Abstract
The parasite Cryptosporidium is responsible for diarrheal disease in young children causing death, malnutrition, and growth delay. Cryptosporidium invades enterocytes where it develops in a unique intracellular niche. Infected cells exhibit profound changes in morphology, physiology, and transcriptional activity. How the parasite effects these changes is poorly understood. We explored the localization of highly polymorphic proteins and found members of the Cryptosporidium parvum MEDLE protein family to be translocated into the cytosol of infected cells. All intracellular life stages engage in this export, which occurs after completion of invasion. Mutational studies defined an N-terminal host-targeting motif and demonstrated proteolytic processing at a specific leucine residue. Direct expression of MEDLE2 in mammalian cells triggered an ER stress response, which was also observed during infection. Taken together, our studies reveal the presence of a Cryptosporidium secretion system capable of delivering parasite proteins into the infected enterocyte.
Highlights
The Apicomplexan parasite Cryptosporidium is a leading cause of diarrheal disease worldwide
We note that the cells that stain for HA were those that were infected with parasites, labeled with Vicia villosa lectin (VVL, green), and conclude that MEDLE2-HA is exported by the parasite into the host cell during or following invasion
The genomic differences observed are focused on families of predicted secretory proteins that have been proposed to contribute to host specificity, prominently among them the MEDLE family (Fei et al, 2018; Li et al, 2017; Su et al, 2019)
Summary
The Apicomplexan parasite Cryptosporidium is a leading cause of diarrheal disease worldwide. Cryptosporidium remodels the host cell in significant ways that include its cytoskeleton (Bonnin et al, 1999; Elliott and Clark, 2000), cellular physiology and metabolism (Argenzio et al, 1990; Kumar et al, 2018), as well as aspects of immune restriction and regulation (Laurent and Lacroix-Lamandé, 2017). We report that the polymorphic protein MEDLE2 is exported to the host cell cytoplasm by all stages of the C. parvum lifecycle in vitro and in vivo. This protein is not injected during invasion, but rather is transported into the host cell following the initial establishment of infection. We demonstrate the presence of a robust translocation mechanism established by intracellular parasites that delivers parasite proteins to the host cell
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