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 1

BCG-induced protection in 24 CC strains and C57BL/6 mice challenged with Mtb.

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BCG-induced protection in 24 CC strains and C57BL/6 mice challenged with...
(A) Lung and (D) spleen CFU of 24 CC mice (n = 120/group; top) or C57BL/6 mice (n = 20/group; bottom) 4 weeks after infection. Each point represents an individual mouse and the line is the median. Δ, Δlog10CFU. Student’s t test; ****P < 0.0001. CFU in (B) lungs and (E) spleens from BCG versus unvaccinated strains (n = 5/group) after Mtb challenge, represented as box-and-whisker plots, with bounds from 25th to 75th percentile, median line and whiskers ranging from minimum to maximum. The Benjamini-Hochberg procedure was used to determine the FDR (above bars). The Δlog10CFU was calculated for each strain (bottom). Correlation in the (C) lung and (F) spleen between susceptibility (y-axis, CFU in unvaccinated group) and protection conferred by BCG (x-axis, Δlog10CFU). The data are relative to the C57BL/6 reference strain, which centers the graph on C57BL/6 mice. The CC strains are divided into 4 quadrants based on their relative susceptibility and protection.