Host genetic background is a barrier to broadly effective vaccine–mediated protection against tuberculosis
Rocky Lai, Diana N. Gong, Travis Williams, Abiola F. Ogunsola, Kelly Cavallo, Cecilia S. Lindestam Arlehamn, Sarah Acolatse, Gillian L. Beamer, Martin T. Ferris, Christopher M. Sassetti, Douglas A. Lauffenburger, Samuel M. Behar
Rocky Lai, Diana N. Gong, Travis Williams, Abiola F. Ogunsola, Kelly Cavallo, Cecilia S. Lindestam Arlehamn, Sarah Acolatse, Gillian L. Beamer, Martin T. Ferris, Christopher M. Sassetti, Douglas A. Lauffenburger, Samuel M. Behar
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Research Article Infectious disease

Host genetic background is a barrier to broadly effective vaccine–mediated protection against tuberculosis

Abstract

Heterogeneity in human immune responses is difficult to model in standard laboratory mice. To understand how host variation affects Bacillus Calmette Guerin–induced (BCG-induced) immunity against Mycobacterium tuberculosis, we studied 24 unique collaborative cross (CC) mouse strains, which differ primarily in the genes and alleles they inherit from founder strains. The CC strains were vaccinated with or without BCG and challenged with aerosolized M. tuberculosis. Since BCG protects only half of the CC strains tested, we concluded that host genetics has a major influence on BCG-induced immunity against M. tuberculosis infection, making it an important barrier to vaccine-mediated protection. Importantly, BCG efficacy is dissociable from inherent susceptibility to tuberculosis (TB). T cell immunity was extensively characterized to identify components associated with protection that were stimulated by BCG and recalled after M. tuberculosis infection. Although considerable diversity is observed, BCG has little impact on the composition of T cells in the lung after infection. Instead, variability is largely shaped by host genetics. BCG-elicited protection against TB correlated with changes in immune function. Thus, CC mice can be used to define correlates of protection and to identify vaccine strategies that protect a larger fraction of genetically diverse individuals instead of optimizing protection for a single genotype.

Authors

Rocky Lai, Diana N. Gong, Travis Williams, Abiola F. Ogunsola, Kelly Cavallo, Cecilia S. Lindestam Arlehamn, Sarah Acolatse, Gillian L. Beamer, Martin T. Ferris, Christopher M. Sassetti, Douglas A. Lauffenburger, Samuel M. Behar

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Figure 7

Identifying signatures of protection in categories of CC strains.

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Identifying signatures of protection in categories of CC strains. Scores...
Scores plot (left) and heatmaps (right) of selected features for PLSDA models comparing (A) resistant CC strains (B) susceptible CC strains and (C) protected resistant and non-protected susceptible mice (i.e., good and poor immunity, respectively). Each dot represents a single mouse. The 2 colors in the scores plots signify the 2 classes being compared. An ellipse is drawn around the 95% CI for each class. Percent of variance of the immune feature data are shown on the axes. Heatmaps show features that were most important for distinguishing the 2 classes. Colors are representations of z-scored features. Columns are averages of the mice in the CC strains, with vaccinated and unvaccinated mice being separated (n = 5 for most cases). Feature names are colored based on the data set from which they come (blue, T cell phenotyping; brown, lung homogenate cytokines; green, ICS; magenta, LEGENDplex). The legend references the protection/susceptibility quadrant (Figure 1C).