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
View: Text | PDF
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

×

Figure 9

Th1/17 cells correlate with BCG-mediated protection in a subset of protected CC mice.

Options: View larger image (or click on image) Download as PowerPoint
Th1/17 cells correlate with BCG-mediated protection in a subset of prote...
(A) 4 weeks after infection, lung cells were stimulated with anti-CD3 mAb, MTB300 megapool,or nothing (media). Representative flow plots of IFN-γ and IL-17–producing CD4 T cells from CC037 and C57BL/6 mice. (B) Frequencies of CD4 T cells that expressed both IFN-γ and IL-17. (C) Representative flow plots of T-bet and RORγt expressing CD4 T cells from CC037 or C57BL/6 mice. (D) Frequencies of CD4 T cells that expressed both T-bet and RORγt. (E) Proportion of CD4 T cells that express combinations of IFN-γ, TNF, IL-2, or IL-17 in unvaccinated or BCG vaccinated mice 4 weeks after Mtb infection, generated using SPICE (41). (F) Correlation of IFN-γ+IL-17+ cells and lung CFU from unvaccinated or BCG vaccinated CC037, CC072, CC001, and CC031 mice 4 weeks after Mtb infection. Unvaccinated and BCG vaccinated mice are combined for the correlation analysis. Spearman ρ and P value are shown. Data are pooled from 2 experiments except for CC031. Data are representative of 2 independent experiments (n = 5 mice/group). 1-way ANOVA corrected with the Benjamini and Hochberg multiple comparison method (FDR = 0.05).