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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

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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 4

T cell populations in protected and unprotected CC mice following Mtb infection.

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T cell populations in protected and unprotected CC mice following Mtb in...
(A) Frequency of CD3+, CD3+CD4+ and CD3+CD8+ T cells in the lungs of unvaccinated and BCG-vaccinated CC mice 4 weeks after infection. (B) Proportion of memory CD4 and CD8 T cells in the lungs of either unvaccinated or BCG-vaccinated CC mice 4 weeks after infection, as defined by CD44+ and various combinations of CD62L and CD127 expression; CD62L+CD127+ (central memory), CD62L–CD127– (effector), CD62L–CD127+ (effector memory). (C) Frequency of resident memory CD4 and CD8 T cells in the lungs of either unvaccinated or BCG-vaccinated CC mice 4 weeks after infection, as defined by CD44+CD103+CD69+. (D) Proportion of Th1, Treg and Th17 cells in the lungs of either unvaccinated or BCG-vaccinated CC mice 4 weeks after infection, as defined by CD44+ and Tbet+ (Th1), Foxp3+ (Treg) or RoRγt (Th17) expression. (E) Frequency of CD4 and CD8 T cells expressing either CXCR3 or CX3CR1 in the lungs of either unvaccinated or BCG-vaccinated CC mice 4 weeks after infection. (F) PCA of the T cell–phenotyping data. Each point represents the average of 5 mice within a given mouse strain that are either BCG vaccinated or unvaccinated. Open symbols, unvaccinated; closed symbols, BCG vaccinated. Each color represents a different mouse strain. The unvaccinated symbol is labeled with the CC strain name. The legend is modeled after the quadrants in Figure 1C. (A–E) The data represent the mean ± SEM from 1 experiment (n = 5/group). 2-way ANOVA with the Benjamini and Hochberg multiple comparison method. The FDR was set to 0.05 and the numbers in the figures are the q value. Quantitative data in panels A, C, and E are represented as box-and-whisker plots, with bounds from 25th to 75th percentile, median line and whiskers ranging from minimum to maximum.

Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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