(A*STAR PROGRAMME) Deciphering new immune-evasive mechanisms during Mycobacterium tuberculosis infection

University of Manchester Supervisors: Gloria Lopez-Castejon, David Brough, Lisa Swanton. A*STAR Supervisor: Amit Singhal (SIgN)

Tuberculosis (TB) is a serious public health threat globally, with an estimated 9.4 million new cases and 1.5 million deaths every year. TB pathogenesis is driven by a complex interplay between the host immune system and the survival strategies of the bacterium. Mtb utilizes these strategies to curb the immune response, to hide within infected cells, and to hijack several innate and adaptive immune mechanisms. The ability of Mtb to persist in protected niches within the body delays the efficacy of current antibiotic therapy, contributing to the emergence of multi-drug resistant (MDR) strains. Therefore, the development of new therapeutic strategies, such as host-directed therapies (HDTs) that enhance Mtb-specific immunity, are urgently needed.
The ubiquitin system plays a crucial role in immune signalling pathways by maintaining a fine balance between addition of ubiquitin and the removal of this post-translational modification by deubiquitinating enzymes (DUBs). Ubiquitin and ubiquitin-like posttranslational modifications finely control immune responses to different danger signals, including infection. Indeed, pathogens can exploit the host ubiquitin system by (i) releasing their own ubiquitin-specific enzymes into the host, and (ii) regulating the expression and/or activity of host DUBs.
The key question for this project is how host deubiquitinases contribute to the pathogenesis of Mycobacterium tuberculosis (Mtb) infection.
We have previously shown a role for DUBs and ubiquitin in the regulation of the inflammasome, important for the host immune defence against pathogens. Moreover, our preliminary data shows that Mtb infection induces the upregulation of several DUBs in macrophages, suggesting that DUBs are involved in the macrophage response to Mtb. How Mtb affects the DUB landscape in macrophages and how this contributes to the regulation of the inflammasome mediated immune responses to Mtb, remains unknown and will be explored during this PhD.
This project will combine the use of human macrophages (cell line and blood derived) as well as murine models of Mtb infection. The project will require the candidate to learn a wide variety of skills including cell culture, molecular biology techniques (western blot, immunoprecipitation, gene editing by CRISR/Cas9), ELISA, imaging, RNA-sequencing and data analysis, animal handling and importantly working in the biosafety level 3 containment facility. All of this will allow the PhD candidate to determine whether DUBs regulate the outcome of host-Mtb interaction, contribute to TB pathogenesis and thus could be targeted to design novel host-directed therapies against TB.

This project is an exciting collaboration between the labs of Gloria Lopez-Castejon at the Manchester Collaborative Centre of Inflammation Research (MCCIR) and Amit Singhal at Singapore Immunology Network (SIgN), A*STAR, Singapore. We are looking for talented, motivated and enthusiastic candidates that want to join this unique opportunity. The PhD candidate will spend two years at Manchester and two years in Singapore allowing the student to benefit and gain invaluable experience from these two world leading institutions.