Regulation of vaccine-induced anti-fungal T17 cells

Summary

Principal Investigator: MARCEL WUETHRICH
Abstract: DESCRIPTION (provided by applicant): Vaccines against infectious disease have been hailed as the greatest achievement in public health over the last century. Despite the growing prevalence of severe fungal infections, no vaccines against fungi are in clinical trials or commercially available. We have engineered a live attenuated vaccine that protects against infection with the primary fungal pathogen Blastomyces dermatitidis. We and others have shown that vaccine immunity to this and other fungal infections is mediated by a dominant T1-cell response. In preliminary data, we found that T17 cells also are induced by vaccination and confer resistance against B. dermatitidis as well as related dimorphic fungi Coccidioides posadasii and Histoplasma capsulatum. In contrast to the prevailing dogma, we observed that T1 cells, but not T17 cells, are dispensable in this vaccine resistance and that T17 cells are also sufficient for the resistance. Vaccine-induced T17 cells mediated protection by recruiting and activating neutrophils and alveolar macrophages to the alveolar space to augment fungal killing. In this application, we propose to decipher the cellular receptors and innate signaling pathways that induce naive antigen-specific T-cells to differentiate into protective anti-fungal T17 cells. We have created a novel Blastomyces TCR transgenic mouse, which represents a key innovation that will let us analyze the requirements for differentiation of naive anti-fungal T-cells. We hypothesize that receptor recognition of Blastomyces mannans by the FcR3-Syk-Card9 and the TLR-Myd88 signaling pathways are essential to induce T17 cells and vaccine immunity. We also posit that Myd88-induced T17 differentiation involves pathway crosstalk between TLRs and Card9, and that TLRs collaborate with the mannose receptor to induce T17 cell differentiation. We provide strong preliminary data to support our hypotheses. Using our new Blastomyces-specific TCR Tg mouse, we have established an in vitro screen with bone marrow derived dendritic cells from knockout mice and an in vivo adoptive transfer system to delineate the signaling adaptors, pathogen recognition receptors, and fungal ligands that induce differentiation of naive antigen-specific CD4+ T- cells into protective T17 cells. Our approach offers a powerful complimentary strategy that will investigate the host receptors and signaling pathways in Aims 1 and 2, and the fungal ligands in Aim 3. Our work will provide new insight into the fungal pathogen recognition receptors and downstream signaling pathways, as well as the pathogen-associated molecular patterns that induce T17 cell differentiation. This knowledge will provide the fundamental basis for developing and designing new vaccine strategies against fungi, and will catalyze the discovery of novel adjuvants useful in vaccines against fungi and microbes in general. PUBLIC HEALTH RELEVANCE: The number of fungal infections has risen dramatically in the United States over the last 10 years, and is now in the top 10 in causes of death, partly because we lack vaccines against fungi. To address that public health need, we have generated an attenuated fungal vaccine, and an experimental model to study mechanisms of vaccine immunity to fungi. In this proposal, we will identify the host-pathogen interactions that are the foundation of vaccine-induced resistance. The knowledge gained from this research will lead to the development of fungal vaccines and adjuvants.
Funding Period: 2011-05-03 - 2016-04-30
more information: NIH RePORT

