immunology seminar series

"The immunological challenges and opportunities of tuberculosis"

Mycobacterium tuberculosis (the bacteria that cause TB) induces apparently robust innate and adaptive immune responses, yet those responses rarely if ever eliminate the bacteria.  Since T cells (especially CD4 T cells) are essential for immune control of M. tuberculosis, and since the bacteria reside in professional antigen presenting cells, we have focused on identifying and characterizing mechanisms used by the bacteria to manipulate antigen presenting cells and avoid elimination by T cell responses.  Some of the mechanisms that will be discussed include: 1) delayed onset of T cell responses that allow 10,000-fold expansion of the bacterial population; 2) bacterial regulation of antigen gene expression; 3) bacterial interference with MHC class II antigen presentation by perturbing the ESCRT pathway and phagosome maturation; 4) export of bacterial antigens from infected cells, to evade T cell recognition of infected cells by antigen-specific CD4 T cells.  The evolutionary and vaccine implications of these mechanisms will also be discussed.

Joel Ernst trained in clinical medicine and cell biology at the University of California, San Francisco and served on its faculty until 2003.  From 2003-2018, he was Director of Infectious Diseases and Immunology at New York University. He returned to UCSF in 2018 as Chief of the Division of Experimental Medicine.  His awards include an honorary doctorate from the University of Linköping, Sweden.  His former trainees include an HHMI Investigator and recipient of a Lasker Award, as well as faculty at institutions in the U.S., England, Switzerland, Canada, Sweden, and China.

Dr. Ernst's research focuses on immunity to tuberculosis, to inform development of TB vaccines, and includes studies of mechanisms of immune evasion in TB, using mice. The Ernst Laboratory also studies human immunity to TB, and discovered that in contrast to pathogens that employ antigenic variation to evade immunity, the human T cell antigens and epitopes of M. tuberculosis are highly conserved.  Recently they identified rare antigens of M. tuberculosis that show evidence of diversifying selection, and are testing the hypothesis that T cell responses to those antigens are associated with superior protective immunity compared with responses to conserved antigens.

Selected original articles:

• Wolf AJ, Desvignes L, Linas B, Banaiee N, Tamura T, Takatsu K, and Ernst JD: Initiation of the adaptive immune response to M. tuberculosis depends on antigen production in the local lymph node, not the lungs. J Exp Med 205: 105, 2008.
• Desvignes L, and Ernst JD: Interferon gamma-responsive nonhematopoietic cells regulate the immune response to Mycobacterium tuberculosis.  Immunity 31:974, 2009
• Comas I, Chakravartti J, Small PM, Galagan J, Niemann S, Kremer K, Ernst JD*, and Gagneux S*: Human T cell epitopes of M. tuberculosis are evolutionarily hyperconserved.  Nature Genetics 42: 498, 2010.
• Bold TD, Banaei N, Wolf AJ, and Ernst JD: Suboptimal activation of antigen-specific CD4⁺ effector cells enables persistence of M. tuberculosis in vivo.  PLoS Pathogens 7(5):e1002063, 2011.
• Srivastava S, Ernst JD:  Cutting Edge: Direct Recognition of Infected Cells by  CD4 T Cells Is Required for Control of Intracellular Mycobacterium tuberculosis In Vivo. J Immunol 191:1016, 2013
• Srivastava S, Ernst JD.  Cell-to-cell transfer of M. tuberculosis antigens optimizes CD4 T cell priming.  Cell Host & Microbe 15: 741, 2014
• Coscolla M*, Copin R*, Sutherland J, Gehre F, de Jong B, Owolabi O, Mbayo G, Giardina F, Ernst JD†, Gagneux S†: M. tuberculosis T Cell Epitope Analysis Reveals Paucity of Antigenic Variation and Identifies Rare Variable TB Antigens.  Cell Host Microbe 18: 538, 2015
• Grace PS and Ernst JD: Suboptimal antigen presentation contributes to virulence of M. tuberculosis in vivo.  J Immunol 196:357, 2016
• Srivastava S, Grace PS, and Ernst JD: Antigen export reduces antigen presentation and limits T cell control of M. tuberculosis.  Cell Host Microbe 19: 44, 2016
• Copin R, Wang X, Louie E, Escuyer V, Coscolla M, Gagneux S, Palmer  GH, Ernst JD:  Within host evolution selects for a dominant genotype of Mycobacterium tuberculosis while T cells increase pathogen genetic diversity.  PLoS Pathogens, 12(12):e1006111, 2016

Hosted by Antje Blumenthal - [email protected]