Tuberculosis causes two million deaths annually world-wide, and mortality rates are increasing with the spread of HIV infection and multidrug-resistant and even 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)-γ. Studies from our laboratory and others showed that IFN-γ 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-γ 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-γ production. The findings from these studies will enhance our understanding of overall host immune responses against tuberculosis infection during host-pathogen interactions and development of tuberculosis infection. Understanding the mechanisms of reduced T cell production of IFN-γ will help us to understand why some people are more susceptible to tuberculosis and others are not, and also allow us to develop new effective tuberculosis vaccines and novel anti-tuberculosis strategies to reduce this susceptibility and provide protection against this devastating human disease.
Research in my lab is focused on understanding the immune responses against tuberculosis infection with a long term goal of developing effective vaccine and novel therapeutic agents against tuberculosis infection. Tuberculosis is primarily a lung infectious disease caused by infection of humans through air with pathogenic microorganism, Mycobacterium tuberculosis (M. tuberculosis). Infection of other organs (extra pulmonary tuberculosis) may also happen but at a lower incidence rate. Tuberculosis has become one of the deadliest infectious diseases of mankind along with infection of human immunodeficiency virus (HIV) and malaria. According to the “2014 Global Tuberculosis Report” by the World Health Organization, 1.5 million people developed tuberculosis and 950 thousand people died from this infection. It was estimated that one third of the world’s population is currently infected with M. tuberculosis. Most often these persons do not develop tuberculosis because of protective immunity provided by proper functioning of two major groups of immune cells in our body, namely innate immune cells and adaptive immune cells. Because of this protective immunity, M. tuberculosis cannot cause tuberculosis in immune competent persons but hides in the body in a “dormant” state, waiting for any opportunity of dysfunction of immune cells and to grow and cause tuberculosis. Therefore, this large pool of persons containing dormant M. tuberculosis may develop tuberculosis infection in their life time because of decline in their immune function due to HIV infection, application of immunosuppressive agents for other disease management, and aging, name a few. Since infection of HIV destroys human T cells and reduces immune responses against infections including tuberculosis, co-infection of M. tuberculosis and HIV has become the dominant life threatening infection in AIDS patients. The patients receiving immunosuppressive agents, such as for preventing transplanted organ from being rejected by recipient immune responses targeting the transplanted organs in patients suffering from organ failures, patients suffering from autoimmune diseases, such as arthritis, receiving immunosuppressive agents to correct over active immunity targeting its own host, and cancer patients receiving chemotherapy will also become susceptible to tuberculosis infection because of deleterious effects of immunosuppressive agents and anti-cancer chemotherapeutics on normal functioning of immune cells. This will prepare a pool of persons containing dormant M. tuberculosis susceptible to tuberculosis infection. Although there is effective anti-tuberculosis therapy available, M. tuberculosis has developed drug resistance against those available few effective antibiotics. The current vaccine against tuberculosis infection is not effective despite provide some level of protection in children. Therefore, it is imperative to study the development of tuberculosis to identify novel drug targets for new drug development and identify potential new vaccine candidates for effective vaccine design for better tuberculosis control. Therefore, the long term goal of my research is to understand the pathology of human tuberculosis by evaluating the T cell immune responses and the effect of M. tuberculosis secreted proteins on protective T cell immune responses. We use human peripheral blood lymphocytes isolated from both healthy donors and tuberculosis patients stimulated with antigens of M. tuberculosis as well as mouse aerosol infection of M. tuberculosis as our model systems. 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-γ 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 human 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 both the clinical studies of children with genetic defects and laboratory studies with gene knockout animals have confirmed that IFN-γ produced by T cells is pivotal in protection against tuberculosis infection. Children with defects in IFN-γ and related cytokines, such as IL-12 and its receptors are susceptible to M. tuberculosis infection, and gene knockout animals with defects in IFN-γ 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-γ 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-γ in response to T cell stimulation. Expression and IFN-γ promoter binding activities of these proteins are reduced in T cells from tuberculosis patients. These findings suggest that the reduced IFN-γ production 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-γ production. Our results demonstrated that ESAT-6 binds to human T cells and inhibits IFN-γ production possibly by reducing transcription factors CREB, ATF-2 and c-Jun possibly through activation of p38 mitogen activated protein kinase (MAPK). 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 protective immunity through antigen presenting cells. Currently, we are performing experiments to underst
Boggaram V, Gottipati KR, Wang X, Samten B. Early Secreted Antigenic Target of 6 kDa (ESAT-6) Protein of Mycobacterium tuberculosis Induces Interleukin-8 (IL-8) Expression in Lung Epithelial Cells via Protein Kinase Signaling and Reactive Oxygen Species. The Journal of Biological Chemistry, 288:25500-25511, 2013.
