Field Studies of Cryptosporidiosis in Bangladesh

Project Summary Introduction: Immunity to Cryptosporidium diarrhea develops by four years of age in children living in an area of high transmission intensity. Hypothesis: Children upon repeated infection develop immunity in part via a unique repertoire and functional capacity of antibodies against the parasite due to Tfh cell activation. Significance: The proposal will provide insight into the human immune system response to intraepithelial parasitism and inform vaccine design to prevent the estimated 7 million Cryptosporidium-attributable cases of diarrhea, 200,000 deaths annually in children under the age of 2 years. Investigators: The application is the product of 25 years of collaboration between Drs. Petri & Gilchrist at the University of Virginia and Dr. Haque at icddr,b in Bangladesh, joined by Dr. Campo at Antigen Discovery. Innovation: The hypothesis is innovative as it challenges the existing paradigm that humoral immunity is unimportant in immunity to cryptosporidiosis. Innovative approaches include the longitudinal study of infection of children in an area of high transmission intensity, probing humoral immunity with a parasite protein microarray and functional measures, and activation-induced marker (AIM) assays of Tfh function during active infection. Progress over the last 5 years of funding: 51 papers published, demonstrating the acquisition of immunity to cryptosporidiosis in children living in a high transmission area, identification of 7/233 parasite antigens recognized by immune sera as associated with protection, discovery of protection from both malnutrition and cryptosporidiosis with an anti-parasite Cp23 protein antibody response, identification of human genetic susceptibility via a polymorphism in protein kinase C, evidence of parasite genotype-specific antibody responses, the importance of the microbiome and prior antibiotics, and transmission during monsoon and within households. Approach: Specific Aim 1 (ADI & UVA): In Depth Characterization of Cryptosporidium Antigens Recognized by the Humoral Immune Response as Children Develop Immunity from Repeated Infections. Specific Aim 2 (UVA & ADI): Functional Characterization of Anti-Cryptosporidium Antibodies. Specific Aim 3 (UVA & icddr,b): Role of T follicular helper (Tfh) Cells in Induction of the Antibody Response. Environment: The University of Virginia is internationally recognized as a center for Global Health research, the icddr,b is the premier institution for the study of diarrheal diseases in low and middle income countries, and ADI Inc. is a leader in protein microarrays.