Host Cell Proteins that Interact with Cryptosporidium

Cryptosporidium parvum is a zoonotic pathogen and can cause one of the opportunistic infections in AIDS patients (AIDS-OI). Because of the lack of highly effective treatment against Cryptosporidium infection and the autoinfection potential of this parasite, cryptosporidiosis in immunocompromised individuals can be prolonged and life-threatening. Despite its globally recognized importance in human and animal health, the pathogenesis of cryptosporidiosis in both humans and animals is still poorly understood. It is particularly unclear how the host cell and parasite interact physically and biochemically with each other during infection. <P> The long-term goal of this project is to elucidate the molecular mechanisms involved in the host-pathogen interactions during the Cryptosporidium infection. Our preliminary analysis has identified a number of genes in human cells that are significantly regulated by the C. parvum infection. One noticeable group of the regulated genes are extracellular matrix (ECM) proteins, including integrin, matrix metalloproteinase (MMP) and laminin, that are likely located at the host cell-parasite interface or around the parasite. Additionally, we have also observed that C. parvum-originated membrane proteins can be targeted to the host cell membranes at the parasite-host boundary and parasitophorous vacuole membrane (PVM), suggesting that both the parasite and host cells actively interact with each other at molecular level. <P> Based on these observations, we hypothesize that host cell proteins are actively involved in the interactions and communications with the intracellular parasite during infection. In this exploratory project, we will test our hypothesis by achieving the following two specific aims: <P> Aim 1) Identify host cell molecules that may directly interact with C. parvum during infection using in vitro models of cryptosporidiosis; <P> Aim 2) Determine the role of the host cell integrin- associated pathway in the host-pathogen interactions. <P> By achieving aim 1, we will identify a list of important host cell surface proteins, particularly those ECM proteins shared in both human and bovine cells, for future studying their potential interactions with Cryptosporidium during invasion and development. By achieving aim 2, we will confirm or refute our hypothesis that host integrin-associated pathway is indeed participated in the establishment of parasite infection.<P> PUBLIC HEALTH RELEVANCE Cryptosporidium parvum is an untreatable opportunistic pathogen in AIDS patients. Little is known on the pathogenesis of cryptosporidiosis, particularly on how the host cell proteins contribute to the infection by this parasite. This exploratory project aims to identify and study the roles of host cell extracellular matrix proteins in infection. The completion of this project will not increase our knowledge on the cause of disease, but also has the potential to find new targets for intervening cryptosporidiosis for which no treatment is yet available in AIDS patients.