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Human variation impacting MCOLN2 restricts Salmonella Typhi replication by magnesium deprivation

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 at...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10203047/
https://www.ncbi.nlm.nih.gov/pubmed/37228749
http://dx.doi.org/10.1016/j.xgen.2023.100290
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author 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.
author_facet 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.
author_sort Gibbs, Kyle D.
collection PubMed
description 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. Mg(2+) currents, conducted through MCOLN2 and out of endolysosomes, were measured directly using patch-clamping of the endolysosomal membrane. Our results reveal Mg(2+) limitation as a key component of nutritional immunity against S. Typhi and as a source of variable host resistance.
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spelling pubmed-102030472023-05-24 Human variation impacting MCOLN2 restricts Salmonella Typhi replication by magnesium deprivation 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. Cell Genom Article 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. Mg(2+) currents, conducted through MCOLN2 and out of endolysosomes, were measured directly using patch-clamping of the endolysosomal membrane. Our results reveal Mg(2+) limitation as a key component of nutritional immunity against S. Typhi and as a source of variable host resistance. Elsevier 2023-04-04 /pmc/articles/PMC10203047/ /pubmed/37228749 http://dx.doi.org/10.1016/j.xgen.2023.100290 Text en © 2023 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
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 variation impacting MCOLN2 restricts Salmonella Typhi replication by magnesium deprivation
title Human variation impacting MCOLN2 restricts Salmonella Typhi replication by magnesium deprivation
title_full Human variation impacting MCOLN2 restricts Salmonella Typhi replication by magnesium deprivation
title_fullStr Human variation impacting MCOLN2 restricts Salmonella Typhi replication by magnesium deprivation
title_full_unstemmed Human variation impacting MCOLN2 restricts Salmonella Typhi replication by magnesium deprivation
title_short Human variation impacting MCOLN2 restricts Salmonella Typhi replication by magnesium deprivation
title_sort human variation impacting mcoln2 restricts salmonella typhi replication by magnesium deprivation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10203047/
https://www.ncbi.nlm.nih.gov/pubmed/37228749
http://dx.doi.org/10.1016/j.xgen.2023.100290
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