title: Do malaria ookinete surface proteins P25 and P28 mediate parasite entry into mosquito midgut epithelial cells?
abstract: BACKGROUND
  P25 and P28 are related ookinete surface proteins highly conserved throughout the Plasmodium genus that are under consideration as candidates for inclusion in transmission-blocking vaccines. Previous research using transgenic rodent malaria parasites lacking P25 and P28 has demonstrated that these proteins have multiple partially redundant functions during parasite infection of the mosquito vector, including an undefined role in ookinete traversal of the mosquito midgut epithelium, and it has been suggested that, unlike wild-type parasites, Dko P25/P28 parasites migrate across the midgut epithelium via an intercellular, rather than intracellular, route.
  
  
  OBJECTIVE
  This paper presents an alternative interpretation for the previous observations of Dko P25/P28 parasites, based upon a recently published model of the route of ookinete invasion across the midgut epithelium. This model claims ookinete invasion is intracellular, with entry occurring through the lateral apical plasma membrane of midgut epithelial cells, and is associated with significant invagination of the midgut epithelium localised at the site of parasite penetration. Following this model, it is hypothesized that: (1) a sub-population of Dko P25/P28 ookinetes invaginate, but do not penetrate, the apical surface of the midgut epithelium and thus remain within the midgut lumen; and (2) another sub-population of Dko P25/P28 parasites successfully enters and migrates across the midgut epithelium via an intracellular route similar to wild-type parasites and subsequently develops into oocysts.
  
  
  METHODS
  These hypotheses are tested by showing how they can account for previously published observations and incorporate them into a coherent and consistent explanatory framework. Based upon these hypotheses, several quantitative predictions are made, which can be experimentally tested, about the relationship between the densities of invading Dko P25/P28 ookinetes in different regions of the midgut epithelium and the number of oocyst stage parasites to which these mutant ookinetes give rise.
  
