We propose a genetic study of the human-pathogen-environment relationship that underlies susceptibility to amebiasis. 8 years ago we started a prospective cohort study of Entamoeba histolytica infection in 300 two to five year old children living in the Mirpur urban slum of Dhaka, Bangladesh. We discovered that amebiasis is common and associated with malnutrition and geohelminth infection, that parasite genotypes differ in propensity to cause disease, and that mucosal IgA and systemic IFN-gamma are markers of protective immunity. Despite a substantial burden of disease, we noted that children differ markedly in their susceptibility to amebiasis. Our hypothesis is that susceptibility is determined by (a) host innate and acquired immune responses that vary between individuals in part due to human genetic polymorphisms;(b) environmental influences including malnutrition and concurrent geohelminth infection;and (c) virulence differences of E. histolytica genotypes.
Three specific aims are proposed to delineate the interaction of host, parasite and environment leading to disease.
Specific Aim (1) will measure the incidence of amebiasis and correlate it with human and parasite genetic polymorphisms, immune responses, and environmental factors such as geohelminth infection and malnutrition. As part of Aim 1 a 2nd cohort of 500 live births will be enrolled to separate innate from acquired immune responses, examine the burden of amebiasis in the first 2 years of life, and independently test genetic polymorphisms found to influence susceptibility in the older child cohort.
Specific Aim (2) will test the hypothesis that protective immunity is mediated both by innate immune responses initiated via TLR stimulation as well as by mucosal IgA against the Gal/GalNAc lectin and systemic IFN-gamma. We will measure innate and acquired immune responses to E. histolytica in the 2 cohorts and correlate them with incidence of infection, host genetic polymorphisms and environmental factors.
Specific Aim (3) will test for the association of common genetic polymorphisms in host innate and acquired immune genes with incidence of amebiasis. In the older child cohort, 2800 SNPs in 89 candidate genes will be typed and correlated with immune responses and susceptibility. Using a 2-stage study design (original cohort followed by birth cohort) candidate genes associated with susceptibility will be validated in the birth cohort. Successful completion of these studies will identify host, environmental and parasitic determinants of infection, while at the same time establishing the burden of infection by completion of the only prospective community-based study of amebiasis from infancy to age 18. Project Narrative Amebiasis is a common cause of diarrhea and is associated with malnutrition in grade- school aged children in an urban slum of Dhaka, Bangladesh. We wish to determine the contribution of amebiasis to illness in the first 2 years of life when most deaths due to diarrhea occur, and understand the immunologic and genetic factors that protect children from amebiasis. Successful completion of these studies will provide an estimate of the impact of amebiasis on the health of the study children, and could lead to new approaches to prevent and treat this disease.
|Steiner, Kevin L; Ahmed, Shahnawaz; Gilchrist, Carol A et al. (2018) Species of Cryptosporidia Causing Subclinical Infection Associated With Growth Faltering in Rural and Urban Bangladesh: A Birth Cohort Study. Clin Infect Dis 67:1347-1355|
|Rogawski, Elizabeth T; Platts-Mills, James A; Colgate, E Ross et al. (2018) Quantifying the Impact of Natural Immunity on Rotavirus Vaccine Efficacy Estimates: A Clinical Trial in Dhaka, Bangladesh (PROVIDE) and a Simulation Study. J Infect Dis 217:861-868|
|Kabir, Mamun; Ahmed, Emtiaz; Hossain, Biplob et al. (2018) Giardia/Cryptosporidium QUIK CHEK Assay Is More Specific Than Quantitative Polymerase Chain Reaction for Rapid Point-of-care Diagnosis of Cryptosporidiosis in Infants in Bangladesh. Clin Infect Dis 67:1897-1903|
|Khalil, Ibrahim A; Troeger, Christopher; Rao, Puja C et al. (2018) Morbidity, mortality, and long-term consequences associated with diarrhoea from Cryptosporidium infection in children younger than 5 years: a meta-analyses study. Lancet Glob Health 6:e758-e768|
|Donowitz, Jeffrey R; Cook, Heather; Alam, Masud et al. (2018) Role of maternal health and infant inflammation in nutritional and neurodevelopmental outcomes of two-year-old Bangladeshi children. PLoS Negl Trop Dis 12:e0006363|
|Jiang, Nona M; Cowan, Maureen; Moonah, Shannon N et al. (2018) The Impact of Systemic Inflammation on Neurodevelopment. Trends Mol Med 24:794-804|
|Schnee, Amanda E; Haque, Rashidul; Taniuchi, Mami et al. (2018) Evaluation of Two New Membrane-Based and Microtiter Plate Enzyme-Linked Immunosorbent Assays for Detection of Campylobacter jejuni in Stools of Bangladeshi Children. J Clin Microbiol 56:|
|Korpe, Poonum S; Valencia, Cristian; Haque, Rashidul et al. (2018) Epidemiology and Risk Factors for Cryptosporidiosis in Children From 8 Low-income Sites: Results From the MAL-ED Study. Clin Infect Dis 67:1660-1669|
|Gilchrist, Carol A; Cotton, James A; Burkey, Cecelia et al. (2018) Genetic Diversity of Cryptosporidium hominis in a Bangladeshi Community as Revealed by Whole-Genome Sequencing. J Infect Dis 218:259-264|
|Mychaleckyj, Josyf C; Nayak, Uma; Colgate, E Ross et al. (2018) Multiplex genomewide association analysis of breast milk fatty acid composition extends the phenotypic association and potential selection of FADS1 variants to arachidonic acid, a critical infant micronutrient. J Med Genet 55:459-468|
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