Evaluating Trichophyton tonsurans Carriage and Infection

描述(由申请人提供)：头癣是一种在儿科人群中占压倒性多数的流行疾病，估计大约每20名儿童中就有1人发生。此外，同样数量且往往更多的儿童是病原体的无症状携带者。特别令人感兴趣的是，一种单一的真菌，即托氏毛霉菌，负责这两种临床表现。对于其他感染性病原体，独特的血清型显然与致病性和毒力有关(例如，大肠杆菌。脑膜炎分枝杆菌、流感嗜血杆菌)；然而，还没有尝试识别和联系托氏锥虫的基因变异体与临床疾病状态。认识到变异的存在，并将特定的亚型与疾病的表现联系起来，是确定不同的分子靶点的第一步，这些靶点可能指导旨在减缓或阻止疾病传播和进展的治疗干预措施的发展。这项拟议的调查将采用有针对性的分子分析，同时对正常健康儿童群体进行横断面抽样和纵向监测，以探索托氏毛滴虫的携带者和感染状态。这项调查将由一般假设驱动：儿童接触的基因变种类型解释了观察到的托氏毛霉菌感染的表现状态。这一假说将通过一系列旨在解决以下具体目标的研究来检验：(1)确定从固定的“高危”儿童群体获得的扁桃体螺旋体分离株的基因分布，并评估基因变异是否可导致个体之间疾病表现的差异，特别是感染与携带的差异；(2)表征个体内连续分离株的关联程度，并确定疾病表现之间的变化是由相同的基因变异发生的，还是由于获得不同的真菌变异而发生的。

DESCRIPTION (provided by the applicant): Tinea capitis is an overwhelmingly prevalent disease in the pediatric population being estimated to occur in approximately 1 in 20 children. Moreover, an equal and often larger number of children serve as asymptomatic carriers of the pathogen. Of particular interest is that a single species of fungus, namely Trichophyton tonsurans, is responsible for both clinical presentations. With other infectious agents, unique serotypes have been clearly associated with pathogenicity and virulence (e.g., E. coli. M. meningitides, H. influenzae); however, there has been no attempt to identify and link genotypic variants of T. tonsurans with clinical disease status. Recognizing that variants exist and linking specific subtypes to disease presentation is the first step toward identifying distinct molecular targets that may guide the development of therapeutic interventions designed to slow or halt disease transmission and progression. The proposed investigation will employ a targeted molecular analysis in tandem with cross sectional sampling and longitudinal surveillance in a population of normal healthy children to explore the carrier and infection states of T. tonsurans. The investigation will be driven by the general hypotheses: the type of genotypic variant to which a child is exposed accounts for the presentation status observed in Trichophyton tonsurans infection. The hypothesis will be tested by a series of studies designed to address the following specific aims: (1) determine the genotype distribution of T. tonsurans isolates acquired from a fixed population of "high-risk" children and evaluate whether variations in genotype are responsible for differences in disease presentation, specifically infection vs. carriage, between individuals and (2) characterize the degree of relatedness for sequential isolates within an individual and identify whether transformation between disease presentations occurs with the same genetic variant or as a result of acquiring a genetically distinct fungal variant.