Top Publications

  1. pmc Vaccine-induced protection against 3 systemic mycoses endemic to North America requires Th17 cells in mice
    Marcel Wuthrich
    Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706, USA
    J Clin Invest 121:554-68. 2011
  2. pmc C-type lectin receptors differentially induce th17 cells and vaccine immunity to the endemic mycosis of North America
    Huafeng Wang
    Department of Pediatrics, University of Wisconsin Medical School, University of Wisconsin Hospital and Clinics, Madison, WI 53792
    J Immunol 192:1107-19. 2014
  3. pmc Interleukin 1 enhances vaccine-induced antifungal T-helper 17 cells and resistance against Blastomyces dermatitidis infection
    Marcel Wuthrich
    Department of Pediatrics, University of Wisconsin Medical School, University of Wisconsin Hospital and Clinics, Madison, WI 53706, USA
    J Infect Dis 208:1175-82. 2013
  4. pmc Chitin elicits CCL2 from airway epithelial cells and induces CCR2-dependent innate allergic inflammation in the lung
    Rene M Roy
    Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA
    J Immunol 189:2545-52. 2012
  5. pmc Immunity to fungi
    Salome Leibundgut-Landmann
    Institute of Microbiology, Swiss Federal Institute of Technology, CH 8093 Zurich, Switzerland
    Curr Opin Immunol 24:449-58. 2012
  6. pmc Fungi subvert vaccine T cell priming at the respiratory mucosa by preventing chemokine-induced influx of inflammatory monocytes
    Marcel Wuthrich
    Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA
    Immunity 36:680-92. 2012
  7. pmc Protective antifungal memory CD8(+) T cells are maintained in the absence of CD4(+) T cell help and cognate antigen in mice
    Som G Nanjappa
    Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706, USA
    J Clin Invest 122:987-99. 2012
  8. pmc Adaptive immunity to fungi
    Marcel Wuthrich
    Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, USA
    Annu Rev Immunol 30:115-48. 2012
  9. pmc Limited model antigen expression by transgenic fungi induces disparate fates during differentiation of adoptively transferred T cell receptor transgenic CD4+ T cells: robust activation and proliferation with weak effector function during recall
    Marcel Wuthrich
    Department of Pediatrics, University of Wisconsin Medical School, University of Wisconsin Hospital and Clinics, Madison, Wisconsin, USA
    Infect Immun 80:787-97. 2012
  10. pmc Vaccine immunity to coccidioidomycosis occurs by early activation of three signal pathways of T helper cell response (Th1, Th2, and Th17)
    Chiung Yu Hung
    Department of Biology, University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249 0662, USA
    Infect Immun 79:4511-22. 2011

