Investigating parasitism-induced immune dysregulation and susceptibility to acute rheumatic fever in children

研究寄生引起的免疫失调和儿童对急性风湿热的易感性

• 批准号: 10303850
• 负责人: Sarah Murphy Gunter
• 金额: $ 22.18万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-22 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10303850
• 关键词: Acute; Age; Antibiotics; Autoimmune; Automobile Driving; Cardiac; Cells; Cessation of life; Child; Childhood; Cicatrix; Clinic; Clinical; Clinical Pathology; Complex; Complication; Country; Data; Development; Diagnostic Procedure; Disease; Disease Progression; Enrollment; Epidemiologist; Epidemiology; Genetic; Goals; Health; Healthcare; Heart Valves; High Prevalence; Hygiene; Immune; Immune response; Immunity; Immunologics; Impaired cognition; Incidence; Income; Infection; Institution; Interleukin-10; Intervention; Laboratories; Location; Malawi; Malnutrition; Mentorship; Morbidity - disease rate; Outcome Study; Parasites; Parasitic infection; Patients; Pharyngeal structure; Play; Population; Predisposition; Prevalence; Prevention program; Prospective Studies; Public Health; Research Personnel; Resources; Rheumatic Fever; Rheumatic Heart Disease; Risk; Role; Schistosoma; Secondary to; Site; Streptococcus pyogenes; Tropical Disease; United States; adaptive immune response; co-infection; cytokine; disability; disability-adjusted life years; disorder prevention; gastrointestinal; high reward; high risk; immunoregulation; low and middle-income countries; mortality; multidisciplinary; novel; parasitism; pathogen; pediatric cardiologist; prevent; public health intervention; response; secondary infection; success; treatment program; treatment strategy; years of life lost

PROJECT SUMMARY Rheumatic heart disease (RHD) is the leading cause of acquired cardiac morbidity and mortality in young people worldwide. RHD, a complication of acute rheumatic fever (ARF), develops as a result of strep throat (causative agent Streptococcus pyogenes). While strep throat is common in pediatric populations, only a small percentage of infected patients will progress to the severe clinical complications of ARF and RHD. Currently, we cannot predict which children will progress to the more severe form of disease. The epidemiology and clinical pathology of RHD is complex and ill-defined. The incidence of RHD in the United States has sharply declined since the early 1900s, though the incidence of strep throat has remained constant. In high-income countries, even when strep throat is not appropriately treated, ARF and RHD are extremely rare. Conversely, RHD and strep throat both remain significant problems in low and middle-income countries (LMIC). Interestingly, the initial decline in clinicial cases was noted prior to the implementation of regular penicilin use. This decline does, however, correspond with implementation of more rigorous hygiene practices and the reduced burden of childhood parasitic infections. Many LMICs, such as Malawi, continue to struggle with a high burden of parasitic infections and RHD within their population. Parasitic infections cause several systemic health problems such as nutritional deficiencies, cognitive impairment, and increased susceptibility to secondary infections. Most importantly, certain parasitic infections skew the immune profile towards Th2 innate and adaptive responses. We believe that this skewed immune response due to parasitic infection is a driving factor in the development of ARF and RHD in people with strep throat. This study aims to investigate the role of immune modulation due to co-infection with gastrointestinal parasites in the progression of strep throat to ARF. We hypothesize that children presenting with ARF in a highly endemic region of Malawi will more commonly have a co-infection with one or more parasite when compared to age-matched controls, thereby providing evidence that a parasite-induced altered immune response leads to increased susceptibility to ARF and severe disease. The overall goal of this study is to determine if parasite co-infection is significantly higher in ARF and RHD patients and to determine alterations to the immune profile. Our aims are as follows: (1) Identify the prevalence of parasite infections in children with acute rheumatic fever who present to health care centers in Malawi compared to age-matched controls, (2) Examine the extent of immune dysregulation in children with ARF compared to age-matched controls. Our overall expected outcome from this study is that we will identify a correlation between parasite burden and ARF and explain the skewed immune profiles that increase risk of severe disease. This study will generate important data to inform larger prospective studies to identify targets for public health intervention and treatment strategies. We believe this is an important first step in identifying underlying causes of ARF and RHD.

项目概要 风湿性心脏病（RHD）是年轻人获得性心脏病发病和死亡的主要原因 全世界。 RHD 是急性风湿热 (ARF) 的一种并发症，由链球菌性咽喉炎（致病菌）引起 化脓性链球菌）。虽然链球菌性咽喉炎在儿科人群中很常见，但只占一小部分 的感染患者将进展为 ARF 和 RHD 的严重临床并发症。目前，我们无法 预测哪些儿童将患上更严重的疾病。流行病学和临床病理学 RHD 的定义是复杂且不明确的。自20世纪90年代以来，美国RHD的发病率急剧下降 1900年代初，尽管链球菌性咽喉炎的发病率一直保持不变。在高收入国家，即使 链球菌性咽喉炎未得到适当治疗，ARF 和 RHD 极为罕见。相反，RHD 和链球菌性咽喉炎 这两个问题在低收入和中等收入国家（LMIC）仍然是重大问题。有趣的是，最初的下降 在定期使用青霉素之前就注意到了临床病例。然而，这种下降确实 与实施更严格的卫生习惯和减轻儿童负担相一致 寄生虫感染。许多中低收入国家，例如马拉维，继续与寄生虫感染的沉重负担作斗争 和 RHD 在其人口中。寄生虫感染会导致一些系统性健康问题，例如营养问题 缺陷、认知障碍和继发感染的易感性增加。最重要的是，确定 寄生虫感染使免疫特征偏向 Th2 先天性和适应性反应。我们相信，这 寄生虫感染引起的免疫反应失调是 ARF 和 RHD 发展的驱动因素 患有链球菌性咽喉炎的人。本研究旨在探讨合并感染引起的免疫调节作用 胃肠道寄生虫在链球菌性咽喉炎进展为 ARF 过程中的作用。我们假设儿童呈现 在马拉维的 ARF 高流行地区，更常见的是一种或多种寄生虫同时感染 与年龄匹配的对照相比，从而提供了寄生虫引起的免疫改变的证据 反应导致对 ARF 和严重疾病的易感性增加。本研究的总体目标是 确定 ARF 和 RHD 患者的寄生虫混合感染是否显着较高，并确定对 免疫特征。我们的目标如下： (1) 确定患有以下疾病的儿童寄生虫感染的流行情况： 与年龄匹配的对照组相比，在马拉维医疗中心就诊的急性风湿热患者，(2) 检查 ARF 儿童与年龄匹配的对照组相比免疫失调的程度。我们的整体 这项研究的预期结果是我们将确定寄生虫负担与 ARF 之间的相关性 解释导致严重疾病风险增加的免疫特征偏差。这项研究将产生重要数据 为更大规模的前瞻性研究提供信息，以确定公共卫生干预和治疗策略的目标。我们 相信这是确定 ARF 和 RHD 根本原因的重要第一步。