TY - JOUR
T1 - A host GPCR signaling network required for the cytolysis of infected cells facilitates release of apicomplexan parasites
AU - Millholland, Melanie G.
AU - Mishra, Satish
AU - Dupont, Christopher D.
AU - Love, Melissa S.
AU - Patel, Bhumit
AU - Shilling, Dustin
AU - Kazanietz, Marcelo G.
AU - Foskett, J. Kevin
AU - Hunter, Christopher A.
AU - Sinnis, Photini
AU - Greenbaum, Doron C.
N1 - Funding Information:
We thank Vann Bennett, James Powers, and David Speicher for key reagents and the following funding sources: NIHT32AI007532 (M.G.M.), 1R01AI097273-01A1 (D.C.G.), University of Pennsylvania TAPITMAT Pilot Program (D.C.G.), UPenn Genome Frontiers Institute (D.C.G.), and NIH R01 AI056840 (P.S.).
PY - 2013/1/16
Y1 - 2013/1/16
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84872569770&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84872569770&partnerID=8YFLogxK
U2 - 10.1016/j.chom.2012.12.001
DO - 10.1016/j.chom.2012.12.001
M3 - Article
C2 - 23332153
AN - SCOPUS:84872569770
SN - 1931-3128
VL - 13
SP - 15
EP - 28
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 1
ER -