Immunity to Cryptosporidium

University Of Pennsylvania, Philadelphia PA

Investigators

Linked publications, trials & patents

Abstract

Cryptosporidium causes self-limiting diarrheal disease in immune competent individuals and life-threatening illness in young children as well as patients with defects in T cell function. Current drugs are poorly efficacious, and a vaccine would be a game changer for the pediatric disease. However, there is a major gap in our understanding of what types of protective immunity would be required for successful vaccination. Based on clinical and experimental studies, we know CD4+ T cells and the production of IFN-γ are important for parasite control but the actual events that restrict Cryptosporidium are unknown. The advent of parasite molecular genetics has transformed the ability to modify Cryptosporidium and in the last funding period these laboratories have generated the tools needed to answer fundamental questions about the mechanisms of resistance to this organism. Remarkably, while IFN-γ is important for parasite control, in vaccination experiments we also found significant protective CD4+ T cell dependent memory even in the absence of IFN-γ and our studies implicate IL- 22 in resistance to Cryptosporidium. Based on this foundation, the vision of this proposal is to leverage our advances in parasite biology, mouse models, and immunological tools to understand: 1) the relationship between the IFN-γ and IL-22- mediated pathways 2) Utilize the differential activities of STAT1 and STAT3 in enterocytes to understand the basic mechanisms that promote parasite clearance 3) Use of novel genetically attenuated parasite strains to understand the parasite and host factors required for long term CD4+ and CD8+-T cell mediated protective immunity. The studies propose here will deliver information on the innate and adaptive pathways that promote T cell mediated control of Cryptosporidium and how EC responses limit parasite growth. This information is relevant to understanding the type of long-lived cellular immunity required for vaccine protection from Cryptosporidium, and insight into how to best target this response to the gut to reduce both parasite burden and damage to the tissues. We expect the mechanisms discovered in the course of this program to be of broad interest to the understanding of numerous diseases of the intestinal tract of infectious, inflammatory and malignant etiology.