Cell-mediated protection against pneumonic plague

Summary

Principal Investigator: Jr Shiuan Lin
Abstract: DESCRIPTION (provided by applicant): Yersinia pestis (Yp) - one of the world's most virulent human pathogens - is the gram-negative bacterium that causes pneumonic plague. Virulent, antibiotic-resistant, Yp strains exist and Cold War scientists devised means to effectively aerosolize Yp. Thus, there is grave concern that Yp will be exploited as a bioweapon. To thwart that possibility, it is essential that we develop effective countermeasures. Recent primate studies suggest that the leading vaccine candidate - a recombinant F1-V fusion protein (rF1V) - may not provide sufficient protection. Moreover, resourceful bioweapon engineers could circumvent this vaccine with an F1-negative V-variant strain. While the rF1V vaccine primarily stimulates antibody-mediated humoral immunity, T cell-dependent cellular immunity comprises a second means by which vaccines can prime long-lived protection. However, it is widely accepted that the extreme virulence of Yp results, in large part, from plasmid-encoded factors that dampen inflammation and debilitate phagocytes, thereby compromising cell-mediated defense. Thus, plague vaccine researchers have devoted little attention to cellular immunity. Nevertheless, the Progress Report demonstrates that T cells can protect against pulmonary Yp infection. As such, we propose that next-generation pneumonic plague vaccines should strive to prime both humoral and cellular immunity, as well as incorporate new antigens. In Aim 1 of this application for grant renewal, we will directly measure the extent to which pulmonary Yp infection suppresses na[unreadable]ve and effector/memory T cell responses in vivo and identify mechanisms underlying any suppression that exists. In Aim 2, we will generate T cell clones that confer protection in mice, identify their cognate protein antigens using a series of complementary genetic, molecular and biochemical approaches, and then quantify the utility of these antigens as vaccines. We will also determine which antigens confer synergistic protection when combined with V-specific antibodies. Our findings will allow next-generation F1/V-based vaccines to harness both the neutralizing capacities of antibodies and the antimicrobial capacities of cellular immunity, while simultaneously reducing opportunities for circumvention by bioweapon engineers. Moreover, our studies will also generate powerful new tools for deciphering the fascinating interplay between Yp virulence factors and host defense mechanisms, thereby advancing basic research aimed at exploiting cellular immunity for defense against virulent bacterial pathogens that infect the lung. PUBLIC HEALTH RELEVANCE: To counter the potential use of pneumonic plague as a bioweapon, it is essential that we develop an effective vaccine. Recent animal studies suggest that the current vaccine candidate, which primarily stimulates B cells to make plague-fighting antibodies, may not suffice. This proposal aims to fundamentally improve that vaccine by incorporating the protective capacities of both B and T cells.
Funding Period: 2004-09-30 - 2015-02-28
more information: NIH RePORT

