Project 2 Bacterial determinants of host adaptation and evolutionary success

Project 2: Bacterial genetic determinants of susceptibility (Project Leader: Sarah Fortune) Abstract: Mycobacterium tuberculosis (Mtb) is an incredibly successful human pathogen, estimated to have infected up to a third of the world’s population. The field has traditionally considered Mtb to have evolved its optimized virulence state in the distant past through thousands of years of coevolution

with early humans. There has been little consideration of the possibility that Mtb is continuing to evolve to enhance its ability to spread within human populations. Here we seek to understand how Mtb might be evolving to optimize its population level transmission, focusing on one family of nearly identical strains of Mtb, here called the G2G strains, which emerged in Lima, Peru from

the globally dominant Lineage 2 strains, roughly 50-years ago and now represent ~90% of all Lineage 2 strains in Lima. There are no obvious epidemiologic drivers of this population sweep but we have identified a human genetic determinant of G2G susceptibility, which is a likely regulatory variant of the lipid raft protein FLOT1, which alters many aspects of the inflammatory

response to Mtb. These discoveries make G2G an ideal case to mechanistically define the bacterial determinants and host interactions that contribute to its population success. In this program, we will address this question in the following Aims: (Aim 1) Genetic dissection of the virulence related intermediate traits that distinguish G2G strains from the L2 strains from which

they emerged; (2) Definition of the course of G2G infection in mouse models of FLOT1 deficiency and associated immune pathways and (3) Understanding macrophage responses to and control of G2G infection using human FLOT1 variant macrophages. Because we understand so little about bacterial determinants of TB transmission success of ongoing evolution of Mtb virulence

traits, this will be provide foundational data for the field to evaluate the emergence of other highly transmitted Mtb strains around the world. These studies will contribute clinically relevant Mtb variants to Project 1, which is studying the role of the unfolded protein response in Mtb infection, because G2G strains fail to elicit transcriptional evidence of the UPR in human macrophages.

Similarly, in an effort to optimize vaccine strategies, Project 3 will use the G2G strain as a clinically relevant challenge strain that is succeeding in the setting of widespread BCG vaccination.