title: Anopheles Midgut FREP1 Mediates Plasmodium Invasion.
abstract: Malaria transmission depends on sexual stage Plasmodium parasites successfully invading Anopheline mosquito midguts following a blood meal. However, the molecular mechanisms of Plasmodium invasion of mosquito midguts have not been fully elucidated. Previously, we showed that genetic polymorphisms in the fibrinogen-related protein 1 (FREP1) gene are significantly associated with Plasmodium falciparum infection in Anopheles gambiae, and FREP1 is important for Plasmodium berghei infection of mosquitoes. Here we identify that the FREP1 protein is secreted from the mosquito midgut epithelium and integrated as tetramers into the peritrophic matrix, a chitinous matrix formed inside the midgut lumen after a blood meal feeding. Moreover, we show that the FREP1 can directly bind Plasmodia sexual stage gametocytes and ookinetes. Notably, ablating FREP1 expression or targeting FREP1 with antibodies significantly decreases P. falciparum infection in mosquito midguts. Our data support that the mosquito-expressed FREP1 mediates mosquito midgut invasion by multiple species of Plasmodium parasites via anchoring ookinetes to the peritrophic matrix and enabling parasites to penetrate the peritrophic matrix and the epithelium. Thus, targeting FREP1 can limit malaria transmission.
authors.affiliation: From the Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma 73019.
authors.forename: Genwei
authors.initials: G
authors.lastname: Zhang
authors.affiliation: From the Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma 73019.
authors.forename: Guodong
authors.initials: G
authors.lastname: Niu
authors.affiliation: From the Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma 73019.
authors.forename: Caio M
authors.initials: CM
authors.lastname: Franca
authors.affiliation: the W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205, and.
authors.forename: Yuemei
authors.initials: Y
authors.lastname: Dong
authors.affiliation: From the Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma 73019.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Wang
authors.affiliation: the Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104.
authors.forename: Noah S
authors.initials: NS
authors.lastname: Butler
authors.affiliation: the W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205, and.
authors.forename: George
authors.initials: G
authors.lastname: Dimopoulos
authors.affiliation: From the Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma 73019, junli@ou.edu.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D000852:Anopheles / Q000235:genetics / Q000254:growth & development / Q000378:metabolism* / Q000469:parasitology*; D004064:Digestive System / Q000378:metabolism / Q000469:parasitology; D005260:Female; D005340:Fibrinogen / Q000235:genetics / Q000378:metabolism*; D006790:Host-Parasite Interactions; D019476:Insect Proteins / Q000235:genetics / Q000378:metabolism*; D007303:Insect Vectors / Q000235:genetics / Q000254:growth & development / Q000378:metabolism* / Q000469:parasitology*; D008297:Male; D010963:Plasmodium falciparum / Q000502:physiology*
chemical_list: D019476:Insect Proteins; D005340:Fibrinogen
keywords: fibrinogen; host-pathogen interaction; insect; invasion; malaria; vaccine