'Strain-specific expression of the Mycobacterium tuberculosis DosR environmental sensor' - MIMM 396 Undergraduate Research Project Application Form

Supervisor's Name: Dr. Michael Reed

Supervisor's Email: michael.reed [at] mcgill.ca

Supervisor's Phone:

Supervisor's Website: http://www.mcgill.ca/tb/investigators/michael-b-reed

Supervisor's department: Microbiology and Immunology

Course number: MIMM 396 (Microbiology)

Term: Fall 2013-2014

Project start date: Tuesday, September 3, 2013

Project end date: Tuesday, December 3, 2013

Project title: Strain-specific expression of the Mycobacterium tuberculosis DosR environmental sensor

Project description (50-100 words suggested): The WHO estimates that there are more than 2 billion individuals worldwide that are infected with the tuberculosis (TB) bacillus, Mycobacterium tuberculosis. From this enormous reservoir, approximately 2 million deaths occur each year despite the availability of effective chemotherapy and a partially effective vaccine (BCG) for well over half a century. Clearly, this situation reflects very poorly on our present level of understanding of the fundamental processes employed by this bacterium to transmit, infect and to cause disease. To add to the complexity of this problem, researchers have recently determined that there are actually six distinct lineages of M. tuberculosis, each of which may possess unique attributes potentially related to the transmission and development of disease.

As part of an ongoing program of research in our laboratory aimed at studying the impact of genetic and antigenic variability on the pathogenesis of clinical M. tuberculosis isolates, we require a student to carry out a research project that aims to identify novel regulatory alterations that account for the observation that strains belonging to the East Asian (or W/Beijing) lineage of M. tuberculosis constitutively over-express the coordinately regulated transcriptional program known as the “Dormancy-Regulon” (DosR). This phenotype sets these strains apart from all the other TB lineages that only express the regulon when grown under conditions of oxygen-limitation or upon exposure to nitric oxide. Importantly, each of these signals is encountered by the bacterium during infection of host tissues.

To begin to examine the basis for this apparent dichotomy in the control of the DosR-regulon, we have generated a range of M. tuberculosis mutants that are either altered or disrupted in their DosR function (the "master switch" responsible for dormancy regulon expression) as well as the two histidine sensor-kinases (DosS, DosT) that signal to DosR in response to a change in oxygen tension or the redox environment of the cell. The student assigned to this project will begin to analyze these recombinant strains using a range of molecular approaches at our disposal that may include transcriptional (gene expression) assays as well as protein immunoprecipitation or “pull-down” assays in an attempt to identify novel mutations or signaling pathways that are unique to strains of the globally important East-Asian M. tuberculosis lineage.

Prerequisite: 1 term completed at McGill + CGPA of 3.0 or higher; or permission of instructor./p>

Grading scheme (The final report must be worth at least 50% of final grade): Final grade shall be based on laboratory performance as evaluated by the research supervisor (50%) and the final written research report (minimum 10 pages) graded by the supervisor and the course coordinator or the coordinator's delegate (50%).

Project status: This project is taken. The professor has no more '396' projects this term.

How students can apply: After all parts of this application form are completed, and the hard copy is signed by the professor and the student, bring this application form and your unofficial transcript to Prof. Gregory Marczynski during office hours, who will review/approve as the course coordinator for MIMM 396 (Microbiology) or MIMM 397 (Immunology).

Ethics, safety, and training: Supervisors are responsible for the ethics and safety compliance of undergraduate students. This project involves: Biohazardous substances; Handling chemicals.