This application proposes the innovative approach of genetic immunization to the development of fungal vaccines. The research focuses on B. dermatitides, a principal endemic mycoses of both humans and mammals of veterinary importance. The focus of the work in a 120 Kd surface protein known as WI-1 which is an immunodominant antigen of B- and T-cell responses in humans and experimental animals and is a fungal adhesin that binds to host tissues. WI-1 has been cloned and sequenced and mice immunized with this protein produce humoral and cell-mediated immune responses that protect against lethal infection. The hypothesis to be tested is that WI-1 elicits specific antibodies and T cells that collaborate in mediating protection against B. dermatitides.
Five specific aims are proposed: 1) To extend previous findings that immunization of mice with native WI-1 confers protective immunity; 2) to define the roles of antibodies, T-cells and T-cell subsets in WI-1 mediated protection; 3) To map WI-1 epitopes recognized by protective antibodies and T-cells; 4) to create and test WI-1 DNA vaccines that encode protective B and T-cell epitopes alone and together; and 5) to modify the vaccine DNA to influence antigen targeting, cellular reconstitution, and tissue immflammation to augment protection. These studies are expected to yield new insight into how antibodies and T cells collaborate in defending against pathogenic fungi and provide a model for evoking these defenses with DNA to engender protective immunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI040996-04
Application #
6169977
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Dixon (Dmid), Dennis M
Project Start
1997-05-01
Project End
2001-06-30
Budget Start
2000-05-01
Budget End
2001-06-30
Support Year
4
Fiscal Year
2000
Total Cost
$319,307
Indirect Cost
Name
University of Wisconsin Madison
Department
Pediatrics
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Kujoth, Gregory C; Sullivan, Thomas D; Merkhofer, Richard et al. (2018) CRISPR/Cas9-Mediated Gene Disruption Reveals the Importance of Zinc Metabolism for Fitness of the Dimorphic Fungal Pathogen Blastomyces dermatitidis. MBio 9:
McDermott, Andrew J; Tumey, Tyler A; Huang, Mingwei et al. (2018) Inhaled Cryptococcus neoformans elicits allergic airway inflammation independent of Nuclear Factor Kappa B signalling in lung epithelial cells. Immunology 153:513-522
Kottom, Theodore J; Hebrink, Deanne M; Jenson, Paige E et al. (2018) Dectin-2 Is a C-Type Lectin Receptor that Recognizes Pneumocystis and Participates in Innate Immune Responses. Am J Respir Cell Mol Biol 58:232-240
Garfoot, Andrew L; Goughenour, Kristie D; W├╝thrich, Marcel et al. (2018) O-Mannosylation of Proteins Enables Histoplasma Yeast Survival at Mammalian Body Temperatures. MBio 9:
Hernández-Santos, Nydiaris; Wiesner, Darin L; Fites, J Scott et al. (2018) Lung Epithelial Cells Coordinate Innate Lymphocytes and Immunity against Pulmonary Fungal Infection. Cell Host Microbe 23:511-522.e5
McBride, Joseph A; Gauthier, Gregory M; Klein, Bruce S (2018) Turning on virulence: Mechanisms that underpin the morphologic transition and pathogenicity of Blastomyces. Virulence :1-9
Nanjappa, Som G; Mudalagiriyappa, Srinivasu; Fites, J Scott et al. (2018) CBLB Constrains Inactivated Vaccine-Induced CD8+ T Cell Responses and Immunity against Lethal Fungal Pneumonia. J Immunol 201:1717-1726
Sui, Pengfei; Wiesner, Darin L; Xu, Jinhao et al. (2018) Pulmonary neuroendocrine cells amplify allergic asthma responses. Science 360:
Wiemann, Philipp; Perevitsky, Adi; Lim, Fang Yun et al. (2017) Aspergillus fumigatus Copper Export Machinery and Reactive Oxygen Intermediate Defense Counter Host Copper-Mediated Oxidative Antimicrobial Offense. Cell Rep 19:1008-1021
Nanjappa, Som Gowda; McDermott, Andrew J; Fites, J Scott et al. (2017) Antifungal Tc17 cells are durable and stable, persisting as long-lasting vaccine memory without plasticity towards IFN? cells. PLoS Pathog 13:e1006356

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