Functionally Overlapping Variants Control Tuberculosis Susceptibility in Collaborative Cross Mice

ABSTRACT Host genetics plays an important role in determining the outcome of Mycobacterium tuberculosis infection. We previously found that Collaborative Cross (CC) mouse strains differ in their susceptibility to M. tuberculosis and that the CC042/GeniUnc (CC042) strain suffered from a rapidly progr...

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Autores principales:	Clare M. Smith, Megan K. Proulx, Rocky Lai, Michael C. Kiritsy, Timothy A. Bell, Pablo Hock, Fernando Pardo-Manuel de Villena, Martin T. Ferris, Richard E. Baker, Samuel M. Behar, Christopher M. Sassetti
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Mycobacterium tuberculosis adaptive immunity Collaborative Cross mice host genetics host response host-pathogen interactions Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/d4cab79506754b9ea4ff592ecc872668
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spelling	oai:doaj.org-article:d4cab79506754b9ea4ff592ecc8726682021-11-15T15:54:45ZFunctionally Overlapping Variants Control Tuberculosis Susceptibility in Collaborative Cross Mice10.1128/mBio.02791-192150-7511https://doaj.org/article/d4cab79506754b9ea4ff592ecc8726682019-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02791-19https://doaj.org/toc/2150-7511ABSTRACT Host genetics plays an important role in determining the outcome of Mycobacterium tuberculosis infection. We previously found that Collaborative Cross (CC) mouse strains differ in their susceptibility to M. tuberculosis and that the CC042/GeniUnc (CC042) strain suffered from a rapidly progressive disease and failed to produce the protective cytokine gamma interferon (IFN-γ) in the lung. Here, we used parallel genetic and immunological approaches to investigate the basis of CC042 mouse susceptibility. Using a population derived from a CC001/Unc (CC001) × CC042 intercross, we mapped four quantitative trait loci (QTL) underlying tuberculosis immunophenotypes (Tip1 to Tip4). These included QTL that were associated with bacterial burden, IFN-γ production following infection, and an IFN-γ-independent mechanism of bacterial control. Further immunological characterization revealed that CC042 animals recruited relatively few antigen-specific T cells to the lung and that these T cells failed to express the integrin alpha L (αL; i.e., CD11a), which contributes to T cell activation and migration. These defects could be explained by a CC042 private variant in the Itgal gene, which encodes CD11a and is found within the Tip2 interval. This 15-bp deletion leads to aberrant mRNA splicing and is predicted to result in a truncated protein product. The ItgalCC042 genotype was associated with all measured disease traits, indicating that this variant is a major determinant of susceptibility in CC042 mice. The combined effect of functionally distinct Tip variants likely explains the profound susceptibility of CC042 mice and highlights the multigenic nature of tuberculosis control in the Collaborative Cross. IMPORTANCE The variable outcome of Mycobacterium tuberculosis infection observed in natural populations is difficult to model in genetically homogeneous small-animal models. The newly developed Collaborative Cross (CC) represents a reproducible panel of genetically diverse mice that display a broad range of phenotypic responses to infection. We explored the genetic basis of this variation, focusing on a CC line that is highly susceptible to M. tuberculosis infection. This study identified multiple quantitative trait loci associated with bacterial control and cytokine production, including one that is caused by a novel loss-of-function mutation in the Itgal gene, which is necessary for T cell recruitment to the infected lung. These studies verify the multigenic control of mycobacterial disease in the CC panel, identify genetic loci controlling diverse aspects of pathogenesis, and highlight the utility of the CC resource.Clare M. SmithMegan K. ProulxRocky LaiMichael C. KiritsyTimothy A. BellPablo HockFernando Pardo-Manuel de VillenaMartin T. FerrisRichard E. BakerSamuel M. BeharChristopher M. SassettiAmerican Society for MicrobiologyarticleMycobacterium tuberculosisadaptive immunityCollaborative Cross micehost geneticshost responsehost-pathogen interactionsMicrobiologyQR1-502ENmBio, Vol 10, Iss 6 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Mycobacterium tuberculosis adaptive immunity Collaborative Cross mice host genetics host response host-pathogen interactions Microbiology QR1-502