Top Publications

  1. pmc Gamma interferon, tumor necrosis factor alpha, and nitric oxide synthase 2, key elements of cellular immunity, perform critical protective functions during humoral defense against lethal pulmonary Yersinia pestis infection
    Michelle A Parent
    Trudeau Institute, 154 Algonquin Avenue, Saranac Lake, NY 12983, USA
    Infect Immun 74:3381-6. 2006
  2. pmc Intranasal prophylaxis with CpG oligodeoxynucleotide can protect against Yersinia pestis infection
    Anthony J Hickey
    Trudeau Institute, Saranac Lake, New York, USA
    Infect Immun 81:2123-32. 2013
  3. pmc Fibrin facilitates both innate and T cell-mediated defense against Yersinia pestis
    Deyan Luo
    Trudeau Institute, Saranac Lake, NY 12983, USA
    J Immunol 190:4149-61. 2013
  4. pmc A protective epitope in type III effector YopE is a major CD8 T cell antigen during primary infection with Yersinia pseudotuberculosis
    Yue Zhang
    Center for Infectious Diseases and Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, USA
    Infect Immun 80:206-14. 2012
  5. pmc Protective roles for fibrin, tissue factor, plasminogen activator inhibitor-1, and thrombin activatable fibrinolysis inhibitor, but not factor XI, during defense against the gram-negative bacterium Yersinia enterocolitica
    Deyan Luo
    Trudeau Institute, Saranac Lake, NY 12983, USA
    J Immunol 187:1866-76. 2011
  6. pmc Yersinia pestis YopE contains a dominant CD8 T cell epitope that confers protection in a mouse model of pneumonic plague
    Jr Shiuan Lin
    Trudeau Institute, Saranac Lake, NY 12983, USA
    J Immunol 187:897-904. 2011
  7. pmc IL-17 contributes to cell-mediated defense against pulmonary Yersinia pestis infection
    Jr Shiuan Lin
    Trudeau Institute, Saranac Lake, NY 12983, USA
    J Immunol 186:1675-84. 2011
  8. pmc TNFα and IFNγ contribute to F1/LcrV-targeted immune defense in mouse models of fully virulent pneumonic plague
    Jr Shiuan Lin
    Trudeau Institute, 154 Algonquin Avenue, Saranac Lake, NY 12983, USA
    Vaccine 29:357-62. 2010
  9. pmc Mycobacterium tuberculosis infection induces il12rb1 splicing to generate a novel IL-12Rbeta1 isoform that enhances DC migration
    Richard T Robinson
    Trudeau Institute, Inc, Saranac Lake, NY 12983, USA
    J Exp Med 207:591-605. 2010
  10. pmc D27-pLpxL, an avirulent strain of Yersinia pestis, primes T cells that protect against pneumonic plague
    Frank M Szaba
    Trudeau Institute, Saranac Lake, New York 12983, USA
    Infect Immun 77:4295-304. 2009

