Abstract
The outcome of an encounter with Mycobacterium tuberculosis (Mtb) depends on the pathogen's ability to adapt to the variable immune pressures exerted by the host. Understanding this interplay has proven difficult, largely because experimentally tractable animal models do not recapitulate the heterogeneity of tuberculosis disease. We leveraged the genetically diverse Collaborative Cross (CC) mouse panel in conjunction with a library of Mtb mutants to create a resource for associating bacterial genetic requirements with host genetics and immunity. We report that CC strains vary dramatically in their susceptibility to infection and produce qualitatively distinct immune states. Global analysis of Mtb transposon mutant fitness (TnSeq) across the CC panel revealed that many virulence pathways are only required in specific host microenvironments, identifying a large fraction of the pathogen's genome that has been maintained to ensure fitness in a diverse population. Both immunological and bacterial traits can be associated with genetic variants distributed across the mouse genome, making the CC a unique population for identifying specific host-pathogen genetic interactions that influence pathogenesis.
Highlights
Infection with Mycobacterium tuberculosis (Mtb) produces heterogeneous outcomes that are influenced by genetic and phenotypic variation in both the host and the pathogen
The relationship between this variant and the mce4-associated Quantitative Trait Loci (QTL) (Hip43) was less clear, as the statistical support for independent QTL was weak (ESX1 and mce4 QTL p=0.17; mbt and mce4 QTL p=0.08) and the effects of founder haplotypes were similar but not identical (Figure 6F). Some of this ambiguity may be related to the relatively small 491 range in trait values for mce4, compared to either ESX1 or mbt (Figure 6G). Based on this data, we report two distinct Host-Interacting-with Pathogen QTL (HipQTL) in this region (Hip42 and 43; Table 2). 494 Two Tuberculosis ImmunoPhenotype Quantitative Trait Loci (TipQTL) overlapped with HipQTL (Figure 7; Tip5/Hip4 on chromosome 2 and Tip9/Hip35 on chromosome 17), suggesting specific interactions between bacterial fitness and immunity
We found that the founder haplotypes associated with extreme trait values at this QTL could differentiate Collaborative Cross (CC) strains with significantly altered total bacterial burden, and the NOD and WSB haplotypes were associated with higher bacterial numbers (p=0.0085 for spleen Chromosomal equivalent (CEQ); p=0.027 for spleen colony forming units (CFU); Figure 6H)
Summary
Our broad profiling of both host and pathogen traits after Mtb infection in a large panel of CC strains, created a reproducible resource to study the diverse host-pathogen interactions that drive tuberculosis disease. Our study indicated that a roughly similar number of genes are important for Mtb fitness in a given mouse strain, even immunodeficient strains that likely represent the most divergent environments While this observation may seem counterintuitive, it is consistent with previous TnSeq studies in both mouse models (Mishra et al, 2017a) and in vitro conditions (Minato et al, 2019), where distinct but sized gene sets are necessary for growth under very different conditions. While some bacterial genetic requirements could be associated with known immune pathways, most of the differential pressures on bacterial mutants could not be attributed to these simple deficiencies in known mechanisms of immune control Instead, it appears that the CC population produces a spectrum of novel environments, and that a relatively large fraction of the pathogen’s genome is needed to adapt to changing immune pressures. While the combinatorial complexity of associating host and pathogen genetic variants in natural populations is daunting, the identification of HipQTL in the CC panel indicates that these inter-species genetic interactions can be important determinants of pathogenesis and can be dissected using this tractable model of diversity
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