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Host-pathogen genetic interactions underlie tuberculosis susceptibility in genetically diverse mice

The outcome of an encounter with Mycobacterium tuberculosis (Mtb) depends on the pathogen’s ability to adapt to the variable immune pressures exerted by the host. Understanding this interplay has proven difficult, largely because experimentally tractable animal models do not recapitulate the heterog...

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Autores principales: Smith, Clare M, Baker, Richard E, Proulx, Megan K, Mishra, Bibhuti B, Long, Jarukit E, Park, Sae Woong, Lee, Ha-Na, Kiritsy, Michael C, Bellerose, Michelle M, Olive, Andrew J, Murphy, Kenan C, Papavinasasundaram, Kadamba, Boehm, Frederick J, Reames, Charlotte J, Meade, Rachel K, Hampton, Brea K, Linnertz, Colton L, Shaw, Ginger D, Hock, Pablo, Bell, Timothy A, Ehrt, Sabine, Schnappinger, Dirk, Pardo-Manuel de Villena, Fernando, Ferris, Martin T, Ioerger, Thomas R, Sassetti, Christopher M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8846590/
https://www.ncbi.nlm.nih.gov/pubmed/35112666
http://dx.doi.org/10.7554/eLife.74419
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author Smith, Clare M
Baker, Richard E
Proulx, Megan K
Mishra, Bibhuti B
Long, Jarukit E
Park, Sae Woong
Lee, Ha-Na
Kiritsy, Michael C
Bellerose, Michelle M
Olive, Andrew J
Murphy, Kenan C
Papavinasasundaram, Kadamba
Boehm, Frederick J
Reames, Charlotte J
Meade, Rachel K
Hampton, Brea K
Linnertz, Colton L
Shaw, Ginger D
Hock, Pablo
Bell, Timothy A
Ehrt, Sabine
Schnappinger, Dirk
Pardo-Manuel de Villena, Fernando
Ferris, Martin T
Ioerger, Thomas R
Sassetti, Christopher M
author_facet Smith, Clare M
Baker, Richard E
Proulx, Megan K
Mishra, Bibhuti B
Long, Jarukit E
Park, Sae Woong
Lee, Ha-Na
Kiritsy, Michael C
Bellerose, Michelle M
Olive, Andrew J
Murphy, Kenan C
Papavinasasundaram, Kadamba
Boehm, Frederick J
Reames, Charlotte J
Meade, Rachel K
Hampton, Brea K
Linnertz, Colton L
Shaw, Ginger D
Hock, Pablo
Bell, Timothy A
Ehrt, Sabine
Schnappinger, Dirk
Pardo-Manuel de Villena, Fernando
Ferris, Martin T
Ioerger, Thomas R
Sassetti, Christopher M
author_sort Smith, Clare M
collection PubMed
description The outcome of an encounter with Mycobacterium tuberculosis (Mtb) depends on the pathogen’s ability to adapt to the variable immune pressures exerted by the host. Understanding this interplay has proven difficult, largely because experimentally tractable animal models do not recapitulate the heterogeneity of tuberculosis disease. We leveraged the genetically diverse Collaborative Cross (CC) mouse panel in conjunction with a library of Mtb mutants to create a resource for associating bacterial genetic requirements with host genetics and immunity. We report that CC strains vary dramatically in their susceptibility to infection and produce qualitatively distinct immune states. Global analysis of Mtb transposon mutant fitness (TnSeq) across the CC panel revealed that many virulence pathways are only required in specific host microenvironments, identifying a large fraction of the pathogen’s genome that has been maintained to ensure fitness in a diverse population. Both immunological and bacterial traits can be associated with genetic variants distributed across the mouse genome, making the CC a unique population for identifying specific host-pathogen genetic interactions that influence pathogenesis.
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spelling pubmed-88465902022-02-16 Host-pathogen genetic interactions underlie tuberculosis susceptibility in genetically diverse mice Smith, Clare M Baker, Richard E Proulx, Megan K Mishra, Bibhuti B Long, Jarukit E Park, Sae Woong Lee, Ha-Na Kiritsy, Michael C Bellerose, Michelle M Olive, Andrew J Murphy, Kenan C Papavinasasundaram, Kadamba Boehm, Frederick J Reames, Charlotte J Meade, Rachel K Hampton, Brea K Linnertz, Colton L Shaw, Ginger D Hock, Pablo Bell, Timothy A Ehrt, Sabine Schnappinger, Dirk Pardo-Manuel de Villena, Fernando Ferris, Martin T Ioerger, Thomas R Sassetti, Christopher M eLife Genetics and Genomics The outcome of an encounter with Mycobacterium tuberculosis (Mtb) depends on the pathogen’s ability to adapt to the variable immune pressures exerted by the host. Understanding this interplay has proven difficult, largely because experimentally tractable animal models do not recapitulate the heterogeneity of tuberculosis disease. We leveraged the genetically diverse Collaborative Cross (CC) mouse panel in conjunction with a library of Mtb mutants to create a resource for associating bacterial genetic requirements with host genetics and immunity. We report that CC strains vary dramatically in their susceptibility to infection and produce qualitatively distinct immune states. Global analysis of Mtb transposon mutant fitness (TnSeq) across the CC panel revealed that many virulence pathways are only required in specific host microenvironments, identifying a large fraction of the pathogen’s genome that has been maintained to ensure fitness in a diverse population. Both immunological and bacterial traits can be associated with genetic variants distributed across the mouse genome, making the CC a unique population for identifying specific host-pathogen genetic interactions that influence pathogenesis. eLife Sciences Publications, Ltd 2022-02-03 /pmc/articles/PMC8846590/ /pubmed/35112666 http://dx.doi.org/10.7554/eLife.74419 Text en © 2022, Smith et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Genetics and Genomics
Smith, Clare M
Baker, Richard E
Proulx, Megan K
Mishra, Bibhuti B
Long, Jarukit E
Park, Sae Woong
Lee, Ha-Na
Kiritsy, Michael C
Bellerose, Michelle M
Olive, Andrew J
Murphy, Kenan C
Papavinasasundaram, Kadamba
Boehm, Frederick J
Reames, Charlotte J
Meade, Rachel K
Hampton, Brea K
Linnertz, Colton L
Shaw, Ginger D
Hock, Pablo
Bell, Timothy A
Ehrt, Sabine
Schnappinger, Dirk
Pardo-Manuel de Villena, Fernando
Ferris, Martin T
Ioerger, Thomas R
Sassetti, Christopher M
Host-pathogen genetic interactions underlie tuberculosis susceptibility in genetically diverse mice
title Host-pathogen genetic interactions underlie tuberculosis susceptibility in genetically diverse mice
title_full Host-pathogen genetic interactions underlie tuberculosis susceptibility in genetically diverse mice
title_fullStr Host-pathogen genetic interactions underlie tuberculosis susceptibility in genetically diverse mice
title_full_unstemmed Host-pathogen genetic interactions underlie tuberculosis susceptibility in genetically diverse mice
title_short Host-pathogen genetic interactions underlie tuberculosis susceptibility in genetically diverse mice
title_sort host-pathogen genetic interactions underlie tuberculosis susceptibility in genetically diverse mice
topic Genetics and Genomics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8846590/
https://www.ncbi.nlm.nih.gov/pubmed/35112666
http://dx.doi.org/10.7554/eLife.74419
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