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.