Striepen lab Research
We are interested in the cell and molecular biology of protozoan parasites. Most of our work is focused on members of the phylum Apicomplexa. Organisms in this group cause a number of important diseases including malaria, severe opportunistic infections associated with AIDS, and fetal and early childhood diseases. We use a broad array of modern genomic, genetic, cell biological and biochemical approaches to understand fundamental parasite biology and use this knowledge to identify and develop targets for disease intervention. Currently we are focusing on the following specific areas:
Cryptosporiosis -- A new genetic handle on an important diseases
10.5% of global child mortality is due to diarrheal disease. Comprehensive epidemiology at the global scale recently revealed Cryptosporidium to be the most important diarrheal pathogen in small children after Rotavirus. Recently, we have developed robust molecular genetics for this important pathogen. Currently we use these exciting new tools to drive progress in a variety of fundamental science as well as translational projects.
The cell biology of parasite sex
Cryptosporidium has a unique single host life cycle. Both asexual and sexual processes unfold in infected animals and to a significant part in tissue culture. We use molecular genetics to mark different stages of the life cycle, to understand the transcriptional control of developmental progression, and to discover genes with stage specific functions. Male gametes find female gametes hidden within the cells of the host. We discover and dissect the mechanisms of gamete biology and fertilization.
Host parasite interaction
Infants are highly susceptible to cryptosporidiosis. However, under constant exposure, children older that two rarely show infection and disease. Most likely they are protected by immunity. The mechanisms that govern host immunity and parasite immune evasion remain largely to be discovered. We have isolate a 'wild' mouse Crytposporidium and have developed a natural mouse model that results in self-limiting infection and protection in immunocompetent mice. We are using this new model to understand the immunology of Cryptosporidium infection and the important role that the microbiome and nutritional state of the host play. Cryptosporidium is also a marvelous model to investigate host specificity. A range of genetically very similar strains and species shows significant differences in the hosts they can infect. We use genetic and genomic studies to unravel the molecular basis of this specificity.
Parasite metabolism & drug development
Currently we lack effective treatment. We collaborate with several groups in academia and industry to change that. Cryptosporidium has a highly stripped down metabolism and steals most of the metabolites it needs from the host. It also interacts with the bacterial flora of the intestine and has acquired the genes for numerous bacterial enzymes by horizontal gene transfer. We use rigorous genetics to unravel this complex metabolism and to evaluate targets for treatment. We use reverse and forward genetics to discover the mode of action of novel chemical entities that target Cryptosporidium.
Apicoplast -- a unique parasite chloroplast
Apicomplexan parasites harbor a remnant chloroplast (the apicoplast) that they obtained through secondary endosymbiosis. This organelle is essential for parasite growth and as human cells lack chloroplasts offers a unique opportunity for anti-parasitic drug development. Using Toxoplasma gondii as a robust genetic model we are characterizing the specific metabolic functions of the organelle to pinpoint which pathway(s) would be most suitable as a drug target. The apicoplast also provides a tractable model to study the cell biology of endosymbiosis. What is the cellular machinery that builds, maintains and replicates and organelle that formed due to the merger of three previously independent organisms (one prokaryotes and two eukaryotes). Our current work uses a mix of genomics and genetics to mechanistically dissect apicoplast biogenesis, protein import and division.
Apicomlexan cell division
Apicomplexans have the ability to delay, or decouple various aspects of their cell cycle, allowing them to undergo multiple rounds of DNA replication before nuclear duplication, or multiple rounds of nuclear duplication before budding. The cell cycle of Toxoplasma gondii tachyzoites represent a simple example of these more complicated modes of division (e.g. those used by the malaria parasites), and thus is a good model to dissect how the apicomplexan cell division cycle occurs. We are studying the mechanistic basis to discovering how the parasites can modulate specific aspects of the cell cycle to match their reproductive output to their specific host cell niche.