Apicomplexan Parasites Co-Opt Host Calpains to Facilitate Their Escape from Infected Cells
Rajesh Chandramohanadas,1
Paul H. Davis,2
Daniel P. Beiting,2
Michael B. Harbut,1
Claire Darling,1
Geetha Velmourougane,1
Ming Yeh Lee,2
Peter A. Greer,3
David S. Roos,2
Doron C. Greenbaum1,*
Apicomplexan parasites, including
Plasmodium falciparum and
Toxoplasma gondii (the causative agents of malaria and toxoplasmosis,
respectively), are responsible for considerable morbidity and
mortality worldwide. These pathogenic protozoa replicate within
an intracellular vacuole inside of infected host cells, from
which they must escape to initiate a new lytic cycle. By integrating
cell biological, pharmacological, and genetic approaches, we
provide evidence that both
Plasmodium and
Toxoplasma hijack
host cell calpain proteases to facilitate parasite egress. Immunodepletion
or inhibition of calpain-1 in hypotonically lysed and resealed
erythrocytes prevented the escape of
P. falciparum parasites,
which was restored by adding purified calpain-1. Similarly,
efficient egress of
T. gondii from mammalian fibroblasts was
blocked by either small interfering RNA–mediated suppression
or genetic deletion of calpain activity and could be restored
by genetic complementation.
2 Department of Biology and the Penn Genome Frontiers Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
3 Department of Pathology and Molecular Medicine, Queen’s Cancer Research Institute, Queen’s University, Kingston, ON K7L 3N6, Canada.
* To whom correspondence should be addressed. E-mail: dorong{at}upenn.edu
