Functionally Overlapping Variants Control Tuberculosis Susceptibility in Collaborative Cross Mice
Abstract
<jats:title>ABSTRACT</jats:title>
<jats:p>Host genetics plays an important role in determining the outcome of <jats:named-content
content-type="genus-species">Mycobacterium tuberculosis</jats:named-content>
infection. We previously found that Collaborative Cross (CC) mouse strains differ
in their susceptibility to <jats:named-content content-type="genus-species">M. tuberculosis</jats:named-content>
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 (<jats:italic>Tip1</jats:italic> to <jats:italic>Tip4</jats:italic>).
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 <jats:italic>Itgal</jats:italic>
gene, which encodes CD11a and is found within the <jats:italic>Tip2</jats:italic>
interval. This 15-bp deletion leads to aberrant mRNA splicing and is predicted to
result in a truncated protein product. The <jats:italic>Itgal<jats:sup>CC042</jats:sup></jats:italic>
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 <jats:italic>Tip</jats:italic> variants likely explains the profound susceptibility
of CC042 mice and highlights the multigenic nature of tuberculosis control in the
Collaborative Cross.</jats:p>
<jats:p><jats:bold>IMPORTANCE</jats:bold> The variable outcome of <jats:named-content
content-type="genus-species">Mycobacterium tuberculosis</jats:named-content> 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 <jats:named-content content-type="genus-species">M.
tuberculosis</jats:named-content> 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 <jats:italic>Itgal</jats:italic>
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.</jats:p>
Type
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https://hdl.handle.net/10161/19607Published Version (Please cite this version)
10.1128/mbio.02791-19Publication Info
Smith, Clare M; Proulx, Megan K; Lai, Rocky; Kiritsy, Michael C; Bell, Timothy A;
Hock, Pablo; ... Sassetti, Christopher M (n.d.). Functionally Overlapping Variants Control Tuberculosis Susceptibility in Collaborative
Cross Mice. mBio, 10(6). 10.1128/mbio.02791-19. Retrieved from https://hdl.handle.net/10161/19607.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Clare Smith
Assistant Professor of Molecular Genetics and Microbiology
The Smith Lab are interested in host genetic diversity, bacterial variation, and how
these host-pathogen genetic interactions drive tuberculosis disease states.Systems
Genetics of Tuberculosis: We leverage host diversity in mice and macrophages from
wild-derived mouse strains and diverse mouse panels, including the Collaborative Cross
and BXD mammalian resources. In parallel, we define the bacterial genetic requi

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