Tuberculosis is the leading causes of death from infectious disease in the world, and the global situation has considerably worsened because of the emergence of multidrug-resistant strains of Mycobacterium tuberculosis (Mtb) This R01 grant application proposes to develop the immunomodulatory glycolipid alpha-galactosylceramide (alphaGalCer) as a treatment for tuberculosis. Our experiments have shown that mice treated with alphaGalCer following inoculation with Mtb survive longer compared to vehicle treated mice. The main action of alphaGalCer is the activation of immunoregulatory CD1d-restricted iNKT cells, which can in turn stimulate both innate and adaptive immunity. This grant proposal will address fundamental questions about the biology of iNKT cells and investigate ways to take advantage of their immunomodulatory effects following activation by alphaGalCer. By defining the pathways that are activated downstream of iNKT cells, we hope to develop a more rational strategy to exploit the immunomodulatory properties of alphaGalCer. It has potential use in three therapeutic arenas. First, its relatively non-selective immunomodulatory properties and potential to provide protection against a variety of pathogens make it a candidate as a biodefense drug for post-exposure prophylaxis. Second, it could be used in combination with traditional antibiotics in the treatment of infectious disease including multidrug resistant Mtb. Third, it could be used as an adjuvant for vaccines. The murine model is an excellent system to investigate the effect of alphaGalCer on Mtb infection since both CD1d and NKT cells are conserved structurally and functionally between mice and humans.
Aim 1 will determine the cellular and molecular pathways activated by alphaGalCer that protect mice from tuberculosis after inoculation with Mtb. Since alphaGalCer has been reported to have adjuvant-like properties, in Aim 2, we will administer alphaGalCer concurrently with anti-mycobacterial subunit or DNA vaccines to determine whether such a combination is synergistic in its ability to induce protective immunity following aerosol challenge with Mtb.
Aim 3 will determine whether alphaGalCer can protect mice from an aerosol challenge of Mtb using a post-exposure or treatment model. Finally, in Aim 4 we will derive Mtb-specific CD 1d-restricted T cells from infected mice. This comprehensive program on the study of the role of CD1d and NKT cells in response to tuberculosis includes innovative directions that may have applications for the treatment or prevention of tuberculosis, increase the understanding of NKT cells, pulmonary immunity and have implications for the immunomodulation of other infectious diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL080312-05
Application #
7459599
Study Section
Special Emphasis Panel (ZRG1-BM-1 (04))
Program Officer
Peavy, Hannah H
Project Start
2004-08-16
Project End
2010-05-21
Budget Start
2008-08-01
Budget End
2010-05-21
Support Year
5
Fiscal Year
2008
Total Cost
$370,635
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Behar, Samuel M; Carpenter, Stephen M; Booty, Matthew G et al. (2014) Orchestration of pulmonary T cell immunity during Mycobacterium tuberculosis infection: immunity interruptus. Semin Immunol 26:559-77
Sille, Fenna C M; Martin, Constance; Jayaraman, Pushpa et al. (2011) Requirement for invariant chain in macrophages for Mycobacterium tuberculosis replication and CD1d antigen presentation. Infect Immun 79:3053-63
Sille, Fenna C M; Martin, Constance; Jayaraman, Pushpa et al. (2011) Critical role for invariant chain in CD1d-mediated selection and maturation of V*14-invariant NKT cells. Immunol Lett 139:33-41
Sada-Ovalle, Isabel; Sköld, Markus; Tian, Tian et al. (2010) Alpha-galactosylceramide as a therapeutic agent for pulmonary Mycobacterium tuberculosis infection. Am J Respir Crit Care Med 182:841-7
Sada-Ovalle, Isabel; Chiba, Asako; Gonzales, Adaena et al. (2008) Innate invariant NKT cells recognize Mycobacterium tuberculosis-infected macrophages, produce interferon-gamma, and kill intracellular bacteria. PLoS Pathog 4:e1000239
Skold, Markus; Behar, Samuel M (2008) Tuberculosis triggers a tissue-dependent program of differentiation and acquisition of effector functions by circulating monocytes. J Immunol 181:6349-60
Skold, Markus; Xiong, Xiaowei; Illarionov, Petr A et al. (2005) Interplay of cytokines and microbial signals in regulation of CD1d expression and NKT cell activation. J Immunol 175:3584-93