Genetic Analysis of Cryptosporidium

Cryptosporidium is an important intestinal pathogen for which neither prophylaxis nor effective treatments are available. The parasite was first recognized as an AIDS-defining opportunistic infection, and immune suppression remains an important risk. However, immunocompetent individuals are also susceptible, and Cryptosporidium is responsible for frequent U.S. waterborne outbreaks. More recently, Cryptosporidium was identified as a leading global cause of disease and death in infants. Humans are susceptible to multiple Cryptosporidium species and strains, and the epidemiology of cryptosporidiosis is a complex web of human to human and zoonotic transmission. Population surveys suggest that genetic exchange between these lineages drives recent adaptation to new hosts and environments. Parasite sex offers an opportunity for recombination and virulence evolution, but this problem has been largely intractable. We developed new technology to harness the parasite lifecycle for forward genetics. We conduct genetic crosses between phenotypically distinct parasites and map quantitative trait loci associated with persistence and host specificity through bulk segregant analysis of selected progeny. Using reverse genetics and phenotypic assays we will validate association and explore specific gene function. We will define the molecular mechanisms that govern the ability to infect and persist in different hosts, understand how these mechanisms interact with host specificity, and establish to what extent they are modulated or breached by sexual recombination. Answers to these questions are not only critical to our understanding of Cryptosporidium epidemiology, but also of great concern to drug and vaccine development to gauge the potential of emerging resistance and evasion.