A host GPCR signaling network required for the cytolysis of infected cells facilitates release of apicomplexan parasites

Melanie G. Millholland, Satish Mishra, Christopher D. Dupont, Melissa S. Love, Bhumit Patel, Dustin Shilling, Marcelo G. Kazanietz, J. Kevin Foskett, Christopher A. Hunter, Photini Sinnis, Doron C. Greenbaum

Research output: Contribution to journalArticle

Abstract

Following intracellular replication, the apicomplexan parasites Plasmodium falciparum and Toxoplasma gondii cause host cell cytolysis to facilitate parasite release and disease progression. Parasite exit from infected cells requires the interplay of parasite-derived proteins and host actin cytoskeletal changes; however, the host proteins underlying these changes remain obscure. We report the identification of a Gαq-coupled host-signaling cascade required for the egress of both P. falciparum and T. gondii. Gαq-coupled signaling results in protein kinase C (PKC)-mediated loss of the host cytoskeletal protein adducin and weakening of the cellular cytoskeleton. This cytoskeletal compromise induces catastrophic Ca2+ influx mediated by the mechanosensitive cation channel TRPC6, which activates host calpain that proteolyzes the host cytoskeleton allowing parasite release. Reinforcing the feasibility of targeting host proteins as an antiparasitic strategy, mammalian PKC inhibitors demonstrated activity in murine models of malaria and toxoplasmosis. Importantly, an orally bioavailable PKC inhibitor prolonged survival in an experimental cerebral malaria model.

Original languageEnglish (US)
Pages (from-to)15-28
Number of pages14
JournalCell Host and Microbe
Volume13
Issue number1
DOIs
StatePublished - Jan 16 2013

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology

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    Millholland, M. G., Mishra, S., Dupont, C. D., Love, M. S., Patel, B., Shilling, D., Kazanietz, M. G., Foskett, J. K., Hunter, C. A., Sinnis, P., & Greenbaum, D. C. (2013). A host GPCR signaling network required for the cytolysis of infected cells facilitates release of apicomplexan parasites. Cell Host and Microbe, 13(1), 15-28. https://doi.org/10.1016/j.chom.2012.12.001