Tuberculosis remains a major global health problem, despite the widespread use of the Mycobacterium bovis bacillus Calmette-Guerin (BCG) vaccine and drug therapies. Coinfection with Mycobacterium tuberculosis and HIV, as well as multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis, makes TB control difficult, complex and challenging. M. tuberculosis is an extraordinarily successful pathogen that has managed to latently infect nearly one third of humanity and is responsible for an estimated two million deaths annually. The success of this pathogen is linked to its ability to manipulate the intracellular environment of phagocytic cells in the host. 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 these T cell subsets. For example, the manipulation of cell death (apoptosis) by virulent mycobacteria is a well-known survival and immune-modulating strategy. By blocking apoptosis of cells early after infection, M. tuberculosis prevents or delays presentation of its antigens and thus fails to stimulate effective T cell responses. The Lee lab is currently studying these immune evasion strategies of M. tuberculosis and is researching novel approaches for improving mycobacterial vaccines by manipulating mycobacterial proteins responsible for evasion of host immune responses. In particular, studies of apoptosis and autophagy, as innate and adaptive immunity defense against intracellular pathogens, are underway.
In sum, the Lee lab research includes the following: (1) development of safe and effective vaccines and immunotherapeutics for tuberculosis via novel strategies and approaches, (2) evaluation of alternative methods to enhance the efficacy of current mycobacterial vaccines, (3) development of recombinant mycobacterial vehicles capable of eliciting strong immune responses to HIV and other foreign antigens, and (4) study of the virulence and immunogenicity of drug-resistant strains of TB.
Currently, one of the greatest challenges in TB vaccine development is to not only construct prophylactic vaccines that prime a strong response to initial infection, but to find interventions that prevent infection from progressing to disease in those previously exposed to TB and importantly MDR and XDR-TB. The long term goal of our laboratory is to engineer safe and more effective live TB vaccines that will contribute to the global control of tuberculosis and also reduce the emergence of drug resistant strains.