Detail Information

Publications17

  1. pmc Gamma interferon, tumor necrosis factor alpha, and nitric oxide synthase 2, key elements of cellular immunity, perform critical protective functions during humoral defense against lethal pulmonary Yersinia pestis infection
    Michelle A Parent
    Trudeau Institute, 154 Algonquin Avenue, Saranac Lake, NY 12983, USA
    Infect Immun 74:3381-6. 2006
    ..pestis challenge. These observations strongly suggest that plague vaccines should strive to maximally prime both cellular and humoral immunity...
  2. pmc Intranasal prophylaxis with CpG oligodeoxynucleotide can protect against Yersinia pestis infection
    Anthony J Hickey
    Trudeau Institute, Saranac Lake, New York, USA
    Infect Immun 81:2123-32. 2013
    ..Indeed, intranasal prophylaxis with CpG ODN provides significant protection against subcutaneous challenge with Y. pestis strain CO92 even though it fails to protect mice from intranasal challenge with that fully virulent strain...
  3. pmc Fibrin facilitates both innate and T cell-mediated defense against Yersinia pestis
    Deyan Luo
    Trudeau Institute, Saranac Lake, NY 12983, USA
    J Immunol 190:4149-61. 2013
    ..The data suggest that T cells combat plague in conjunction with neutrophils, which require help from fibrin to withstand Y. pestis encounters and effectively clear bacteria...
  4. pmc A protective epitope in type III effector YopE is a major CD8 T cell antigen during primary infection with Yersinia pseudotuberculosis
    Yue Zhang
    Center for Infectious Diseases and Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, USA
    Infect Immun 80:206-14. 2012
    ..Determining the features of YopE that are important for this response will lead to a better understanding of how protective CD8 T cell immunity is generated against Yersinia and other pathogens with type III secretion systems...
  5. pmc Protective roles for fibrin, tissue factor, plasminogen activator inhibitor-1, and thrombin activatable fibrinolysis inhibitor, but not factor XI, during defense against the gram-negative bacterium Yersinia enterocolitica
    Deyan Luo
    Trudeau Institute, Saranac Lake, NY 12983, USA
    J Immunol 187:1866-76. 2011
    ....
  6. pmc Yersinia pestis YopE contains a dominant CD8 T cell epitope that confers protection in a mouse model of pneumonic plague
    Jr Shiuan Lin
    Trudeau Institute, Saranac Lake, NY 12983, USA
    J Immunol 187:897-904. 2011
    ....
  7. pmc IL-17 contributes to cell-mediated defense against pulmonary Yersinia pestis infection
    Jr Shiuan Lin
    Trudeau Institute, Saranac Lake, NY 12983, USA
    J Immunol 186:1675-84. 2011
    ..pestis challenge, and we suggest that pneumonic plague vaccines should aim to induce mixed type 1 and type 17 cellular responses...
  8. pmc TNFα and IFNγ contribute to F1/LcrV-targeted immune defense in mouse models of fully virulent pneumonic plague
    Jr Shiuan Lin
    Trudeau Institute, 154 Algonquin Avenue, Saranac Lake, NY 12983, USA
    Vaccine 29:357-62. 2010
    ..pestis challenge will be an important co-determinant of antibody-mediated defense against pneumonic plague...
  9. pmc Mycobacterium tuberculosis infection induces il12rb1 splicing to generate a novel IL-12Rbeta1 isoform that enhances DC migration
    Richard T Robinson
    Trudeau Institute, Inc, Saranac Lake, NY 12983, USA
    J Exp Med 207:591-605. 2010
    ..tuberculosis-specific T cell activation. IL-12Rbeta1DeltaTM thus represents a novel positive-regulator of IL12Rbeta1-dependent DC function and of the immune response to M. tuberculosis...
  10. pmc D27-pLpxL, an avirulent strain of Yersinia pestis, primes T cells that protect against pneumonic plague
    Frank M Szaba
    Trudeau Institute, Saranac Lake, New York 12983, USA
    Infect Immun 77:4295-304. 2009
    ..This study describes a new model for studying T-cell-mediated protection against pneumonic plague and demonstrates the capacity for live, highly attenuated, Y. pestis vaccine strains to prime protective memory T-cell responses safely...
  11. pmc Antibodies and cytokines independently protect against pneumonic plague
    Lawrence W Kummer
    Trudeau Institute, Saranac Lake, NY 12983, USA
    Vaccine 26:6901-7. 2008
    ..pestis...
  12. pmc Immune defense against pneumonic plague
    Stephen T Smiley
    Trudeau Institute, Saranac Lake, NY 12983, USA
    Immunol Rev 225:256-71. 2008
    ..Here, I review the immunology of pneumonic plague, focusing on evidence that humoral and cellular defense mechanisms collaborate to defend against pulmonary Y. pestis infection...
  13. pmc Yersinia pestis evades TLR4-dependent induction of IL-12(p40)2 by dendritic cells and subsequent cell migration
    Richard T Robinson
    Trudeau Institute, Saranac Lake, NY 12983, USA
    J Immunol 181:5560-7. 2008
    ..pestis-26 degrees. The data demonstrate the molecular pathway by which Y. pestis evades induction of early DC activation as measured by migration and IL-12(p40)(2) production...
  14. pmc Current challenges in the development of vaccines for pneumonic plague
    Stephen T Smiley
    Trudeau Institute, 154 Algonquin Avenue, Saranac Lake, NY 12983, USA
    Expert Rev Vaccines 7:209-21. 2008
    ..pestis may be exploited as a bioweapon. Here, I review the history and status of plague vaccine research and advocate that pneumonic plague vaccines should strive to prime both humoral and cellular immunity...
  15. ncbi Cell-mediated defense against Yersinia pestis infection
    Stephen T Smiley
    Trudeau Institute, Saranac Lake, NY, USA
    Adv Exp Med Biol 603:376-86. 2007
    ..We conclude that next-generation plague vaccines should strive to prime both cellular and humoral immunity...
  16. pmc Vaccination with live Yersinia pestis primes CD4 and CD8 T cells that synergistically protect against lethal pulmonary Y. pestis infection
    Alexander V Philipovskiy
    Trudeau Institute, 154 Algonquin Avenue, Saranac Lake, NY 12983, USA
    Infect Immun 75:878-85. 2007
    ..pestis strains lacking the capacity to express F1, LcrV, and all pCD1/pPCP-encoded proteins, suggesting that protective T cells likely recognize antigens distinct from those previously defined as targets for humoral immunity...
  17. pmc TNFα and IFNγ but not perforin are critical for CD8 T cell-mediated protection against pulmonary Yersinia pestis infection
    Frank M Szaba
    Trudeau Institute, Saranac Lake, New York, United States of America
    PLoS Pathog 10:e1004142. 2014
    ..pestis infection and we suggest that assays detecting Ag-specific TNFα production in addition to antibody titers may be useful correlates of vaccine efficacy against plague and other acutely lethal septic bacterial pneumonias. ..