Serological Biomarkers for Coccidioidomycosis

球孢子菌病的血清学生物标志物

• 批准号: 10418810
• 负责人: DOUGLAS F. LAKE
• 金额: $ 38.03万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-07 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10418810
• 关键词: Activities of Daily Living; Acute; Acute Disease; Aerosols; American; Antibiotics; Antibodies; Antibody Response; Antibody titer measurement; Antigens; Area; Arizona; Bacterial Pneumonia; Biological Assay; Biological Markers; Blastomycosis; Blood Tests; Bronchoalveolar Lavage; California; Categories; Centers for Disease Control and Prevention (U.S.); Chronic; Cloning; Coccidioides; Coccidioidomycosis; Complement; Coughing; Data; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Elderly; Ensure; Enzyme Immunoassay; Enzyme-Linked Immunosorbent Assay; Evaluation; Fungal Spores; Gold; Growth; Health Personnel; Histoplasmosis; Illness Days; Immunoassay; Immunocompetent; Immunodiffusion; Immunoglobulin G; Immunoglobulin M; Incidence; Individual; Infection; Inhalation; Laboratories; Laboratory Diagnosis; Learning; Life; Lung; Measures; Medical; Meninges; Morbidity - disease rate; Nucleic Acids; Patient Monitoring; Patients; Performance; Phase; Plasmids; Pneumonia; Population; Precipitins; Preparation; Printing; Procedures; Production; Prognosis; Protein Array; Protein Microchips; Proteins; Proteome; Publishing; Recombinants; Reporting; Reproducibility; Reproduction spores; Resources; Sampling; Schools; Sensitivity and Specificity; Serodiagnoses; Serology; Serology test; Serum; Sick Leave; Site; Skin; Soil; Specificity; Sputum; Standardization; Surveys; Symptoms; System; Testing; Time; Translating; Tube; Tuberculosis; Validation; Viral; Viral Pneumonia; Work; accurate diagnosis; antibody detection; antigen detection; bone; clinical diagnosis; community acquired pneumonia; cross reactivity; desert fever; diagnosis standard; diagnostic strategy; economic impact; experience; follow-up; fungus; immunoreactivity; improved; mortality; performance tests; prevent; programs; response; retiree; sample fixation; screening; seropositive; success

PROJECT SUMMARY As of 2017, coccidioidomycosis (Cocci) also known as Valley Fever (VF) was designated a reportable disease in 22 states (1). The majority of the cases in the US occur in southern Arizona and California where the population is increasing with influx of naïve individuals, in particular, elderly retirees. Since Coccidioides sp, can cause significant morbidity and mortality in fully immunocompetent hosts, this represents an important threat to these regions where >10% percent of the US population resides, not including substantial tourist or part-time resident populations in Arizona and California. Importantly, the reporting criteria require a positive laboratory test for inclusion, yet ~50% of patients–who will eventually test positive–test negative while acutely ill (2). Testing has low sensitivity and specificity leaving sick patients and their health care providers without an accurate diagnosis. Thus, there is a profound need for better diagnostic approaches to properly identify Cocci patients to ensure appropriate follow-up and therapy ensues. Coccidioides spp. grow as mycelia in the desert soils and produce spores (arthroconidia) to survive during times of adverse growth conditions. When this soil is disturbed, arthroconidia aerosolize and are inhaled to initiate infection. Inside the host, the spores transform into spherules containing endospores which grow in the lung. When spherules burst, endospores, are released and can each disseminate to form a new spherule. Clinical diagnosis is difficult because patients’ symptoms resemble other bacterial and viral pneumonias. Laboratory diagnosis often relies solely on serology, but ~50% of patients do not test positive while they are acutely ill which results in inaccurate diagnosis an inappropriate treatment. We propose that it is time for a re- evaluation of seroreactive coccidioidal antigens. For the past six decades, serologic diagnosis of coccidioidomycosis has relied on IgM responses to tube precipitin (TP) and IgG responses to complement fixation (CF) antigens. Since these antigens are primarily expressed in mycelia, not in spherules which is the fungal form that grows in the host, it is not surprising that many patients are seronegative because they have not yet generated antibodies to spherule antigens during acute pulmonary illness. The GOAL of this proposal is to identify new coccidioidal antigens that react with acutely infected patient sera. The objectives are to utilize the recently published Coccidioides spp. proteome to create a nucleic acid programmable protein array (NAPPA) in which every coccidioidal protein is screened for reactivity with VF patient sera. Our hypothesis is that this survey of the Coccidioides proteome will reveal new spherule-phase antigens that are reactive with more patients, especially acutely ill patients who are seronegative for TP and/or CF antigens. Once we identify a small panel of seroreactive antigens, they can be incorporated into existing antigen preparations or a separate reliable, consistent, accurate test that will increase the number of positive diagnoses in acutely ill patients with early disease.

项目摘要 截至2017年，球孢子菌病（球菌）也称为山谷热（VF）被指定为可报告的 22个国家的疾病（1）。美国的大多数病例发生在亚利桑那州南部和加州， 随着天真的人，特别是老年退休人员的涌入，人口正在增加。由于球孢子菌可以 在完全免疫活性的宿主中引起显著的发病率和死亡率，这代表了对 这些地区有超过10%的美国人口居住，不包括大量的游客或兼职 亚利桑那州和加州的常住人口。重要的是，报告标准要求阳性实验室 尽管有一些患者进行了纳入试验，但约50%的患者最终将检测为阳性，而在急性病时检测为阴性（2）。测试 敏感性和特异性低，使患者及其医疗保健提供者无法准确评估 诊断.因此，迫切需要更好的诊断方法来正确识别球菌患者， 确保适当的随访和治疗。 球孢子菌属在沙漠土壤中以菌丝体形式生长，并产生孢子（节孢子）， 不利的生长条件。当这种土壤受到干扰时，节孢子会雾化并被吸入， 引发感染。在宿主体内，孢子转化为含有内生孢子的小球， 肺。当小球体破裂时，内生孢子被释放出来，并且每个内生孢子都可以传播形成新的小球体。 临床诊断是困难的，因为患者的症状类似于其他细菌和病毒性肺炎。 实验室诊断通常仅依赖于血清学，但约50%的患者在治疗期间检测结果不呈阳性。 急性病，导致诊断不准确和治疗不适当。我们建议是时候重新- 评价血清反应性球孢子虫抗原。在过去的六十年里， 球孢子菌病依赖于对管沉淀素（TP）的IgM反应和对补体的IgG反应， 固定（CF）抗原。由于这些抗原主要在菌丝体中表达，而不是在小球中表达，而小球是抗原的主要来源。 真菌的形式，生长在宿主，这并不奇怪，许多患者是血清阴性，因为他们没有 但在急性肺部疾病期间产生针对小球抗原的抗体。 该提案的目标是鉴定与急性感染患者反应的新的球孢子虫抗原 sera.目的是利用最近发表的球孢子菌属。蛋白质组产生核酸 可编程蛋白质阵列（NAPPA），其中筛选每种球孢子蛋白与VF患者的反应性 sera.我们的假设是，这种调查的球孢子菌蛋白质组将揭示新的球相抗原 与更多患者反应，尤其是TP和/或CF血清阴性的急性病患者 抗原一旦我们鉴定出一小组血清反应性抗原， 准备或单独的可靠，一致，准确的测试，将增加阳性诊断的数量 在急性病患者早期疾病。