Approximately one-third of the world's population is infected with Mycobacterium tuberculosis (Mtb). The World Health Organization estimates that in 2011 approximately 1.4 million people died from tuberculosis (TB), more people than from any other single infectious agent except for HIV. Mtb is able to establish this enormous worldwide burden of disease by subverting innate and adaptive defenses of the host. Although the worldwide disease burden is enormous, it remains poorly understood as to what accounts for successful host resistance and why it fails in 10% of infected individuals. Recent work has demonstrated the importance of autophagy in host resistance to bacterial pathogens. Autophagy is a general phenomenon by which host cells eradicate diverse bacteria, including human pathogens such as Listeria, Salmonella, Group A Streptococcus, and mycobacteria. A prevailing model of how autophagy contributes to host defense begins with bacteria damaging or escaping from phagosomes, followed by recognition of the bacteria by adaptor proteins such as p62 and Ndp52, which contain an ubiquitin associated (UBA) domain that binds ubiquitinated proteins and an LC3 binding motif. These adaptors are thought to link bacterial cargo to the autophagosome, although the determinants that are recognized on the bacteria are not known. Once captured in an autophagosome, bacterial replication is curtailed as the autophagosome fuses with lysosomes to form an autolysosome. Our work has identified 13 Mtb surface proteins (which we refer to as MUPs for Mycobacterial-Ubiquilin (Ubqln)- interacting Proteins) that interact with a family of related host proteins, Ubiquilin 1, Ubiquilin 2, and Ubiquilin 4, that ar implicated in autophagy and proteasomal degradation. We hypothesize that the interaction between Ubqln1 and MUPs results in targeting of intact Mtb bacilli and/or MUPs for degradation. The goal of this proposal is to determine whether Ublqn1 links Mtb and/or MUPs to the autophagy or proteasomal pathway, and thereby regulates intracellular Mtb survival, degradation of MUPs, and/or antigen presentation. These experiments have important implications for Mtb vaccine development and will provide insight into the anti- microbial capacity of macrophages. Ultimately, we might be able to improve the mycobacterial killing capacity of the infected macrophage. This would enable novel therapeutic development that could significantly shorten therapy, and in turn, change the face of the global epidemic. In addition, given the conservation of MUPs, this work may offer insight into innate resistance to an array of bacterial pathogens.
Approximately one-third of the world's population is infected with Mycobacterium tuberculosis (Mtb), but not everyone becomes sick;the reasons for this difference in susceptibility to disease remain unknown, and understanding it holds great promise for global health. We found that numerous Mtb surface proteins interact with a family of human proteins that we hypothesize are important in determining how infected macrophages (immune cells) control bacterial growth. Exploring these interactions will advance our understanding of how Mtb survives in its human host, which might enable the creation of new therapies to treat tuberculosis.