spellingShingle	Mycobacterium tuberculosis adaptive immunity Collaborative Cross mice host genetics host response host-pathogen interactions Microbiology QR1-502 Clare M. Smith Megan K. Proulx Rocky Lai Michael C. Kiritsy Timothy A. Bell Pablo Hock Fernando Pardo-Manuel de Villena Martin T. Ferris Richard E. Baker Samuel M. Behar Christopher M. Sassetti Functionally Overlapping Variants Control Tuberculosis Susceptibility in Collaborative Cross Mice
description	ABSTRACT Host genetics plays an important role in determining the outcome of Mycobacterium tuberculosis infection. We previously found that Collaborative Cross (CC) mouse strains differ in their susceptibility to M. tuberculosis and that the CC042/GeniUnc (CC042) strain suffered from a rapidly progressive disease and failed to produce the protective cytokine gamma interferon (IFN-γ) in the lung. Here, we used parallel genetic and immunological approaches to investigate the basis of CC042 mouse susceptibility. Using a population derived from a CC001/Unc (CC001) × CC042 intercross, we mapped four quantitative trait loci (QTL) underlying tuberculosis immunophenotypes (Tip1 to Tip4). These included QTL that were associated with bacterial burden, IFN-γ production following infection, and an IFN-γ-independent mechanism of bacterial control. Further immunological characterization revealed that CC042 animals recruited relatively few antigen-specific T cells to the lung and that these T cells failed to express the integrin alpha L (αL; i.e., CD11a), which contributes to T cell activation and migration. These defects could be explained by a CC042 private variant in the Itgal gene, which encodes CD11a and is found within the Tip2 interval. This 15-bp deletion leads to aberrant mRNA splicing and is predicted to result in a truncated protein product. The ItgalCC042 genotype was associated with all measured disease traits, indicating that this variant is a major determinant of susceptibility in CC042 mice. The combined effect of functionally distinct Tip variants likely explains the profound susceptibility of CC042 mice and highlights the multigenic nature of tuberculosis control in the Collaborative Cross. IMPORTANCE The variable outcome of Mycobacterium tuberculosis infection observed in natural populations is difficult to model in genetically homogeneous small-animal models. The newly developed Collaborative Cross (CC) represents a reproducible panel of genetically diverse mice that display a broad range of phenotypic responses to infection. We explored the genetic basis of this variation, focusing on a CC line that is highly susceptible to M. tuberculosis infection. This study identified multiple quantitative trait loci associated with bacterial control and cytokine production, including one that is caused by a novel loss-of-function mutation in the Itgal gene, which is necessary for T cell recruitment to the infected lung. These studies verify the multigenic control of mycobacterial disease in the CC panel, identify genetic loci controlling diverse aspects of pathogenesis, and highlight the utility of the CC resource.
format	article
author	Clare M. Smith Megan K. Proulx Rocky Lai Michael C. Kiritsy Timothy A. Bell Pablo Hock Fernando Pardo-Manuel de Villena Martin T. Ferris Richard E. Baker Samuel M. Behar Christopher M. Sassetti
author_facet	Clare M. Smith Megan K. Proulx Rocky Lai Michael C. Kiritsy Timothy A. Bell Pablo Hock Fernando Pardo-Manuel de Villena Martin T. Ferris Richard E. Baker Samuel M. Behar Christopher M. Sassetti
author_sort	Clare M. Smith
title	Functionally Overlapping Variants Control Tuberculosis Susceptibility in Collaborative Cross Mice
title_short	Functionally Overlapping Variants Control Tuberculosis Susceptibility in Collaborative Cross Mice
title_full	Functionally Overlapping Variants Control Tuberculosis Susceptibility in Collaborative Cross Mice
title_fullStr	Functionally Overlapping Variants Control Tuberculosis Susceptibility in Collaborative Cross Mice
title_full_unstemmed	Functionally Overlapping Variants Control Tuberculosis Susceptibility in Collaborative Cross Mice
title_sort	functionally overlapping variants control tuberculosis susceptibility in collaborative cross mice
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/d4cab79506754b9ea4ff592ecc872668
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Functionally Overlapping Variants Control Tuberculosis Susceptibility in Collaborative Cross Mice

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