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Early in vivo Expressed Antigens and their Role in Virulence, Immune Response, and Vaccines for Coccidioidomycosis

早期体内表达的抗原及其在球孢子菌病毒力、免疫反应和疫苗中的作用

基本信息

批准号：
10689662
负责人：
Paul Stephen Keim
金额：
$ 154.27万
依托单位：
NORTHERN ARIZONA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-24 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10689662
关键词：
Animal Model Animals Antibodies Antigens Basic Science CRISPR/Cas technology Clinical Clinical Trials Coccidioides Coccidioides immitis Coccidioides posadasii Coccidioidomycosis Communities Complex DNA DNA Vaccines DNA sequencing Data Development Diagnostic Diagnostic tests Disease Epitopes Gene Expression Gene Expression Profile Genes Goals Human Immune Immune response Immunization Infection Infrastructure Insecta Institution Knock-out Knowledge Link Lipids Location Macaca nemestrina Messenger RNA Modality Modeling Morbidity - disease rate Mus Nucleic Acid Amplification Tests Nucleic Acid Vaccines Nucleic Acids Pathogenesis Patients Pattern Peptides Population Prevention Process Protein Secretion Proteins RNA RNA replication RNA vaccination RNA vaccine Research Research Personnel Research Project Grants Role Serology test T cell response T-Cell Receptor T-Lymphocyte T-cell receptor repertoire Technology Testing Therapeutic Therapeutic Agents Time Translational Research United States Vaccination Vaccine Antigen Vaccine Design Vaccines Vertebrates Virulence Virulence Factors Waxes Work clinical research site companion diagnostics desert fever design diagnostic signature diagnostic strategy diagnostic tool disease diagnosis gene gun gene product human disease in vivo insight knockout gene longitudinal analysis mortality mouse model nano-string nanoGold nanoparticle nonhuman primate novel novel diagnostics novel vaccines pathogen prevent respiratory response screening serological marker therapeutic evaluation tool transcriptome sequencing vaccine candidate vaccine development vaccine evaluation virulence gene

项目摘要

OVERALL Section Title: Early in vivo expressed antigens and their role in virulence, immune response, and vaccines for coccidioidomycosis. SUMMARY Coccidioidomycosis, also known as Valley Fever (VF), is an important fungal disease caused by two different Coccidioides species that results in regionally important mortality and even greater morbidity. We have assembled a team to define the changes that occur in human and animal immune responses to VF, and to use this knowledge for designing new vaccines and diagnostic tests. This work will capitalize upon our detailed observations of Coccidioides gene expression patterns during the earliest stages of infections. We hypothesize that some Coccidioides early genes are virulence factors and critical for causing disease. Research Project 1 will test their role through gene knockouts using CRISPR-Cas9 technology and virulence testing in wax worm (Galleria) and mouse VF models. Critical virulence factors will become diagnostic and vaccine targets. In addition to the wax worm and mouse models, we develop a non-human primate (pig-tailed macaques) that will more closely resemble VF in humans. In humans and vertebrate animal models, the role of T cells cannot be overemphasized and Research Project 2 will use focused deep DNA sequencing to identify classes of T cell receptors (TCR) that develop in response to early expressed Coccidioides genes. We will generate TCR sequences from patients at three clinical locations that span the endemic zones for the pathogen. The TCR repertoire from patients will be used to identify novel diagnostic signatures (e.g., public TCRs) and, also, help identify immune responses to key antigens that can be targeted for vaccine development. Hence, both TCR and early virulence genes represent excellent candidates for vaccine design that will be explored in Research Project 3 using nucleic acid (NA) based vaccines (RNA and DNA) that can rapidly test a large panel of antigens through the immunization of mice against infection. The DNA vaccine will be based upon delivery on gold nanoparticles and Gene Gun, while the mRNA employs self-replicating RNA molecules (repRNA) and a Lipid InOrganic Nanoparticle (LION). Both are proven technologies that are moving forward into clinical trials for other diseases. Our goal in the NA vaccine mouse studies is to identify the best antigens and delivery modality for vaccine testing in the NHP model and to define their immune mechanisms of protection. This work is only possible through the integrated efforts of investigators at seven different institutions, including three clinical sites, as no single institution has the requisite breadth of expertise and infrastructure. While we will generate fundamental knowledge about Coccidioides and VF, we will also make translational advances towards preventing and diagnosing the disease.

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