Tuberculosis is a global health emergency with approximately 8 million new cases annually and one third of the world’s population latently infected. Over 400 patients are treated for active TB annually in Ireland, with an increasing number of drug-resistant cases emerging. The emergence of multi-drug resistant strains of Mycobacterium tuberculosis (Mtb) and the failure of BCG vaccine to control the epidemic highlight the need to achieve a better understanding of the host immune response to mycobacterial infection.
After phagocytosis by macrophages, Mtb survives and persists by interfering with host defence mechanisms, such as phagosome maturation, apoptosis, cytokine secretion. Autophagy is an important innate response, resulting in degradation of cellular debris, bacteria/viruses, which can also be manipulated by mycobacteria spp. However the autophagy pathway in human alveolar macrophages infected Mtb is undefined. We have shown that Mtb induces autophagy in human alveolar macrophages, however importantly autophagic flux is blocked by Mtb (see additional data). We have preliminary data, using pharmacological inhibitors, suggesting Mtb-induced autophagy is independent of PI3K activity. Further understanding of this important immune response will significantly impact global efforts to improve current vaccine and treatments for this disease.
Our hypothesis is by elucidating the Mtb-induced autophagy pathway in human alveolar macrophages we will identify novel host and anti-microbial targets for development of improved treatments for TB and vaccine candidates.
Specifically the key questions we will ask (i) how does Mtb induce autophagy in human alveolar macrophages, (ii) what drugs can be used to restore autophagic flux and promote host immunity (bacillary killing, cytokine secretion, T cell activation) and (iii) what Mtb genes modulate autophagy induction and flux in human alveolar macrophages.
In the long term we want to translate this knowledge to design a) improved host-directed inhalable therapies for TB patients and b) microbial candidates for novel vaccine development.
