title: Adenylyl cyclase alpha and cAMP signaling mediate Plasmodium sporozoite apical regulated exocytosis and hepatocyte infection.
abstract: Malaria starts with the infection of the liver of the host by Plasmodium sporozoites, the parasite form transmitted by infected mosquitoes. Sporozoites migrate through several hepatocytes by breaching their plasma membranes before finally infecting one with the formation of an internalization vacuole. Migration through host cells induces apical regulated exocytosis in sporozoites. Here we show that apical regulated exocytosis is induced by increases in cAMP in sporozoites of rodent (P. yoelii and P. berghei) and human (P. falciparum) Plasmodium species. We have generated P. berghei parasites deficient in adenylyl cyclase alpha (ACalpha), a gene containing regions with high homology to adenylyl cyclases. PbACalpha-deficient sporozoites do not exocytose in response to migration through host cells and present more than 50% impaired hepatocyte infectivity in vivo. These effects are specific to ACalpha, as re-introduction of ACalpha in deficient parasites resulted in complete recovery of exocytosis and infection. Our findings indicate that ACalpha and increases in cAMP levels are required for sporozoite apical regulated exocytosis, which is involved in sporozoite infection of hepatocytes.
authors.affiliation: Department of Medical Parasitology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ono
authors.forename: Laura
authors.initials: L
authors.lastname: Cabrita-Santos
authors.forename: Ricardo
authors.initials: R
authors.lastname: Leitao
authors.forename: Esther
authors.initials: E
authors.lastname: Bettiol
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Purcell
authors.forename: Olga
authors.initials: O
authors.lastname: Diaz-Pulido
authors.forename: Lucy B
authors.initials: LB
authors.lastname: Andrews
authors.forename: Takushi
authors.initials: T
authors.lastname: Tadakuma
authors.forename: Purnima
authors.initials: P
authors.lastname: Bhanot
authors.forename: Maria M
authors.initials: MM
authors.lastname: Mota
authors.forename: Ana
authors.initials: A
authors.lastname: Rodriguez
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D000953:Antigens, Protozoan / Q000235:genetics / Q000378:metabolism; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005089:Exocytosis / Q000187:drug effects / Q000502:physiology*; D020868:Gene Silencing; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000469:parasitology*; D006801:Humans; D008136:Longevity / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009068:Movement / Q000187:drug effects; D010961:Plasmodium / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D034101:Sporozoites / Q000187:drug effects / Q000201:enzymology; D014498:Uracil / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000953:Antigens, Protozoan; D012333:RNA, Messenger; D014498:Uracil; D000242:Cyclic AMP; D000262:Adenylyl Cyclases