Grant: Project Grant - PA: Pandemic Preparedness and Health Emergencies Research

Tuberculosis (TB) is a highly contagious airborne disease that sickens and kills millions of people world-wide. TB to some extent is vaccine preventable. Indeed, the existing vaccine is effective at protecting newborn infants against the deadlier childhood forms of the disease but for reasons that are as yet unclear, the same vaccine is inadequate in protecting adults against the more prevalent pulmonary form of TB. While people with TB can be treated and cured using a cocktail of antibiotics, the emergence of antibiotic-resistant TB bacteria has rendered most of these drugs useless. Thus, better anti-TB vaccines and drugs are urgently needed. Gaining a deeper understanding of what the TB bacteria does when it infects a host to cause disease will help identify new targets for anti-TB intervention. For instance, powerful immune cells called macrophages are normally mobilized to engage and successfully destroy foreign microbes when they enter the lungs of a person. TB bacteria however produce and release virulence factors that help it evade destruction by macrophages, thus allowing the bacteria to persist and eventually cause disease in the infected host. Our research, past and present, has shown that virulence factors exported by the TB bacteria through a specialized protein secretion system called ESX-1 are critical for the bacteria to cause disease. In this proposal, we will undertake mechanistic studies to figure out how two poorly understood ESX-1 associated virulence factors called EspB and EspD are exported by the TB bacteria, how they work at the molecular level to counteract the anti-bacterial activities of immune cells like macrophages and how they contribute to TB disease in an infected host. Addressing these questions will not only increase our understanding of TB infection but also inform the development novel anti-TB vaccines and drugs that block the deployment and/or functions of EspB and EspD.