Genome-wide screen identifies host loci that modulateM. tuberculosisfitness in immunodivergent mice

Abstract

AbstractGenetic differences among mammalian hosts andMycobacterium tuberculosis(Mtb) strains determine diverse tuberculosis (TB) patient outcomes. The advent of recombinant inbred mouse panels and next-generation transposon mutagenesis and sequencing approaches has enabled dissection of complex host- pathogen interactions. To identify host and pathogen genetic determinants ofMtbpathogenesis, we infected members of the BXD family of mouse strains with a comprehensive library ofMtbtransposon mutants (TnSeq). Members of the BXD family segregate forMtb-resistant C57BL/6J (B6 orB) andMtb-susceptible DBA/2J (D2 orD) haplotypes. The survival of each bacterial mutant was quantified within each BXD host, and we identified those bacterial genes that were differentially required forMtbfitness across BXD genotypes. Mutants that varied in survival among the host family of strains were leveraged as reporters for “endophenotypes”, each bacterial fitness profile directly probing specific components of the infection microenvironment. We conducted QTL mapping of these bacterial fitness endophenotypes and identified 140host-pathogenquantitative trait loci (hpQTL). We identified a QTL hotspot on chromosome 6 (75.97–88.58 Mb) associated with the genetic requirement of multipleMtbgenes;Rv0127(mak),Rv0359(rip2),Rv0955(perM), andRv3849(espR). Together, this screen reinforces the utility of bacterial mutant libraries as precise reporters of the host immunological microenvironment during infection and highlights specific host-pathogen genetic interactions for further investigation. To enable downstream follow-up for both bacterial and mammalian genetic research communities, all bacterial fitness profiles have been deposited into GeneNetwork.org and added into the comprehensive collection of TnSeq libraries in MtbTnDB.