Systems Infection Biology
A fundamental question in pathogenesis is what makes some diseases chronic. The disease agent, which may be a virus, bacterium or parasite, is cleared very slowly, and in some diseases never cleared, by the immune system or therapy. The reasons in the case of HIV and TB can be broken down into latency (HIV) or dormancy (TB), incomplete drug or immune effector penetration and function, and modes of spread that make infection very probable despite inhibition by cellular or pharmacologic agents.
The goal of our laboratory is to better understand reservoir formation in HIV and TB infection, and specifically what interactions in the cellular milieu of the infection microenvironment make infection insensitive to inhibition by the immune system or therapy. Furthermore, we will focus on understanding the dynamics and constraints of one mechanism whereby the reservoir can re-seed more generalized infection in the presence of therapy, which is the evolution of drug resistance.
To study HIV reservoirs and evolution we will continue to use in vitro culture where we have the ability to control the system and add or remove layers of complexity and thereby define the important components that affect the degree of inhibitor insensitivity and the rate and trajectory of the evolution of genetic resistance. In TB, we will investigate the contribution of non-genetic cell-to-cell variability to the persister phenotype, as well as T cell specificities that may enable the sequestration of the disease in a reservoir for life.
The long-term goal of our research is
- Define key cellular players in persistence of HIV and TB
- Understand evolutionary trajectories as a function of inhibitor concentration, genetic makeup of the pathogen population, and microenvironment
- Study the persistence of TB due to cell-to-cell variability in the bacterial population, and
- Study the elements of a successful immune response to TB that prevent it from exiting the reservoir and causing active disease