title: Hemolytic C-type lectin CEL-III from sea cucumber expressed in transgenic mosquitoes impairs malaria parasite development.
abstract: The midgut environment of anopheline mosquitoes plays an important role in the development of the malaria parasite. Using genetic manipulation of anopheline mosquitoes to change the environment in the mosquito midgut may inhibit development of the malaria parasite, thus blocking malaria transmission. Here we generate transgenic Anopheles stephensi mosquitoes that express the C-type lectin CEL-III from the sea cucumber, Cucumaria echinata, in a midgut-specific manner. CEL-III has strong and rapid hemolytic activity toward human and rat erythrocytes in the presence of serum. Importantly, CEL-III binds to ookinetes, leading to strong inhibition of ookinete formation in vitro with an IC(50) of 15 nM. Thus, CEL-III exhibits not only hemolytic activity but also cytotoxicity toward ookinetes. In these transgenic mosquitoes, sporogonic development of Plasmodium berghei is severely impaired. Moderate, but significant inhibition was found against Plasmodium falciparum. To our knowledge, this is the first demonstration of stably engineered anophelines that affect the Plasmodium transmission dynamics of human malaria. Although our laboratory-based research does not have immediate applications to block natural malaria transmission, these findings have significant implications for the generation of refractory mosquitoes to all species of human Plasmodium and elucidation of mosquito-parasite interactions.
authors.affiliation: Division of Medical Zoology, Department of Infection and Immunity, Jichi Medical University, Tochigi, Japan. shigeto@jichi.ac.jp
authors.forename: Shigeto
authors.initials: S
authors.lastname: Yoshida
authors.forename: Yohei
authors.initials: Y
authors.lastname: Shimada
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kondoh
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kouzuma
authors.forename: Anil K
authors.initials: AK
authors.lastname: Ghosh
authors.forename: Marcelo
authors.initials: M
authors.lastname: Jacobs-Lorena
authors.forename: Robert E
authors.initials: RE
authors.lastname: Sinden
mesh_terms: D000818:Animals; D000852:Anopheles / Q000235:genetics / Q000378:metabolism / Q000469:parasitology; D003001:Cloning, Molecular; D048016:Cucumaria / Q000737:chemistry / Q000378:metabolism*; D004064:Digestive System; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology; D005260:Female; D015870:Gene Expression; D006461:Hemolysis; D053878:Hemolytic Agents / Q000378:metabolism*; D006790:Host-Parasite Interactions; D006801:Humans; D066298:In Vitro Techniques; D007303:Insect Vectors / Q000235:genetics / Q000378:metabolism / Q000469:parasitology; D037102:Lectins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D008288:Malaria; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D030781:Organisms, Genetically Modified; D010962:Plasmodium berghei / Q000187:drug effects* / Q000378:metabolism / Q000472:pathogenicity; D010963:Plasmodium falciparum / Q000472:pathogenicity; D051381:Rats; D011914:Rats, Inbred BN
chemical_list: C402644:CEL-III lectin, Cucumaria echinata; D053878:Hemolytic Agents; D037102:Lectins