Coccidioides spp. are fungal pathogens that normally causes a pneumonia associated with considerable morbidity and attendant economic or medical care costs. Some infections produce respiratory failure, soft tissue abscesses, osteomyelitis or meningitis. Even in otherwise healthy persons, inhalation of a single spore is sufficient to result in death from one or more of these complications, and this degree of infectivity was responsible, in part, for past development programs by the U.S. and the Soviet Union to use Coccidioides spp. as biological weapons. Coccidioides spp., recently classified as Category C agents by NIAID, are also considered emerging public health pathogens. Because coccidioidal infection so often produces life-long protection against reinfection, it is likely that a preventative vaccine could be effective. A screening program of approximately two dozen coccidioidal proteins identified a recombinant vaccine that was recommended for clinical trials. However, manufacturing difficulties related to the antigen's specific sequence has impeded its further development. In this project, we shall use in vitro protein expression to permit antigen screening on a larger scale as a means of identifying equally protective antigens that are more amenable to formulation. A proteomic analysis of spherule cell walls has identified 650 proteins and of these we shall screen approximately 1,000 exons with the least similarity to mammalian proteins, using first seroreactivity and subsequently reactivity of lymphocytes from mice previously infected with Coccidioides or immunized with protective whole cell vaccines. Our goal is to identify a second-generation recombinant vaccine candidate that could be developed for clinical testing. This project will also use tandem mass spectrometry to develop antigen-detecting assays as a more sensitive diagnostic for early Valley Fever. We have recently detected in the lungs of infected mice dozens of coccidioidal proteins. Three of these have no similarity to mammalian proteins and <45% similarity to other fungal proteins. We shall express these biosignature targets by recombinant methods and use the purified proteins to raise high-affinity antibodies. Tandem mass spectrometry will also be used to characterize the strength and specificity of antigen-antibody interactions to serve as independent analyses for the rational and optimal design of direct fluorescent staining or ELISA methods to detect antigens in clinical specimens.

Public Health Relevance

A protective vaccine against coccidioidomycosis could be used to prevent this disease in the general public. A more sensitive diagnostic test would also be an advance in distinguishing Valley Fever pneumonia from pneumonia from other causes since current antibody tests are falsely negative in half of first blood tests.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI065359-08
Application #
8378814
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
Project End
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
8
Fiscal Year
2012
Total Cost
$266,734
Indirect Cost
$34,422
Name
University of California Irvine
Department
Type
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Waggoner, Jesse J; Gresh, Lionel; Mohamed-Hadley, Alisha et al. (2016) Single-Reaction Multiplex Reverse Transcription PCR for Detection of Zika, Chikungunya, and Dengue Viruses. Emerg Infect Dis 22:1295-7
Ziegler, Christopher M; Eisenhauer, Philip; Bruce, Emily A et al. (2016) The Lymphocytic Choriomeningitis Virus Matrix Protein PPXY Late Domain Drives the Production of Defective Interfering Particles. PLoS Pathog 12:e1005501
Barbour, Alan G (2016) Infection resistance and tolerance in Peromyscus spp., natural reservoirs of microbes that are virulent for humans. Semin Cell Dev Biol :
Park, Arnold; Yun, Tatyana; Hill, Terence E et al. (2016) Optimized P2A for reporter gene insertion into Nipah virus results in efficient ribosomal skipping and wild-type lethality. J Gen Virol 97:839-43
Levin, Mattias; King, Jasmine J; Glanville, Jacob et al. (2016) Persistence and evolution of allergen-specific IgE repertoires during subcutaneous specific immunotherapy. J Allergy Clin Immunol 137:1535-44
Chomel, Bruno B; Molia, Sophie; Kasten, Rickie W et al. (2016) Isolation of Bartonella henselae and Two New Bartonella Subspecies, Bartonellakoehlerae Subspecies boulouisii subsp. nov. and Bartonella koehlerae Subspecies bothieri subsp. nov. from Free-Ranging Californian Mountain Lions and Bobcats. PLoS One 11:e0148299
Kern, Aurelie; Zhou, Chensheng W; Jia, Feng et al. (2016) Live-vaccinia virus encapsulation in pH-sensitive polymer increases safety of a reservoir-targeted Lyme disease vaccine by targeting gastrointestinal release. Vaccine 34:4507-13
Zeltina, Antra; Bowden, Thomas A; Lee, Benhur (2016) Emerging Paramyxoviruses: Receptor Tropism and Zoonotic Potential. PLoS Pathog 12:e1005390
Waggoner, Jesse J; Ballesteros, Gabriela; Gresh, Lionel et al. (2016) Clinical evaluation of a single-reaction real-time RT-PCR for pan-dengue and chikungunya virus detection. J Clin Virol 78:57-61
Sanman, Laura E; Qian, Yu; Eisele, Nicholas A et al. (2016) Disruption of glycolytic flux is a signal for inflammasome signaling and pyroptotic cell death. Elife 5:e13663

Showing the most recent 10 out of 434 publications