Research Overview: In the Smith Lab, we are interested in the genome-wide host-pathogen interactions that underlie susceptibility to tuberculosis. Our work encompasses diverse mouse genetics, new bacterial genetic technologies, immunological approaches to infection, vaccine interventions and bioinformatics tools.
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 mammalian resources. From these diverse mammalian systems, we have identified new mouse models that represent distinct tuberculosis disease states and mapped novel host loci (QTL) that underly susceptibility, resistance, tolerance, and immunopathologies.
In parallel, we define the bacterial genetic requirements for growth and adaptation across these diverse host environments through new mycobacterial genetic approaches, including saturated libraries of transposon mutants (TnSeq), CRISPRi and knockouts generated through ORBIT (“oligonucleotide-mediated recombineering followed by Bxb1 integrase targeting”). These combined host and bacterial genome-wide approaches allows the interrogation of each host-pathogen interaction underlying TB.
Altogether, using these Systems Genetics approaches, we are defining the host-pathogen interactions that drive specific arms of immunity, with the long-term goal of rationally designing new host-pathogen paired vaccines and therapeutics.