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.

项目摘要截至2017年，Coccidioycomisois（COCCI）也被称为Valley Fever（VF） 22个州（1）的疾病。美国的大多数案件发生在亚利桑那州南部和加利福尼亚州人口随着个人的影响，特别是退休人员的影响而增加。由于球虫剂SP可以在完全免疫能力的宿主中引起明显的发病率和死亡率，这代表了对这些地区>美国人口的10％> 10％，不包括大量的游客或兼职亚利桑那州和加利福尼亚州的居民人口。重要的是，报告标准需要阳性实验室纳入的测试，但约有50％的患者（最终将在急性病时测试阳性 - 检验阴性）（2）。测试具有低灵敏度和特异性，使生病的患者及其医疗保健提供者无法准确诊断。这是非常需要更好地诊断方法才能正确识别球菌患者确保随后进行适当的随访和治疗。球虫剂属。在沙漠土壤中成长为菌丝体，并产生孢子（关节炎），以生存不良生长条件的时代。当这种土壤受到干扰时，Arthrconidia雾化并继承为引发感染。在宿主内部，孢子转变为含有内生孢子的球形，这些孢子生长在肺。当球形爆裂时，释放出内孢子，可以分发以形成一个新的球体。临床诊断很困难，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，但约有50％的患者在他们的同时未测试阳性急性病，导致诊断不当。我们建议现在是时候重新评估静脉反应性球粒抗原。在过去的六十年中，血清学诊断球虫菌病依赖于IgM对管质蛋白（TP）的反应和IgG对完成的反应固定（CF）抗原。由于这些抗原主要在菌丝体中表达，而不是在球形中在宿主中生长的真菌形式，许多患者具有血清质，因为他们没有然而，在急性肺部疾病期间产生了针对球形抗原的抗体。该提案的目的是鉴定与急性感染患者反应的新球菌抗原血清。这些目的是利用最近发表的球虫下菌SPP。蛋白质组产生核酸可编程蛋白阵列（NAPPA），其中筛选每个球粒蛋白的反应性与VF患者的反应性血清。我们的假设是，对球虫蛋白蛋白质组的调查将揭示新的球形相抗原与更多的患者，尤其是急性病患者的反应性，这些患者对TP和/或CF具有血清负责人抗原。一旦我们识别出一小部分静脉反应性抗原，它们就可以掺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在患有早期疾病的急性疾病患者中。