Human variation impacting MCOLN2 restricts Salmonella Typhi replication by magnesium deprivation.
Human variation impacting MCOLN2 restricts Salmonella Typhi replication by magnesium deprivation.
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DOI：
10.1016/j.xgen.2023.100290
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发表时间：
2023-05-10
期刊：
影响因子：
--
通讯作者：
Ko, Dennis C.
中科院分区：
文献类型：
--
作者：
Gibbs, Kyle D.;Wang, Liuyang;Yang, Zhuo;Anderson, Caroline E.;Bourgeois, Jeffrey S.;Cao, Yanlu;Gaggioli, Margaret R.;Biel, Martin;Puertollano, Rosa;Chen, Cheng-Chang;Ko, Dennis C.
Human genetic diversity can reveal critical factors in host-pathogen interactions. This is especially useful for human-restricted pathogens like Salmonella enterica serovar Typhi (S. Typhi), the cause of typhoid fever. One key defense during bacterial infection is nutritional immunity: host cells attempt to restrict bacterial replication by denying bacteria access to key nutrients or supplying toxic metabolites. Here, a cellular genome-wide association study of intracellular replication by S. Typhi in nearly a thousand cell lines from around the world—and extensive follow-up using intracellular S. Typhi transcriptomics and manipulation of magnesium availability—demonstrates that the divalent cation channel mucolipin-2 (MCOLN2 or TRPML2) restricts S. Typhi intracellular replication through magnesium deprivation. Mg2+ currents, conducted through MCOLN2 and out of endolysosomes, were measured directly using patch-clamping of the endolysosomal membrane. Our results reveal Mg2+ limitation as a key component of nutritional immunity against S. Typhi and as a source of variable host resistance. Cellular GWAS revealed MCOLN2 as an inhibitor of S. Typhi intracellular replication MCOLN2 acts as an inward rectifying Mg2+ channel on endolysosomes MCOLN2 deprives S. Typhi of Mg2+ to restrict growth S. Typhi replication in MCOLN2 knockout cells depends on bacterial PhoPQ signaling Gibbs et al. conducted a cellular GWAS of nearly a thousand lymphoblastoid cells to identify genetic variation affecting the MCOLN2 (TRPML2) divalent cation channel as the primary genetic determinant of variation in Salmonella Typhi intracellular replication. MCOLN2 deprives S. Typhi of Mg2+, serving as an important mechanism of nutritional immunity.
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影响因子：
3.5
作者：
CHEREPANOV, PP;WACKERNAGEL, W
通讯作者：
WACKERNAGEL, W
影响因子：
16.6
作者：
Dong, Xian-ping;Shen, Dongbiao;Wang, Xiang;Dawson, Taylor;Li, Xinran;Zhang, Qi;Cheng, Xiping;Zhang, Yanling;Weisman, Lois S.;Delling, Markus;Xu, Haoxing
通讯作者：
Xu, Haoxing
影响因子：
13.6
作者：
Chen CC;Krogsaeter E;Butz ES;Li Y;Puertollano R;Wahl-Schott C;Biel M;Grimm C
通讯作者：
Grimm C
影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ
影响因子：
8.6
作者：
Chen, Cheng-Chang;Butz, Elisabeth S.;Grimm, Christian
通讯作者：
Grimm, Christian