Christopher Sassetti to lead international team studying biology of TB

National Institute of Allergy and Infectious Diseases awards $11 million grant to improve treatment of TB

Understanding the biology of the disease is difficult because of the variability in the population. With the new grant, Dr. Sassetti, professor of microbiology & physiological systems, and colleagues will leverage a new experimental system they developed to model these variables so they can identify the underlying disease mechanisms and improve the effectiveness of current and future interventions.

Sassetti will oversee the multidisciplinary project and work with colleagues from the medical school and Harvard T.H. Chan School of Public Health, University of North Carolina, University of Washington, University of Cape Town and University of Melbourne. Together, they will look more deeply into the underlying human and pathogen genetics related to infectious disease, specifically TB.

“If we’re going to rationally develop interventions that are effective in diverse populations, we need to understand the biological differences between individuals in the group. The problem is it’s really hard to discover these underlying mechanisms by studying the human population,” Sassetti said.

A program project grant from the National Institutes of Health is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. The project is usually under the leadership of an established investigator and generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective.

Four years ago, Sassetti began working with colleagues at UNC and in Vietnam to develop an animal model that provides them with two groups of known diversity that can be mixed together in a controlled setting. This model will help researchers better understand the genetic diversity found in the human TB population.

“We know that both genetic variation and environmental factors can predispose an individual to disease. So far, we’ve discovered that host genetics does influence susceptibility, but it’s not the only factor. Outcome also depends on the genetic composition of the bacterium and interactions between genetic variants in host and pathogen. Also, genetic background influences the protection conferred by vaccination. Now that we have a model, we can start to understand the mechanisms that underlie vaccine efficacy,” Sassetti said.

Under the Systems Genetics of Tuberculosis project, the Sassetti lab will focus on foundational work by studying host determinants of TB susceptibility. The lab of UMMS colleague Samuel M. Behar, MD, PhD, professor of microbiology & physiological systems, will focus on the genetic determinants of vaccine efficacy. The Harvard lab will consider how the genetics of the host predisposes differentially to diverse strains of the pathogen.

The scientific projects will be supported by core facilities at UNC and University of Washington and will work closely with human clinical cohorts in Vietnam, South Africa and Australia.

The goal of the program is to use the controlled small animal model system of genetic diversity to find the mechanisms that control outcomes or the effectiveness of interventions in the human population.

“The biggest thing we could do is develop this concept into a system that will allow us to understand why interventions work in some people but not others, and use this system to develop interventions that work in better in a larger fraction of people. The variable effect of intervention is a really a huge limitation right now,” Sassetti said.

Although the project focuses on TB, Sassetti said he doesn’t think the research model and scientific process should be limited to the study of TB.

“Once you have an established small animal model that incorporates genetic diversity, you can start to understand how genetics and the environment interact. I think this concept is translatable to all sorts of systems and chronic infections and diseases,” he said.

Source: University of Massachusetts