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.

项目摘要 风湿性心脏病（RHD）是年轻人获得心脏发病率和死亡率的主要原因 全世界。 RHD是急性风湿热（ARF）的并发症 代理化脓性链球菌）。虽然链球菌性喉咙在小儿种群中很常见，但只有很小的百分比 受感染的患者将发展为ARF和RHD的严重临床并发症。目前，我们不能 预测哪些儿童将发展为更严重的疾病形式。流行病学和临床病理学 RHD的复杂且定义不明。自从美国的RHD发病率下降以来 1900年代初，尽管链球菌喉咙的发病率保持恒定。在高收入国家，即使 链球菌性喉咙没有适当治疗，ARF和RHD极为罕见。相反，RHD和链球菌性喉咙 两者在低收入和中等收入国家（LMIC）仍然存在重大问题。有趣的是，最初的下降 在实施定期使用青霉素之前，请注意临床病例。但是，这种下降确实 与实施更严格的卫生实践和童年负担相对应 寄生虫感染。许多LMIC，例如马拉维，继续为寄生虫感染负担很大而挣扎 和人口中的RHD。寄生虫感染引起了几种全身健康问题，例如营养 缺陷，认知障碍和对继发感染的敏感性增加。最重要的是，确定 寄生虫感染偏向于Th2先天和适应性反应的免疫特征。我们相信这个 由于寄生虫感染引起的偏斜免疫反应是ARF和RHD发展的驱动因素 患有链球菌性喉咙的人。这项研究旨在研究由于与 链球菌喉向ARF的进展中的胃肠道寄生虫。我们假设孩子们展示 在马拉维高度流行地区的ARF通常会与一个或多个寄生虫共同感染 与年龄匹配的对照相比，因此提供了证据表明寄生虫引起的免疫改变了 反应导致对ARF和严重疾病的敏感性增加。这项研究的总体目标是 确定ARF和RHD患者的寄生虫共感染是否明显更高，并确定改变 免疫轮廓。我们的目标如下：（1）确定患有儿童的寄生虫感染的患病率 与年龄匹配的对照相比，急性风湿热是马拉维医疗中心的 与年龄匹配的对照相比，检查ARF儿童的免疫失调的程度。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 解释增加严重疾病风险的偏斜免疫特征。这项研究将产生重要数据 告知更大的前瞻性研究，以确定公共卫生干预和治疗策略的目标。我们 认为这是确定ARF和RHD的根本原因的重要第一步。