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:
    10689682
  • 负责人:
  • 金额:
    $ 31.55万
  • 依托单位:
  • 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

项目摘要

PROJECT SUMMARY/ABSTRACT Coccidioidomycosis or Valley Fever (VF), is caused by the fungus Coccidioides immitis and C. posadasii with highest reported prevalence in Arizona and California. Due to similar clinical presentations, VF is frequently misdiagnosed and mistreated as bacterial or viral pneumonia, resulting in unnecessary antibiotics and longer times to resolve illness. Patients lose productivity and experience symptoms for many months. Severe CM manifests in <5% of symptomatic cases but can be life-threatening. T cell responses plays an important role in vaccine induced protection in animal models. In fact, this activity appears to be critical for defense against Coccidioides in humans, as evidenced by the fact that humans with low CD4+ T cell counts due to HIV infection are at increased risk of severe VF. The objective of this proposal is to identify T cell clones and their associated epitopes that are generated in human patients and animal models. For Coccidioides spp. epitopes, we will focus on previously confirmed and novel in vivo early expressed antigens and we will link these epitopes to their TCRs using a T cell peptide stimulation strategy. Our hypothesis is that epitopes from these Coccidioides antigens drive patient TCR profiles and, hence, will contain “public” TCR sequences that can be used for VF diagnosis and prioritize vaccine candidates. We predict that the TCR profiles are indicative of immune and disease states. We will address this hypothesis by deep TCR sequencing of activated T cells stimulated with Coccidioides peptide epitopes. We will identify TCRs specific to these and other Coccidioides proteins in patient samples from both Arizona (C. posadasii) and California (C. immitis). We will also confirm that mouse and macaque T cells detect epitopes from these antigens to aid in Coccidioides challenge model development. In addition, the immunogenic Coccidioides antigens will be evaluated for protection in these animal models after vaccination. Finally, we will generate a TCR sequencing diagnostic test to detect VF patients. Specifically, we aim to: 1) Characterize C. posadasii and C. immitis epitopes and associated T cell clones (TCR) in human specimens using T cell receptor sequencing and standard cell sorting techniques, 2) Determine TCRs and epitopes recognized during animal model (mouse and pig-tailed macaque) challenge, natural exposure, and RNA/DNA vaccinations, and 3) Compare the sensitivity between traditional serology and TCR sequencing using endemic and non-endemic populations. If successful, this project will make available to the community a novel set of T cell epitopes for VF in humans, mice, and macaques. The TCR sequences can be used to develop next generation diagnostics and aid in antigens identification for vaccination. Finally, T cell clonotypes specific to these epitopes will be correlated to protection through the models and disease outcomes in VF patients.
项目总结/文摘

项目成果

期刊论文数量(0)
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会议论文数量(0)
专利数量(0)

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Erik W Settles其他文献

Erik W Settles的其他文献

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{{ truncateString('Erik W Settles', 18)}}的其他基金

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
  • 批准号:
    10356629
  • 财政年份:
    2022
  • 资助金额:
    $ 31.55万
  • 项目类别:
Discovery of H. pylori T cell epitopes unique to minority populations that could contribute to increased gastric cancer rates.
发现少数群体特有的幽门螺杆菌 T 细胞表位,可能导致胃癌发病率增加。
  • 批准号:
    10198572
  • 财政年份:
    2021
  • 资助金额:
    $ 31.55万
  • 项目类别:

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