Detail Information

Publications13

  1. pmc Vaccine-induced protection against 3 systemic mycoses endemic to North America requires Th17 cells in mice
    Marcel Wuthrich
    Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706, USA
    J Clin Invest 121:554-68. 2011
    ..These data suggest that human vaccines against systemic fungal infections should be designed to induce Th17 cells if they are to be effective...
  2. pmc C-type lectin receptors differentially induce th17 cells and vaccine immunity to the endemic mycosis of North America
    Huafeng Wang
    Department of Pediatrics, University of Wisconsin Medical School, University of Wisconsin Hospital and Clinics, Madison, WI 53792
    J Immunol 192:1107-19. 2014
    ..Our work provides new insight into innate immune mechanisms that drive vaccine immunity and Th17 cells. ..
  3. pmc Interleukin 1 enhances vaccine-induced antifungal T-helper 17 cells and resistance against Blastomyces dermatitidis infection
    Marcel Wuthrich
    Department of Pediatrics, University of Wisconsin Medical School, University of Wisconsin Hospital and Clinics, Madison, WI 53706, USA
    J Infect Dis 208:1175-82. 2013
    ....
  4. pmc Chitin elicits CCL2 from airway epithelial cells and induces CCR2-dependent innate allergic inflammation in the lung
    Rene M Roy
    Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA
    J Immunol 189:2545-52. 2012
    ..Thus, airway epithelial cells secrete CCL2 in response to chitin and CCR2 signaling mediates chitin-induced alternative activation of macrophages and allergic inflammation in vivo...
  5. pmc Immunity to fungi
    Salome Leibundgut-Landmann
    Institute of Microbiology, Swiss Federal Institute of Technology, CH 8093 Zurich, Switzerland
    Curr Opin Immunol 24:449-58. 2012
    ..These advances form a basis for the development of fungal vaccines and immune-based therapeutic adjuncts...
  6. pmc Fungi subvert vaccine T cell priming at the respiratory mucosa by preventing chemokine-induced influx of inflammatory monocytes
    Marcel Wuthrich
    Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA
    Immunity 36:680-92. 2012
    ..Mucosal vaccination against fungi and perhaps other respiratory pathogens may require manipulation of host MMPs in order to alter chemokine signals needed to recruit Ly6C(hi) monocytes and prime T cells at the respiratory mucosa...
  7. pmc Protective antifungal memory CD8(+) T cells are maintained in the absence of CD4(+) T cell help and cognate antigen in mice
    Som G Nanjappa
    Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706, USA
    J Clin Invest 122:987-99. 2012
    ..This has implications for the development of novel antifungal vaccine strategies effective in immunocompromised patients...
  8. pmc Adaptive immunity to fungi
    Marcel Wuthrich
    Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, USA
    Annu Rev Immunol 30:115-48. 2012
    ..Also emphasized is how the latter deploy effector and regulatory mechanisms that eliminate these nasty invaders while also constraining collateral damage to vital tissue...
  9. pmc Limited model antigen expression by transgenic fungi induces disparate fates during differentiation of adoptively transferred T cell receptor transgenic CD4+ T cells: robust activation and proliferation with weak effector function during recall
    Marcel Wuthrich
    Department of Pediatrics, University of Wisconsin Medical School, University of Wisconsin Hospital and Clinics, Madison, Wisconsin, USA
    Infect Immun 80:787-97. 2012
    ..However, the limited availability of model Ag expressed by Tg fungi during T cell priming blunts the downstream generation of effector and memory T cells...
  10. pmc Vaccine immunity to coccidioidomycosis occurs by early activation of three signal pathways of T helper cell response (Th1, Th2, and Th17)
    Chiung Yu Hung
    Department of Biology, University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249 0662, USA
    Infect Immun 79:4511-22. 2011
    ....
  11. pmc A TCR transgenic mouse reactive with multiple systemic dimorphic fungi
    Marcel Wuthrich
    Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, University of Wisconsin Madison, Madison, WI 53792, USA
    J Immunol 187:1421-31. 2011
    ....
  12. pmc Safety, tolerability, and immunogenicity of a recombinant, genetically engineered, live-attenuated vaccine against canine blastomycosis
    Marcel Wuthrich
    Department of Pediatrics, University of Wisconsin Madison, Madison, WI 53706, USA
    Clin Vaccine Immunol 18:783-9. 2011
    ..Thus, the live-attenuated vaccine against blastomycosis studied here proved safe, well tolerated, and immunogenic in dogs and merits further studies of vaccine efficacy...
  13. pmc Interleukin-1 receptor but not Toll-like receptor 2 is essential for MyD88-dependent Th17 immunity to Coccidioides infection
    Chiung Yu Hung
    Department of Biology and South Texas Center for Emerging Infectious Diseases, University of Texas, San Antonio, Texas, USA
    Infect Immun 82:2106-14. 2014
    ..An antimicrobial action of Th17 cells is to promote early recruitment of neutrophils to infection sites. Our data revealed that neutrophils are required for vaccine immunity to this respiratory disease. ..

Research Grants30

  1. Pacific NorthWest Regional Center of Excellence (PNWRCE)
    Jay A Nelson; Fiscal Year: 2013
    ..pseudomallei host pathogen response during both the septicemic as well as the intracellular phases of the disease. ..
  2. Southeast Regional Centers of Excellence for Biodefense &Emerging Infectious Di
    Philip Frederick Sparling; Fiscal Year: 2013
    ..SERCEB brings new investigators to the biodefense effort through a combination of educational programs, support of innovative new projects, and the synergistic interactions among its world-class investigators. ..
  3. New England Regional Center of Excellence in Biodefense and Emerging Infectious D
    Dennis L Kasper; Fiscal Year: 2013
    ..NERCE will also continue its Developmental Projects program and Career Development in Biodefense program in an effort to initiate new research efforts and to attract new investigators to this field. ..
  4. Northeast Biodefense Center
    W Ian Lipkin; Fiscal Year: 2013
    ..As a Center based in a School of Public Health and a State Department of Health, the NBC has a firm commitment to and practical understanding of Emergency Preparedness. ..
  5. Molecular Analyses and Interventions for Biodefense and Emerging Pathogens
    Olaf Schneewind; Fiscal Year: 2013
    ..Research and training at the GLRCE is governed by a mechanism involving ongoing review of scientific excellence and translational goals, inter-institutional advisory boards and external scientific advisory bodies. ..