Pushpa Jayaraman, PhD

Learning How the Immune System Defends Itself Against TB Bacteria

Mycobacterium tuberculosis, which causes pulmonary tuberculosis, is able to establish chronic infection in humans and evade the body’s immune system defenses. Pushpa Jayaraman, PhD, used an American Lung Association Senior Research Training Fellowship to study a novel mechanism to kill M. tuberculosis. Dr. Jayaraman, who is from India, is particularly interested in TB, because she has seen the high toll the disease has taken in her country.

Jayaraman, P, Sada-Ovalle, I, Beladi, S., Anderson AC, Dardalhon V, Hotta C, Kuchroo VK, Behar SM. Tim3 binding to galectin-9 stimulates antimicrobial immunity. J Exp Med 2010. 207 (11) 2343-2354.

Sakuishi K, Jayaraman P, Behar SM, Anderson AC, Kuchroo VK. Emerging Tim-3 functions in antimicrobial and tumor immunity. Trends Immunol. 2001. 32(8): 345-9.
Her research is centered on immune system cells called macrophages that are the first line of defense against airborne pathogens. They engulf M. tuberculosis, bringing it to white blood cells called T cells, which should kill the TB germ. However, M. tuberculosis is able to take refuge in macrophages by diverting some host defense mechanisms. This hijacking of the macrophage defense system interferes with the ability of the immune system to protect people from disease.

She focused on recently discovered molecules called Tim3 on the surface of T cells, and how they regulate the macrophage response to M. tuberculosis. Tim3 expression levels on T cells increase following M. tuberculosis infection. She found that mice infected with TB who were treated with the Tim3 protein experienced a dramatic reduction in the TB bacteria in their lungs. Dr. Jayaraman’s American Lung Association grant allowed her to discover the signaling pathways activated by Tim3 in M. tuberculosis-infected macrophages. She studied a novel way in which Tim3 on T cells can activate M. tuberculosis-infected macrophages by binding to its receptor, Galectin-9 (Gal9) on M. tuberculosis-infected macrophages. Gal9 sends a signal into the macrophage and activates it through the secretion of antimicrobial immune system cells called cytokines, such as IL-1b and TNF, arming the macrophages to efficiently kill M. tuberculosis.

Her research demonstrated a new biological function of Tim3, discovering how it stimulates immunity against microbes. Based on her findings, she concludes that Tim3 and Gal9 represent novel cell targets that could be used to develop new medications to activate macrophages to fight TB.

Dr. Jayaraman’s American Lung Association grant led to further grants to study Tim3 and tuberculosis, from the National Institutes of Health and the Harvard University Center for AIDS Research.