Cryptosporidiosis is a leading cause of diarrheal illness in children worldwide;however there are limited therapies and no available vaccine for this protozoal infection. In this project, Passive and Acquired Immunity to Cryptosporidiosis in Bangladeshi Children, I propose to study the natural history of cryptosporidiosis in a birth cohort of children in Bangladesh as a means to understand human immune responses to the infection. We have found that 40% of children in this cohort are infected with Cryptosporidium spp. by age one, and I have discovered that anti-cryptosporidium breast milk IgA is associated with protection from Cryptosporidium spp. infection in breastfeeding infants. Since the last submission, I have found that the presence of anti-cryptosporidium IgG in 12-month old children is associated with protection from infection in year two of life, suggesting the development of acquired immunity. In this proposal, Aim 1 will elucidate the mechanism by which breast milk may interfere with infection, using a novel in vitro parasite invasion assay.
Aim 2 involves the first application of single-cell mass cytometry (CyTOF) to describe the phenotype and functional capacity of stimulated immune cells to evaluate whether a robust cell-mediated response to Cryptosporidium spp. can predict protection from recurrent infection. This proposal leverages a longitudinal cohort study already in place for my mentor's NIH and Gates Foundation funded projects. Determining the role of passive and active immunity in protection from cryptosporidiosis will inform immunization strategies aimed to prevent Cryptosporidium spp. infection in young children. The Division of Infectious Diseases at the University of Virginia, where I am currently completing a fellowship, has a strong history of commitment to academic medicine and international health, and provides a supportive environment for advancement of young investigators. The proposed career development plan is designed to address specific skill sets that will be required for evolution to independent investigator status, and includes mentorship by Dr. Petri and advisors who are experts in the fields of parasitology and immunology. Additionally, the career development plan outlines graduate level courses in immunology, biostatistics, clinical investigation, as well as technical training in immunologic methods, and professional development activities. I will submit my own R01 during year 4 of the K award on the cryptosporidiosis work. Successful completion of the Mentored Career Development Award will leave me well-positioned as an independent investigator with a focus on preventative strategies to cryptosporidiosis.
Currently, there are limited therapies and no vaccine available for cryptosporidiosis, a protozoal infection which is a leading cause of diarrheal illness in children worldwide, and is associated with long-term growth faltering and cognitive deficits. Before novel therapeutic or preventative strategies can be developed, we must further elucidate the role of passive and active immunity in controlling this infection. This proposal aims to describe the natural history of cryptosporidiosis in a birth cohort of children living in an endemi region, to study whether passive immunity via breast milk IgA can prevent infection, and whether cell mediated immunity is acquired after natural infection. Completion of this project will inform immunization strategies aimed to prevent Cryptosporidium spp. infection in young children.