Research

Samten, Buka, M.D., M.S.

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Contact: buka.samten@uthct.edu

Education:

M.D., Xinjiang Medical University, 1987, Urumqi, P. R. China
M.S., Immunology, Peking University, Health Science Center, 1996, Beijing, P. R. China

Research Interest:

TUBERCULOSIS- The long term goal of my laboratory is to understand the mechanisms through which human tuberculosis develops, by evaluating the T cell immune response against tuberculosis infection and the effect of Mycobacterium tuberculosis secreted proteins on human T cell immune responses. We use human peripheral blood lymphocytes stimulated with antigens of M. tuberculosis as well as mouse aerosol infection of M. tuberculosis as our model systems. lymphocytes stimulated with antigens of M. tuberculosis as a model system.

Current Projects:

  • Evaluation of intracellular signaling molecules that control production of interferon-gamma in peripheral blood lymphocytes in response to M. tuberculosis infection.
  • Immune regulatory activities of M. tuberculosis secreted proteins.

Lay Summary:

Tuberculosis causes two million deaths annually world-wide, and mortality rates are increasing with the spread of HIV and multidrug-resistant and extensively drug resistant M. tuberculosis infection. Global control of tuberculosis hinges on development of an effective vaccine, which, in turn, depends on understanding the human immune response to M. tuberculosis infection. T-lymphocytes are the major cells that mediate protection against tuberculosis in part by secretion of a soluble factor called interferon (IFN)-gamma. Studies from our laboratory and others showed that IFN-gamma production by peripheral blood lymphocytes from most tuberculosis patients without known immune defects is reduced, compared to the findings in normal donors infected with M. tuberculosis but without clinical symptoms of overt tuberculosis. We are trying to understand this question through studying both the host and the pathogen. From the host perspective, we are evaluating the mechanisms that control transcriptional regulation of the IFN-gamma gene in T cells from tuberculosis patients. From the pathogen angle, we are studying the effect of secreted proteins of M. tuberculosis on human T cell IFN-gamma production. The findings from these studies will enhance our understanding of overall host immune responses against tuberculosis infection during host-pathogen interactions. Understanding the mechanisms of reduced production of IFN-gamma will help us to understand why some people are more susceptible to tuberculosis, and allow development of new strategies to reduce this susceptibility and provide protection against the disease.

Research Overview:

The research in my laboratory is aimed at deciphering the molecular mechanisms of interaction between host immunity and M. tuberculosis by studying the changes in cellular proteins of human T cells that regulate IFN-gamma production and the effect of bacterial secreted proteins on human T-cell mediated immunity against M. tuberculosis infection, as development of tuberculosis is ultimately decided by the consequences of interaction between M. tuberculosis and host immune cells. Bacterial products may play a role in manipulating host immunity to favor bacterial growth in the body, and development of tuberculosis.

Evidence accumulated from the clinical studies of children with genetic defects and laboratory studies from the gene knockout animals have confirmed that IFN-gamma produced by T cells is pivotal in protection against tuberculosis infection. Children with defects in IFN-gamma and related cytokines, such as IL-12 and its receptors are susceptible to M. tuberculosis infection, and gene knockout animals with defects in IFN-gamma and its receptor succumb to death after infection with M. tuberculosis. Patients with active tuberculosis demonstrated reduced IFN-gamma production by peripheral blood lymphocytes after in vitro restimulation with antigens from M. tuberculosis. To understand the underlying mechanisms of this reduced production of IFN-gamma in tuberculosis patients, we studied a group of transcription factors, namely, cyclic AMP response element binding protein (CREB), activating transcription factor (ATF)-2 and activating protein (AP)-1, c-Jun, which normally bind to the proximal promoter of IFN-gamma in response to T cell stimulation. Expression and IFN-gamma promoter binding activities of these proteins are reduced in T cells from tuberculosis patients. These findings suggest that the reduced expression of IFN-gamma by T cells from tuberculosis patients is in part due to reduced expression and function of these proteins in T cells. Currently, we are trying to understand the mechanisms for reduced expression of these transcription factors in T cells from tuberculosis patients.

We have also studied the effect of secreted protein, early secreted antigenic target of 6kDa (ESAT-6), from M. tuberculosis on human T cell IFN-gamma production. Our results demonstrated that ESAT-6 binds to human T cells and inhibits IFN-gamma production possibly by reducing transcription factors CREB, ATF-2 and c-Jun. We also studied the effect of ESAT-6 on antigen presenting cells, using human monocyte derived dendritic cells as model. The findings from this research demonstrated that ESAT-6 reprograms DC to produce reduced levels of IL-12 and enhanced IL-23 and IL-1beta, and thus support enhanced Th17 and reduced Th1 immune responses, suggesting that ESAST-6 also manipulates host adaptive immunity through antigen presenting cells. Currently, we are performing experiments to understand how ESAT-6 exerts all these effects on our immune system using both human and mouse models.

Selected Papers and Abstracts:

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