Blastomycosis, one of the principal systemic mycoses, often produces a progressive pulmonary disease, but the factors that account for immune failure and resistance during infection with Blastomyces dermatitidis infection are ill defined. We created a WI-1 knockout of B. dermatitidis that is attenuated and controlled in a murine model of primary pulmonary infection. Its administration to mice vaccinates them against re-infection and evokes sterilizing immunity. We propose here to use the isogenic attenuated and wild-type strains and mouse models developed in the last funding period to define the cellular and molecular bases of immune failure and resistance in experimental pulmonary blastomycosis. We hypothesize: that B. dermatitidis subverts generation of immune T-cells in a nonimmune host, leading to progressive infection. In a vaccinated host, T-cells mediate resistance, and show plasticity in the requirements of T-cell subsets for generation and maintenance of vaccine immunity and memory.
Our specific aims are to: (1) Decipher the role of the immunosuppressive cytokine transforming growth factor-beta (TGF- beta) in failure of T-cell immunity during progressive primary infection, and the participation of CTLA-4, a negative regulator of T-cell activation, during TGF-beta-induced cellular immune suppression. (2) Delineate differential mechanisms - cytokines (IFN-gamma, TNF-alpha), cytolysis, and direct antimicrobial activity - by which CD4+ and CD8+ T-cells mediate vaccine immunity to B. dermatitidis, and requirements for CD28 co- stimulation and IL-12 signaling in generating and maintaining these recall immune responses. (3) Identify and clone antigens that protective T-cells recognize in vitro from expressed products of a B. dermatitidis cDNA library, and in T-cell immunoblots of a crude, protective cell-wall membrane antigen, and demonstrate that the cloned recombinant antigens confer protective immunity in vivo to B. dermatitidis. Understanding mechanisms of immune failure and resistance to fungi will assist in planning vaccine and treatment strategies in healthy people, and in patients with impairments of host defense such as AIDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI040996-08
Application #
6746888
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Duncan, Rory A
Project Start
1997-05-01
Project End
2006-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
8
Fiscal Year
2004
Total Cost
$363,750
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
Sui, Pengfei; Wiesner, Darin L; Xu, Jinhao et al. (2018) Pulmonary neuroendocrine cells amplify allergic asthma responses. Science 360:
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
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

Showing the most recent 10 out of 71 publications