In 2015 there were more than 10.4 million new cases and 1.8 million deaths associated with tuberculosis (TB) globally. Furthermore, infection with Mycobacterium tuberculosis (Mtb), the causative agent of TB, is the leading cause of death in human immunodeficiency virus (HIV)+ individuals. Together TB and HIV account for more than 2 million deaths per year, and HIV+ individuals are 30 times more likely to develop active TB. Individually, both diseases are characterized by a chronic, largely asymptomatic latent infection period that often lasts for several decades. However, if both diseases occur simultaneously, fulminant and often fatal disease develops. Management of this deadly co-infection is a significant global health challenge that is exacerbated by the lack of efficient vaccines against both Mtb and HIV, as well as the lack of reliable and robust animal models for Mtb/HIV co-infection.
To a great extent this situation is due to the failure of BCG, the only licensed vaccine against TB, to afford protection against pulmonary TB in adults. Its moderate efficacy combined with a sharp increase in drug resistance urgently calls for improved TB vaccination strategies. My research focuses on the development of new and unconventional strategies to improve live-attenuated TB vaccines. I will highlight how we have successfully utilized a mouse model of tuberculosis to elucidate the mechanistic in vivo regulation of Mtb-antigen-independent T and NK cell responses through intracellular pattern recognition. Additionally, I will cover aspects of a mucosal vaccination strategy to generate protective mycobacteria-specific resident memory T cells and to overcome the shortcoming of the current subcutaneous BCG administration route - the weak memory lymphocyte generation in the lung. Furthermore, I will describe a novel, tractable and reproducible mouse model to study the reactivation dynamics of latent Mtb infection following the loss of CD4+ T cells as it occurs in HIV-co-infected individuals.