Environmental determinants of KSHV transmission in rural Uganda

乌干达农村 KSHV 传播的环境决定因素

• 批准号: 9765819
• 负责人: ROSEMARY ROCHFORD
• 金额: $ 48.92万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-07 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765819
• 关键词: 4 year old; Acute; Address; Adult; Africa South of the Sahara; Age; Age-Months; Biological Assay; Blood; Blood specimen; Cancer Burden; Cancer Etiology; Cells; Child; Childhood; Clinical; Cross-Sectional Studies; Cytometry; Data; Detection; Diagnosis; Enrollment; Environment; Environmental Risk Factor; Epidemic; Epidemiology; Frequencies; Future; Gender; General Population; Geography; HIV; Health; Herpesviridae; Herpesviridae Infections; Homeostasis; Human; Human Herpesvirus 8; Immune; Immune response; Immunosuppressive Agents; Infant; Infection; Inflammatory; Kaposi Sarcoma; Knowledge; Lead; Location; Longitudinal Studies; Malaria; Measures; Molecular; Molecular Epidemiology; Monitor; Oncogenic; Outcome; Parasitemia; Parasites; Pathogenesis; Phenotype; Plasma; Plasmodium falciparum; Population; Predisposition; Prevalence; Prevention; Publishing; Reporting; Research; Resources; Risk; Risk Factors; Role; Rural; Saliva; Sampling; Seroprevalences; Testing; Uganda; Variant; Viral; Viral Load result; Whole Blood; Work; base; cellular targeting; cohort; cytokine; follow-up; immune function; malaria infection; malaria transmission; monocyte; peripheral blood; population based; programs; prospective; seroconversion; seropositive; therapy development; transmission process; trend

PROJECT SUMMARY/ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV), the causative agent of Kaposi's sarcoma (KS), is unique among human herpesviruses in that it is not ubiquitous in human populations, but rather shows marked geographic hotspots in prevalence, being particularly common in sub-Saharan Africa (SSA). Moreover, there is variation in prevalence even between geographically proximate locations within the same population in SSA. This strongly suggests the presence of modifiable environmental factors that facilitate and maintain high levels of transmission in SSA and we posit that malaria infection is a key underlying factor. We provide extensive published and preliminary data supporting an interaction between malaria infection in children and KSHV seroprevalence. We hypothesize that malaria infection in children increases their susceptibility to KSHV through alterations in immune function or expansion of KSHV cellular targets or both. For children that are already KSHV infected, malaria infection could lead to viral reactivation resulting in higher viral loads in peripheral blood, higher frequency of shedding or both. The General Population Cohort (GPC) in rural Uganda is a longitudinal study investigating the trends and determinants of the HIV epidemic, as well as non- communicable disease risk factors. We found that KSHV seroprevalence in the GPC is among the highest ever reported (>90%) and children are infected at an early age (~30% by 3 years). The early age of KSHV infection, the endemic malaria transmission and the high levels of KSHV seroprevalence in the Ugandan GPC provides us with a unique opportunity to directly test our hypothesis. We will do this by enrolling a prospective infant cohort within the GPC determining the effect of P. falciparum on the establishment of KSHV infection; characterizing immune phenotype in children prior to KSHV infection and evaluate effects of P. falciparum on KSHV reactivation. In this proposal, we will capitalise on an ongoing substantive research program on KSHV and will embed the proposed work within a long-standing population-based cohort in rural Uganda, with a substantial body of existing data. The proposed work will address the profound knowledge gap regarding factors that influence KSHV transmission. This may, in the future, lead to the development of interventions to reduce transmission and thereby reduce the burden of KS.

项目摘要/摘要 Kaposi的肉瘤相关疱疹病毒（KSHV）是Kaposi的肉瘤（KS）的病因，是 在人类疱疹病毒中独有的是，它在人类人群中并非无处 在撒哈拉以南非洲（SSA）中尤其常见的地理热点。而且，有 SSA中同一人群中地理位置近端的地理位置之间的差异。 这强烈表明存在促进和维持高水平的可修改环境因素 SSA的传播，我们认为疟疾感染是关键因素。我们提供广泛的 已发布和初步数据支持儿童疟疾感染与KSHV之间的相互作用 血清阳性。我们假设儿童的疟疾感染增加了他们对KSHV的敏感性 通过改变免疫功能或KSHV细胞靶标或两者的扩展。适用于儿童 疟疾感染已经感染了KSHV，可能导致病毒再活化，导致较高的病毒载量 外围血，脱落或两者兼而有之。乌干达农村地区的一般人群队列（GPC） 是一项纵向研究，研究了HIV流行的趋势和决定因素，以及非 传染病风险因素。我们发现GPC中的KSHV血清阳性是有史以来最高的 报告（> 90％），儿童从小就被感染（约30％到3岁）。 KSHV感染的年龄， 乌干达GPC中的地方性疟疾传播和高水平的KSHV血清阳性提供 我们有一个独特的机会直接检验我们的假设。我们将通过注册潜在的婴儿来做到这一点 在GPC内的队列确定恶性疟原虫对建立KSHV感染的影响； 在KSHV感染之前表征儿童的免疫表型，并评估恶性疟原虫对 KSHV重新激活。在此提案中，我们将利用KSHV正在进行的实质性研究计划 并将将拟议的工作嵌入到乌干达农村的长期以来的人群中， 大量现有数据。拟议的工作将解决有关有关的深刻知识差距 影响KSHV传播的因素。将来，这可能会导致干预措施的发展 减少传输，从而减轻KS的负担。