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 lar...