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Serological Biomarkers for Coccidioidomycosis

球孢子菌病的血清学生物标志物

基本信息

批准号：
10625357
负责人：
DOUGLAS F. LAKE
金额：
$ 37.93万
依托单位：
ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
依托单位国家：
美国
项目类别：
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/10625357
关键词：
Absenteeism at work Activities of Daily Living Acute Acute Disease American Antibiotics Antibodies Antibody Response Antibody titer measurement Antigens Area Arizona Bacterial Pneumonia Biological Assay Biological Markers Blastomycosis Blood Tests Bronchoalveolar Lavage California Categories Chronic Cloning Coccidioides Coccidioidomycosis Complement Coughing Development Diagnosis Diagnostic Diagnostic tests Disease Dryness Elderly Ensure Enzyme Immunoassay Enzyme-Linked Immunosorbent Assay Evaluation Fungal Spores 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 Micro Array Data 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 Reaction 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 accurate diagnosis aerosolized antibody detection antigen detection bone clinical diagnosis community acquired pneumonia cross reactivity desert fever detection assay diagnosis standard diagnostic strategy economic impact experience fabrication follow-up fungus immunoreactivity improved mortality prevent response retiree sample fixation screening seropositive success

项目摘要

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.

项目概要截至 2017 年，球孢子菌病 (Cocci) 也称为谷热 (VF) 被指定为需报告的疾病 22 个州患病 (1)。美国的大多数病例发生在亚利桑那州南部和加利福尼亚州，那里随着天真的人，特别是老年退休人员的涌入，人口正在增加。由于球孢子菌 sp，可以在完全免疫功能正常的宿主中引起显着的发病率和死亡率，这对这些地区居住着超过 10% 的美国人口，不包括大量游客或兼职人员亚利桑那州和加利福尼亚州的常住人口。重要的是，报告标准需要阳性实验室测试是否包含在内，但约 50% 的患者（最终测试呈阳性）在病情严重时测试呈阴性 (2)。测试敏感性和特异性较低，使患病患者及其医疗保健提供者无法获得准确的信息诊断。因此，迫切需要更好的诊断方法来正确识别球菌患者确保进行适当的随访和治疗。球孢子菌属在沙漠土壤中作为菌丝体生长并产生孢子（节孢子）以在不利生长条件的时期。当土壤受到干扰时，节孢子就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，内生孢子在宿主体内生长。肺。当小球破裂时，内生孢子被释放，并且可以各自散布形成新的小球。临床诊断很困难，因为患者的症状类似于其他细菌性和病毒性肺炎。实验室诊断通常仅依赖于血清学检测，但约 50% 的患者在检测时并未检测出阳性病情严重，导致诊断不准确、治疗不当。我们建议现在是重新考虑的时候了血清反应性球孢子抗原的评估。在过去的六十年里，血清学诊断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，这是由于真菌形式在宿主体内生长，因此许多患者呈血清阴性也就不足为奇了，因为他们没有然而在急性肺部疾病期间产生了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发生反应的新球孢子抗原血清。目标是利用最近发表的球孢子菌属。蛋白质组创建核酸可编程蛋白质阵列 (NAPPA)，其中筛选每种球孢子蛋白与 VF 患者的反应性血清。我们的假设是，对球孢子菌蛋白质组的调查将揭示新的小球相抗原对更多患者有反应，尤其是 TP 和/或 CF 血清阴性的急性患者抗原。一旦我们鉴定出一小部分血清反应性抗原，就可以将它们纳入现有抗原中准备工作或单独的可靠、一致、准确的测试将增加阳性诊断的数量患有早期疾病的急性患者。