Wang X, Barnes PF, Huang F, Alvarez IA, Neuenschwander PF, Sherman DR and B Samten. Early Secreted Antigenic Target of 6-kD Protein of Mycobacterium tuberculosis Primes Dendritic Cells to Stimulate Th17 and Inhibits Th1 Immune Responses. Journal of Immunology, 189:3092-3103, 2013.
Samten B, Wang X, Barnes BF. Immune regulatory activities of early secreted antigenic target of 6-kD protein of Mycobacterium tuberculosis and implications for tuberculosis vaccine design. Tuberculosis (Edinb). 91:Suppl (1):S114-8, 2011.
Peng H, Wang X, Barnes PF, Tang H, Townsend JC, Samten B. The Mycobacterium tuberculosis Early Secreted Antigenic Target of 6 kDa Inhibits T Cell Interferon-gamma production through the p38 Mitogen-activated Protein Kinase Pathway. The Journal of Biological Chemistry. 286:24508-24518, 2011.
Feng Y, Kong Y, Barnes PF, Huang F, Klucar P, Wang X, Samten B, Sengupta M, Machona B, Donis R, Tvinnereim AR, Shams H. Exposure to Cigarette Smoke Inhibits the Pulmonary T cell Response to Influenza and Mycobacterium tuberculosis. Infection and Immunity. 79:229-37, 2011.
Samten B, Wang X, Barnes PF. Mycobacterium tuberculosis EXS-1 system-secreted protein ESAT-6 but not CFP10 inhibits human T-cell immune responses. Tuberculosis (Edinb). 89:Suppl (1):S74-76. 2009.
Pasquinelli V, Townsend JC, Jurado JO, Alvarez IB, Quiroga MF, Barnes PF, Samten B, Garcia VE. IFN-gamma production during active tuberculosis is regulated by mechanisms that involve IL-17, SLAM and CREB. Journal of Infectious Diseases. 199:661-665, 2009.
Wang X, Barnes PF, Dobod-Elder KM, Townsend JC, Chung Y, Shams H, Weis SE, Samten B. ESAT-6 inhibits production of interferon-gamma by M. tuberculosis-responsive human T cells. The Journal of Immunology. 182:3668-3677, 2009.
Samten B, Townsend JC, Weis SE, Bhoumick A, Klucar P, Shams H, Barnes PF. CREB, ATF and AP-1 transcription factors regulate IFN-gamma secretion by human T cells in response to microbial antigen. The Journal of Immunology. 181:2056-2064, 2008.
Samten B, Townsend JC, Sever-Chroneos Z, Pasquinelli V, Barnes PF, Chroneos ZC. An antibody against the surfactant protein A (SP-A)-binding domain of the SP-A receptor inhibits T cell mediated immune responses to Mycobacterium tuberculosis. Journal of Leukocyte Biology. 84:115-123, 2008.
Pang X, Vu P, Byrd TF, Ghanny S, Soteropoulos P, Mukamolova GV, Wu S, Samten B, Howard ST. Evidence for complex interactions of stress-associated regulons in an mprAB deletion mutant of Mycobacterium tuberculosis. Microbiology. 153:1229 – 1242, 2007.
Samten B, Howard ST, Weis SE, Wu S, Shams H, Townsend JC, Safi H, Barnes PF. Cyclic AMP response element-binding protein positively regulates production of interferon-gamma by T-cells in response to a microbial pathogen. The Journal of Immunology. 174:6357–6363, 2005.
Dr. Samten graduated from the Xinjiang Medical University (Urumqi, China), with Bachelor of Medicine (equals MD in US) in 1987. After graduation, he was appointed as Assistant Professor of Microbiology and Immunology at the Xinjiang Medical University and taught Microbiology and Immunology to the students from the schools of medicine, pharmacology, nursing and preventive medicine.
Dr. Samten also has a Master of Science degree in Immunology from the Peking University, Health Science Center (Beijing, China), in 1996. He was then appointed as Assistant Professor of Immunology in the Department of Immunology, Peking University Health Science Center. He taught immunology and experimental immunology to the students in medical school and graduate students. Besides teaching, he also involved in research projects, such as development of targeted therapies for bladder cancer and induction of immune tolerance for organ transplantation in mice.
Dr. Samten joined Professor Peter F. Barnes’ research group at the University of Texas Health Science Center at Tyler in 1998 as a Postdoctoral Research Associate focusing on T cell immune responses against tuberculosis infection.
In 2002, he was appointed as Instructor of Microbiology and Immunology at the Center for Pulmonary and Infectious Disease Control at the University of Texas Health Science Center at Tyler. Currently, he is a full time employed Associate Professor of Microbiology and Immunology.
Bockgie Jung, DVM, PhD, postdoctoral research fellow
Na Yi, MD, MS, visiting scientist
Justin Ma, graduate student
Our Research was supported by grants from the National Institutes of Health, and is supported by the funds from the Presidential Research Council of the University of Texas Health Science Center at Tyler and support from the institutional funds.