Grant: Project Grant

Ever since German scientist Robert Koch first discovered Mycobacterium tuberculosis (Mtb) to be the infectious agent of tuberculosis in 1882, it has defied efforts by scientists to prevent or cure the disease. The presence of Mtb DNA in ancient Egyptian mummies (dated 1550- 1080 BC) suggests a long-standing evolutionary relationship between this bacterium and humans. Despite the world-wide application of BCG vaccination and other anti-Mtb interventions, Mtb remains one of the deadliest human pathogens killing annually two million people. Eight to ten million new cases of active tuberculosis occur each year due in large part to asymptomatic people chronically infected with Mtb. The ability of Mtb to persist in individuals with apparently normal immune systems implies that Mtb has developed strategies to avoid, evade, and even subvert our host defense system. Considering Mtb also desires to be a "residence" of the bone marrow, which is home to stem cells that produce all immune cells, Mtb potentially hijack the control centre of the immune response. Although we know a great deal about the immune response to Mtb in the lung, our understanding of BM immunity to Mtb is extremely limited. The tropism of Mtb for the bone marrow may also explain why it is an incredibly successful pathogen, as the vast majority of our efforts have been dedicated to controlling its growth in the lung while the root of the disease is seeded in the bone marrow. Thus the major objective of this proposal is to define the cellular and molecular signatures involved in HSC activation/function during infection with virulent strains of Mtb or vaccine with the ultimate goal of developing a roadmap of protective versus detrimental immunity to this devastating disease.