Tuberculosis Susceptibility and Vaccine Protection Are Independently Controlled by Host Genotype

Abstract

The outcome of Mycobacterium tuberculosis infection and the immunological response to the bacillus Calmette-Guerin (BCG) vaccine are highly variable in humans. Deciphering the relative importance of host genetics, environment, and vaccine preparation for the efficacy of BCG has proven difficult in natural populations. We developed a model system that captures the breadth of immunological responses observed in outbred individual mice, which can be used to understand the contribution of host genetics to vaccine efficacy. This system employs a panel of highly diverse inbred mouse strains, consisting of the founders and recombinant progeny of the “Collaborative Cross” project. Unlike natural populations, the structure of this panel allows the serial evaluation of genetically identical individuals and the quantification of genotype-specific effects of interventions such as vaccination. When analyzed in the aggregate, our panel resembled natural populations in several important respects: the animals displayed a broad range of susceptibility to M. tuberculosis, differed in their immunological responses to infection, and were not durably protected by BCG vaccination. However, when analyzed at the genotype level, we found that these phenotypic differences were heritable. M. tuberculosis susceptibility varied between lines, from extreme sensitivity to progressive M. tuberculosis clearance. Similarly, only a minority of the genotypes was protected by vaccination. The efficacy of BCG was genetically separable from susceptibility to M. tuberculosis, and the lack of efficacy in the aggregate analysis was driven by nonresponsive lines that mounted a qualitatively distinct response to infection. These observations support an important role for host genetic diversity in determining BCG efficacy and provide a new resource to rationally develop more broadly efficacious vaccines.

Reactogenicity to major tuberculosis antigens absent in BCG is linked to improved protection against Mycobacterium tuberculosis

“…In line with this finding, the importance of host genotype for tuberculosis susceptibility and vaccine protection in the mouse model has been recently reported39. Thus, our results indicate that MTBVAC-vaccinated mice reactogenic for CFP10 and ESAT6 are more protected against tuberculosis than non-reactogenic strains.…”

Heterogeneity in tuberculosis

“…Using an inbred recombinant mouse panel known as the ‘Collaborative Cross’ (REFS 134,135), Smith et al . 130 found that host susceptibility to TB and BCG vaccine efficacy were remarkably variable and genetically uncoupled from one another, such that protection to vaccination correlated with the intrinsic quality of the immune response.…”

Mechanisms of M. tuberculosis Immune Evasion as Challenges to TB Vaccine Design

“…The architecture of (Marakalala et al, 2016) and animals (Gideon et al, 2015; Smith et al, 2016), and in a common form of TB granulomas, T cells are confined to the peripheral regions, while infected cells are in the central core (Figure 2) (Ernst et al, 2018; Kauffman et al, 2018). Since CD4 T cells must directly recognize and contact infected cells to control intracellular M. tuberculosis (Srivastava and Ernst, 2013), the architecture of TB granulomas may limit the efficacy of T cells in TB.…”