Host genetic background is a barrier to broadly effective vaccine–mediated protection against tuberculosis
Name
167762.3-20240129220602-covered-4fa089109ce452e764bbb8648b44a723.pdf
Description
Published version
Size
10.51 MB
Format
Adobe PDF
Checksum (MD5)
9f8cf4313345d113a76903cf33815ce0
Author(s)
Lai, Rocky
Gong, Diana N
Williams, Travis
Ogunsola, Abiola F
Cavallo, Kelly
Lindestam Arlehamn, Cecilia S
Acolatse, Sarah
Beamer, Gillian L
Ferris, Martin T
Sassetti, Christopher M
Date Issued
May 18, 2023
Journal
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Version
Final published version
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.
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DOI of Published Version
https://doi.org/10.1172/jci167762
