique virulence strategy of Yersinia pseudotuberculosis (Yptb) involving modulation of the availability of Mn2+, an immunostimulatory metal ion in host cells. We showed that the Yptb type VI secretion system (T6SS) delivered a micropeptide, TssS, into host cells to enhance its virulence. The mutant strain lacking TssS (Delta tssS) showed substantially reduced virulence but induced a significantly stronger host innate immune response, indicating an antagonistic role of this effector in host antimicrobial immunity. Subsequent studies revealed that TssS is a Mn2+-chelating protein and that its Mn2+-chelating ability is essential for the disruption of host innate immunity. Moreover, we showed that Mn2+ enhances the host innate immune response to Yptb infection by activating the stimulator of interferon genes (STING)-mediated immune response. Furthermore, we demonstrated that TssS counteracted the cytoplasmic Mn2+ increase to inhibit the STING-mediated innate immune response by sequestering Mn2+. Finally, TssS-mediated STING inhibition sabotaged bacterial clearance in vivo. These results reveal a previously unrecognized bacterial immune evasion strategy involving modulation of the bioavailability of intracellular metal ions and provide a perspective on the role of the T6SS in pathogenesis.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据