We are pursuing the mechanisms by which genetic variation in the host alters the immune pressures experienced by Mycobacterium tuberculosis. By understanding how these interactions drive specific arms of immunity, new host-pathogen paired vaccines and therapeutics can be rationally designed.
We leverage host diversity in mice and macrophages from wild-derived mouse strains and diverse mouse panels, including the Collaborative Cross, Diversity Outbred and BxD resources. In parallel, we define the bacterial requirements for growth and adaptation in these diverse host environments through bacterial genetics approaches, including libraries of transposon mutants (TnSeq), CRISPRi and knockouts generated through ORBIT (“oligonucleotide-mediated recombineering followed by Bxb1 integrase targeting”).
Altogether, using these Systems Genetics approaches, we have identified host loci that control specific aspects of the host-pathogen microenvironment, that can potentially be targeted by vaccination and therapeutic intervention.