Mathematical Modeling of Mycobacterium Tuberculosis Dissemination

Co-Principal Investigator:
Michael A. Langston, Department of Electrical Engineering and Computer Science, University of Tennessee
Abstract:
The main focus of this project is on tuberculous (TB) and the dissemination of its cause, Mycobacterium tuberculosis (Mtb). While TB is primarily a pulmonary disease, its extrapulmonary forms are a hallmark of infection in young children and immunocompromised adults. There it is often hard to diagnose and can lead to extremely lethal forms such as TB meningitis. A number of highly innovative techniques will be employed. These include a mouse model with ultra-low dose Mtb colony forming units, a large set of barcoded Mtb strains, a special Mtb strain H37Rv-pBP10 with the replication clock plasmid, and mRNA-based gene signatures with which we can predict bacterial counts in murine lungs and TB disease progression risk in humans. With these we will investigate dissemination across lung tissues, and study the supposition that Mtb spreads locally between lobes versus an alternate hypothesis that Mtb spreads hematogenously after disseminating systemically. We will also seek to determine the relative contribution of different cell populations to the kinetics of Mtb dissemination with the use of both conventional and plasmid-carrying Mtb strains. Furthermore, we will derive a novel signature that can predict systemic Mtb dissemination in the spleen and determine whether this new signature can predict TB dissemination in monkeys and humans. We are optimistic that the experimental and analytical framework we will generate can help lay the groundwork for the study of dissemination in HIV and other diseases known to spread systemically from a local infection site.
Research Partners:
The PI for this project is Vitaly V. Ganusov at the University of Tennessee. Other investigators include John Aitchison, Fergal Duffy, and Kevin B. Urdahl at Seattle Children's Research Institute, Samuel M Behar at the University of Massachusetts, and David Sherman at the University of Washington.