My laboratory’s focus concerns the study of the virulence factors and immune evasion strategies of Mycobacterium tuberculosis, the causative agent of tuberculosis (TB). TB remains a major global health problem, despite the widespread use of the Mycobacterium bovis bacillus Calmette-Guerin (BCG) vaccine and drug therapies. Additionally, coinfection of M. tuberculosis
and HIV (TB/HIV), as well as multidrug-resistant (MDR) and extensively
drug-resistant (XDR) tuberculosis, makes TB control even more difficult,
complex and challenging. The long-term goal of my laboratory is the
generation of safe and effective mycobacterial vaccines and therapeutics
through the study, manipulation, and exploitation of mycobacterial
proteins responsible for virulence and evasion of host immune responses.
Many lines of evidence indicate that M. tuberculosis
has evolved mechanisms to evade host immunity, in some cases by
inhibiting the priming and effector functions of various T cell subsets.
Cell death pathways are central to the interaction between pathogenic
mycobacteria and host macrophages. The inhibition of cell death of
infected host cells is a well-documented, but poorly understood,
function of pathogenic mycobacteria.
Several advantages may accrue to mycobacteria as a result
of delaying or inhibiting macrophage cell death, including preservation
of a protected growth environment, prevention of intrinsic microbicidal
activities in the host cell, and reduced stimulation of protective
immunity. The genetic basis for this anti-cell death phenotype has not
been fully elucidated. Using a M. tuberculosis transposon mutant library, we screened pro-cell death mutants of M. tuberculosis
and found multiple genetic loci that are responsible for inhibiting
infection-induced cell death of macrophages. My lab studies these genes
in relation to virulence and immunogenicity of pathogenic mycobacteria.
We seek to identify key components of the genetic basis for important
virulence traits of mycobacteria, thereby providing the tools necessary
to investigate the details of this host-pathogen interaction.
My
laboratory also researches on pathogenesis and vaccine development of
the nontuberculous mycobacteria (NTMs). One of the nontuberculous NTMs
we study is Buruli ulcer, which is an emerging ulcerative skin disease
caused by infection with Mycobacterium ulcerans and is one of
the Neglected Tropical Diseases (NTDs) prioritized by the World Health
Organization. The extensive cutaneous and subcutaneous lesions provoked
by Buruli ulcer often lead to severe deformities and permanent
disability in humans, and the condition has a high mortality rate in
young children. Currently, there are no specific vaccines against Buruli
ulcer. We generated the recombinant BCG strains expressing the M. ulcerans antigens and showed significantly improved antigen-specific T cell responses, correlating with the protection against virulent M. ulcerans in
the mouse footpad model. These recombinant vaccines are the most
protective experimental Buruli ulcer vaccines to date. We are using
systemic approaches to identify the protective antigens and virulence
determinants of M. ulcerans, the results of which can be used
to develop viable novel recombinant or subunit BU vaccine candidates
targeting both the early intracellular and the subsequent extracellular
stage of the infection cycle.