Host genetic background is a barrier to broadly effective vaccine–mediated protection against tuberculosis
Rocky Lai, … , Douglas A. Lauffenburger, Samuel M. Behar
Rocky Lai, … , Douglas A. Lauffenburger, Samuel M. Behar
Published May 18, 2023
Citation Information: J Clin Invest. 2023;133(13):e167762. https://doi.org/10.1172/JCI167762.
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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 3

BCG-protected CC mice have an altered lung cytokine environment after Mtb infection.

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BCG-protected CC mice have an altered lung cytokine environment after Mt...
(A) Lung homogenate IFN-γ levels from BCG vaccinated or unvaccinated CC mice 4 weeks after infection, represented as box-and-whisker plots, with bounds from 25th to 75th percentile, median line and whiskers ranging from minimum to maximum. A 2-way ANOVA was performed using the original FDR method of Benjamini and Hochberg. FDR values indicated above bars. (B–D) Pearson correlation between lung CFU and ln transformed (B) IL-17, LIF, KC, IL-6, and MIP-1α; (C) IFN-γ and TNF; and (D) LIX, RANTES, and IP-10 comparing unvaccinated and BCG vaccinated C57BL/6 mice, and unprotected or protected CC mice. R values indicate the Pearson correlation coefficients for unvaccinated (blue) and BCG (red) groups, with the accompanying P values indicate the Benjamini-Hochberg corrected significances of those correlations. Within each category of C57BL/6, not-protected CC mice, and protected CC mice, the correlations between BCG vaccinated and unvaccinated mice were compared using a Fisher’s z transformation of the correlation coefficients followed by a z test, and the significance of the difference in the correlations is reported as a Benjamini-Hochberg corrected pdiff. Significant P values are in bold.