Barnes, Peter, M.D.
B.S. (Biology) with Distinction, 1977, Stanford University
M.D., 1981, University of Southern California
- Evaluation of the contribution of natural killer cells to the innate and adaptive immune response to Mycobacterium tuberculosis.
- Understanding the effects of a candidate M. tuberculosis vaccine antigen on the human immune response.
- Developing immune-based therapy for influenza.
Tuberculosis causes 1.7 million deaths annually world-wide, and mortality rates are increasing with the spread of HIV and multidrug-resistant tuberculosis. Most tuberculosis patients live in developing nations where effective medications are not available. Global control of tuberculosis hinges on development of an effective vaccine, which, in turn, depends on understanding the human immune response to tuberculosis. Our immunologic research focuses on identifying the cells and the cellular secreted factors that mediate protective immunity against tuberculosis, so that these can be harnessed to develop better vaccines. This is done by immunologic studies of blood and tissue of tuberculosis patients, evaluation of human cells cultured in the laboratory, and studies of animals infected with Mycobacterium tuberculosis.
Influenza is the most common cause of vaccine-preventable disease in the U. S., causing 36,000 deaths and 200,000 hospitalizations annually. Influenza pandemics have killed up to 50 million people, and the recent swine influenza pandemic highlights this threat. Influenza vaccines are variably effective and require periodic reformulation. In addition, many influenza strains are drug-resistant. We are developing methods to treat and prevent influenza by stimulating the immune system.
Most persons who are infected with M. tuberculosis develop protective immunity and remain well. We are working to understand the underlying mechanisms of protection so that they can be harnessed in improved antituberculosis vaccines.
In work led by Dr. Vankayalapati, we are working to understand the role of natural killer (NK) cells in both innate and adaptive immunity. We have found that NK cells lyse M. tuberculosis-infected cells and produce IL-22, which inhibits mycobacterial growth in macrophages. NK cells also contribute to adaptive immunity by enhancing CD8+ T-cell function and by destroying activated T regulatory cells that suppress immune responses.
In studies directed by Dr. Samten, we are delineating the intracellular signaling pathways that T-cells utilize to produce interferon-γ, as this cytokine is central to protection against tuberculosis. We have also found that a M. tuberculosis protein, ESAT-6, directly inhibits T-cell responses and are working to define the underlying molecular mechanisms. Because ESAT-6 is a vaccine candidate, it is important to be able to negate any immunosuppressive effects of this protein.
In work led by Dr. Shams, we have found that intranasal administration of granulocyte-macrophage colony-stimulating hormone (GM-CSF) to mice prior to influenza infection completely abrogates an otherwise fatal disease, and that this is mediated through alveolar macrophages. We are working to delineate the mechanisms underlying this remarkable protection and to translate this finding into therapy that can be used in patients with influenza. Because GM-CSF acts by stimulating immunity, it should act against multiple influenza strains for many years, including drug-resistant strains.
Selected Papers and Abstracts:
- Huang F-F, Barnes PF, Feng Y, Donis R, Chroneos ZC, Idell S, Allen T, Perez DR, Whisett JA, Dunussi-Joannopoulos K, Shams H. GM-CSF in the lung protects against lethal influenza infection. Am J Respir Crit Care Med 2011 Epub April 7 (in press).
- 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-γ production through the p38 mitogen-activated protein kinase pathway. J Biol Chem 2011;286:24508-18.
- Dhiman R, Bandaru A, Barnes PF, Saha S, Tvinnereim A, Nayak RC, Paidipally P, Valluri V, Rao VM, Vankayalapati R. c-Maf-dependent growth of Mycobacterium tuberculosis in a CD14hi subpopulation of monocyte-derived macrophages. J Immunol 2011;186:1638-45.
- Wang X, Barnes PF, Dobos K, Townsend JC, Chong YT, Shams H, Weis SE, Samten B. ESAT-6 inhibits production of interferon-γ production by Mycobacterium tuberculosis-responsive human T-cells. J Immunol 2009;182:3668-77.
- Klucar P, Barnes PF, Kong Y, Howard ST, Pang X, Huang F-F, Tvinnereim AR, Samten B, Shams H. Vaccination strategies to enhance local immunity and protection against Mycobacterium tuberculosis. Vaccine 2009;27:1816-24.
- Paidipally P, Periasamy S, Barnes PF, Dhiman R, Griffith DE, Cosman D, Vankayalapati R. NKG2D-dependent-IL-17 production by human T-cells in response to an intracellular pathogen. J Immunol 2009;183:1940-5.
- Dhiman R, Indramohan M, Barnes PF, Nayak R, Paidipally P, Rao LVM, Vankayalapati R. IL-22 produced by human natural killer cells inhibits growth of Mycobacterium tuberculosis by enhancing phagolysosomal fusion. J Immunol 2009;183:6639-6645.
- Roy S, Barnes PF, Garg A, Wu S, Cosman D, Vankayalapati R. NK cells lyse T regulatory cells in human infection with an intracellular pathogen. J Immunol 2008;180:1729-36.
- Samten B, Townsend JC, Weis SE, Bhoumik A, Klucar P, Shams H, Barnes PF. CREB, ATF and AP-1 transcription factors regulate IFN-γ secretion by human T-cells in response to mycobacterial antigen. J Immunol 2008;181:2056-64.