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Coppens Lab


The Coppens Lab: 
- Studies the dynamics and functions of the PV membrane
- Investigates host organelle interactions with the PV
- Examines the mechanisms of host lipid scavenging and storage by Apicomplexa
- Analyzes the trafficking and homeostatic pathways of cholesterol within Toxoplasma
- Explores parasite transporters and storage enzymes as drug targets
- Examines the contribution of autophagy to the differentiation of Plasmodium in liver cells
- Assesses the vaccine potential of genetically attenuated parasites for autophagy genes


Hijacking Nutrients 

Brief - Apicomplexan parasites lost the ability to synthesize many basic metabolites. For instance, they rely on host cholesterol for survival. Our project is to decipher the cellular and molecular mechanisms developed by Apicomplexa to scavenge and store cholesterol, in order to discover strategies to starve to death these human pathogens.

Cholesterol is vital for membrane structural integrity and cell signaling. Apicomplexan parasites require cholesterol for survival but are incapable of cholesterol biosynthesis, and therefore are strictly dependent on their ability to retrieve this lipid from the intracellular environment. How these intravacuolar parasites acquire host cell cholesterol from mammalian cells has been an intriguing question in cell biology and represents a window of opportunity for controlling these human pathogens. We identified the sources of host cholesterol that are exploited by ToxoplasmaPlasmodium spp., and Cryptosporidium parvum. We have characterized the critical tricks used by these parasites for co-opting the host cell to deliver cholesterol to the parasitophorous vacuole and for trafficking cholesterol within the parasite – both points of parasite vulnerability. Our work identified unique parasite factors involved in cholesterol uptake and homeostasis in Toxoplasma. Among them, two enzymes implicated in cholesterol storage are essential factors required for parasite survival in mammalian cells and are thus attractive drug targets. These findings have triggered a surge of research activities seeking to exploit the auxotrophies and metabolic limitations in Apicomplexa for the development of novel therapeutics to halt the replication of these major public health threats.

Manipulating the Host Cell

Brief - Within mammalian cells, Toxoplasma multiplies in a non-fusogenic parasitophorous vacuole. The parasite is proficient in subverting host membrane trafficking pathways and sequestering host Rab vesicles into its vacuole. Our aim is to investigate how this parasite recruits and processes host organelles to retrieve their nutrient content, in order to develop strategies to interfere with parasite intracellular development.

Mammalian organelles represent copious sources of nutrients for intracellular Apicomplexa, yet these pathogens are cloistered in a parasitophorous vacuole that is nonfusogenic, and thus insulated from nutrient-rich host organelles. How these parasites obtain their nutrients from the cell’s organelles has been a longstanding puzzle. We illustrated that Toxoplasma manipulates host microtubules to intercept vesicular trafficking along the endocytic, recycling and secretory pathways. Also, we showed how the parasite sequesters host vesicles into its parasitophorous vacuole, via engulfment of intact vesicles without the need for membrane fusion. These findings point to an unexpected mechanism of nutrient acquisition through selective recruitment of host organelles to the parasitophorous vacuole and subsequent internalization of vesicles into the vacuole. From a therapeutic perspective, our work is directed towards potential mechanisms for starving Toxoplasma by identifying unique and essential parasite proteins that are important for the delivery host vesicles to the parasitophorous vacuole.

Getting Infectious

Brief - In the liver, malaria parasites undergo a spectacular metamorphosis associated with morphological and metabolic changes, allowing them to become replication-competent. They eliminate unwanted organelles by selective exophagy. Our goal is to delineate the remodeling processes of intrahepatic parasites by uncovering unique parasite autophagy-related proteins, in order to exploit them as potential drug targets to defeat malaria before the onset of symptoms.

Our work has identified an autophagy-like process encoded by the malaria parasite. Upon infection, malaria parasites primarily take up residence inside cells of the mammalian liver where they multiply prior to transitioning to erythrocytes. Within hepatocytes, the sporozoite undergoes an astonishing metamorphosis to become a replication-competent trophozoite. This conversion is key for the successful intracellular development of Plasmodium, but the molecular mechanisms involved remain to be elucidated. We reported that parasite differentiation into trophozoites is associated with organelle clearance and remodeling, which involves the formation of hybrid autophagosome-endosome structures in liver forms, suggesting a synergy between endocytic-exocytic and autophagic systems for parasite organelle disposal. Our work focuses on the identification of unique components of the parasite autophagic machinery as potential pharmacologic targets. Among them, Plasmodium ATG8 is essential for parasite development and uniquely associates with the ancient endosymbiotic apicoplast organelle of Plasmodium. This localization in the apicoplast likely reflects parasite-specific mechanisms and represents a previously unexplored form of autophagy. In addition, we are engineering Plasmodium autophagy mutants for use as a genetically attenuated, liver stage arresting pre-erythrocytic vaccine candidate and examining the protective immune responses these mutants elicit using mouse infection models.