Genome-wide screen identifies host loci that modulate Mycobacterium tuberculosis fitness in immunodivergent mice

Rachel K Meade; Jarukit E Long; Adrian Jinich; Kyu Y Rhee; David G Ashbrook; Robert W Williams; Christopher M Sassetti; Clare M Smith

doi:10.1093/g3journal/jkad147

Genome-wide screen identifies host loci that modulate Mycobacterium tuberculosis fitness in immunodivergent mice

G3 (Bethesda). 2023 Aug 30;13(9):jkad147. doi: 10.1093/g3journal/jkad147.

Authors

Rachel K Meade^{1

2}, Jarukit E Long^{3

4}, Adrian Jinich⁵, Kyu Y Rhee⁵, David G Ashbrook⁶, Robert W Williams⁶, Christopher M Sassetti³, Clare M Smith^{1

2}

Affiliations

¹ Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27710, USA.
² University Program in Genetics and Genomics, Duke University, Durham, NC 27710, USA.
³ Department of Microbiology and Physiological Systems, UMass Chan Medical School, Worcester, MA 01655, USA.
⁴ Research Animal Diagnostic Services, Charles River Laboratories, Wilmington, MA 01887, USA.
⁵ Division of Infectious Diseases, Weill Cornell Medical College, New York, NY 10021, USA.
⁶ Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA.

Abstract

Genetic differences among mammalian hosts and among strains of Mycobacterium tuberculosis (Mtb) are well-established determinants of 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 of Mtb pathogenesis, we infected members of the highly diverse BXD family of strains with a comprehensive library of Mtb transposon mutants (TnSeq). Members of the BXD family segregate for Mtb-resistant C57BL/6J (B6 or B) and Mtb-susceptible DBA/2J (D2 or D) haplotypes. The survival of each bacterial mutant was quantified within each BXD host, and we identified those bacterial genes that were differentially required for Mtb fitness across BXD genotypes. Mutants that varied in survival among the host family of strains were leveraged as reporters of "endophenotypes," each bacterial fitness profile directly probing specific components of the infection microenvironment. We conducted quantitative trait loci (QTL) mapping of these bacterial fitness endophenotypes and identified 140 host-pathogen QTL (hpQTL). We located a QTL hotspot on chromosome 6 (75.97-88.58 Mb) associated with the genetic requirement of multiple Mtb genes: Rv0127 (mak), Rv0359 (rip2), Rv0955 (perM), and Rv3849 (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.

Keywords: BXD; QTL mapping; TnSeq; bacterial genetics; complex traits; genetic diversity; genomics; host–pathogen interactions; mouse models; mycobacteria; natural variation; systems genetics; tuberculosis.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural

MeSH terms

Animals
Mammals / genetics
Mice
Mice, Inbred C57BL
Mice, Inbred DBA
Mutagenesis
Mycobacterium tuberculosis* / genetics
Quantitative Trait Loci

Associated data

Dryad/10.5061/dryad.0gb5mkm04

Abstract

Publication types

MeSH terms

Associated data

Grants and funding