  
  CONCLUSIONS
  The recently published model of ookinete invasion implies that Dko P25/P28 parasites are greatly, although not completely, impaired in their ability to enter the midgut epithelium. Therefore, P25 and/or P28 have a novel, previously unrecognized, function in mediating ookinete entry into midgut epithelial cells, suggesting that one mode of action of transmission-blocking antibodies to these ookinete surface proteins is to inhibit this function.
authors.affiliation: Division of Infection and Immunity, Institute of Biomedical and Life Sciences, Joseph Black Building, University of Glasgow, Glasgow, G12 8QQ, UK. 0003788b@student.gla.ac.uk
authors.forename: Luke A
authors.initials: LA
authors.lastname: Baton
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Ranford-Cartwright
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan / Q000502:physiology*; D000954:Antigens, Surface / Q000502:physiology*; D009033:Culicidae / Q000469:parasitology*; D004064:Digestive System / Q000469:parasitology; D005544:Forecasting; D006790:Host-Parasite Interactions / Q000502:physiology; D007303:Insect Vectors / Q000469:parasitology*; D007413:Intestinal Mucosa / Q000469:parasitology; D017780:Malaria Vaccines; D008954:Models, Biological; D010962:Plasmodium berghei / Q000502:physiology*; D015800:Protozoan Proteins / Q000502:physiology*
chemical_list: D000953:Antigens, Protozoan; D000954:Antigens, Surface; D017780:Malaria Vaccines; D015800:Protozoan Proteins; C121474:Pvs28 protein, P vivax; C067548:ookinete antigen P25, Plasmodium
references.citation: Proc Natl Acad Sci U S A. 1998 May 12;95(10):5700-5
references.pmid: 9576947
references.citation: Mol Med. 1998 Dec;4(12):772-82
references.pmid: 9990863
references.citation: Mol Biochem Parasitol. 1999 Jan 25;98(2):163-73
references.pmid: 10080386
references.citation: Proc Natl Acad Sci U S A. 2004 Nov 16;101(46):16310-5
references.pmid: 15520375
references.citation: Trends Parasitol. 2005 Jan;21(1):22-8
references.pmid: 15639737
references.citation: Parasitology. 2004 Dec;129(Pt 6):663-76
references.pmid: 15648689
references.citation: Cell Microbiol. 2005 Feb;7(2):181-90
references.pmid: 15659062
references.citation: Parasite Immunol. 1988 Mar;10(2):193-207
references.pmid: 2453831
references.citation: EMBO J. 1999 Nov 15;18(22):6221-7
references.pmid: 10562534
references.citation: Parasitology. 1999 Oct;119 ( Pt 4):331-6
references.pmid: 10581609
references.citation: J Cell Sci. 2000 Oct;113 Pt 19:3419-26
references.pmid: 10984433
references.citation: Mol Biochem Parasitol. 2000 Sep;110(1):147-59
references.pmid: 10989152
references.citation: Proc Natl Acad Sci U S A. 2000 Oct 10;97(21):11516-21
references.pmid: 11027351
references.citation: Mol Biochem Parasitol. 2000 Oct;110(2):429-34
references.pmid: 11071297
references.citation: EMBO J. 2000 Nov 15;19(22):6030-40
references.pmid: 11080150
references.citation: Infect Immun. 2000 Dec;68(12):6618-23
references.pmid: 11083773
references.citation: Mol Biochem Parasitol. 2001 Feb;112(2):229-37
references.pmid: 11223130
references.citation: Vaccine. 2001 Mar 21;19(17-19):2309-14
references.pmid: 11257353
references.citation: Mol Biochem Parasitol. 2001 Apr 6;113(2):341-4
references.pmid: 11295191
references.citation: EMBO J. 2001 Aug 1;20(15):3975-83
references.pmid: 11483501
references.citation: Int J Parasitol. 2002 Jan;32(1):91-8
references.pmid: 11796126
references.citation: Chem Immunol. 2002;80:287-307
references.pmid: 12058646
references.citation: Parasitol Int. 2003 Mar;52(1):1-11
references.pmid: 12543142
references.citation: J Biol Chem. 2003 Feb 7;278(6):4184-93
references.pmid: 12456678
references.citation: Cell. 2004 Mar 5;116(5):661-70
references.pmid: 15006349
references.citation: Cell Microbiol. 2004 Jul;6(7):671-85
references.pmid: 15186403
references.citation: Infect Immun. 1984 Sep;45(3):775-7
references.pmid: 6540756
references.citation: Mol Biochem Parasitol. 1984 Oct;13(2):235-41
references.pmid: 6151115
references.citation: Mol Biochem Parasitol. 1985 Feb;14(2):127-39
references.pmid: 4039406
references.citation: J Exp Med. 1985 Nov 1;162(5):1460-76
references.pmid: 2865324
references.citation: Mol Biochem Parasitol. 1986 Aug;20(2):155-63
references.pmid: 3528848
references.citation: Science. 1986 Oct 31;234(4776):607-10
references.pmid: 3532325
references.citation: Proc R Soc Lond B Biol Sci. 1987 May 22;230(1261):443-58
references.pmid: 2440053
references.citation: Parasitol Res. 1987;73(6):500-6
references.pmid: 3321042
references.citation: Nature. 1988 May 5;333(6168):74-6
references.pmid: 3283563
references.citation: J Parasitol. 1988 Jun;74(3):432-9
references.pmid: 3379524
references.citation: Mol Biochem Parasitol. 1989 Mar 15;33(3):283-7
references.pmid: 2468086
references.citation: Parasitol Res. 1989;76(1):13-9
references.pmid: 2695921
references.citation: Exp Parasitol. 1990 Aug;71(2):229-35
references.pmid: 2197114
references.citation: Mol Biochem Parasitol. 1990 Nov;43(1):143-5
references.pmid: 2290442
references.citation: Exp Parasitol. 1991 Feb;72(2):145-56
references.pmid: 2009919
references.citation: Parasitol Res. 1991;77(3):230-6
references.pmid: 2047369
references.citation: J Protozool. 1992 Jul-Aug;39(4):449-54
references.pmid: 1403980
references.citation: Parasite Immunol. 1992 Sep;14(5):471-9
references.pmid: 1437237
references.citation: J Exp Med. 1993 Feb 1;177(2):505-10
references.pmid: 8426118
references.citation: Mol Biochem Parasitol. 1993 Jun;59(2):263-75
references.pmid: 8341324
references.citation: J Eukaryot Microbiol. 1993 Sep-Oct;40(5):569-76
references.pmid: 8401470
references.citation: Parasitology. 1993 Sep;107 ( Pt 3):225-31
references.pmid: 8233585
references.citation: Exp Parasitol. 1994 May;78(3):326-30
references.pmid: 7909295
references.citation: Parasitology. 1994 Jul;109 ( Pt 1):11-7
references.pmid: 8058360
references.citation: Parasitology. 1994 Nov;109 ( Pt 4):403-11
references.pmid: 7800408
references.citation: Mol Biochem Parasitol. 1994 Dec;68(2):189-96
references.pmid: 7739665
references.citation: Mol Biochem Parasitol. 1994 Dec;68(2):259-66
references.pmid: 7739671
references.citation: Eur J Cell Biol. 1996 Nov;71(3):270-6
references.pmid: 8929565
references.citation: Infect Immun. 1997 Mar;65(3):1109-13
references.pmid: 9038325
references.citation: Int J Parasitol. 1997 Feb;27(2):183-9
references.pmid: 9088989
references.citation: Mol Biochem Parasitol. 1997 Mar;85(1):131-4
references.pmid: 9108555
references.citation: Infect Immun. 1997 Jun;65(6):2260-4
references.pmid: 9169761
references.citation: Mol Biochem Parasitol. 1997 Jul;87(1):107-11
references.pmid: 9233679