Do malaria ookinete surface proteins P25 and P28 mediate parasite entry into mosquito midgut epithelial cells?
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.
Baton
Luke A
LA
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
Ranford-Cartwright
Lisa C
LC
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*
D000953:Antigens, Protozoan; D000954:Antigens, Surface; D017780:Malaria Vaccines; D015800:Protozoan Proteins; C121474:Pvs28 protein, P vivax; C067548:ookinete antigen P25, Plasmodium
Proc Natl Acad Sci U S A. 1998 May 12;95(10):5700-5
9576947
Mol Med. 1998 Dec;4(12):772-82
9990863
Mol Biochem Parasitol. 1999 Jan 25;98(2):163-73
10080386
Proc Natl Acad Sci U S A. 2004 Nov 16;101(46):16310-5
15520375
Trends Parasitol. 2005 Jan;21(1):22-8
15639737
Parasitology. 2004 Dec;129(Pt 6):663-76
15648689
Cell Microbiol. 2005 Feb;7(2):181-90
15659062
Parasite Immunol. 1988 Mar;10(2):193-207
2453831
EMBO J. 1999 Nov 15;18(22):6221-7
10562534
Parasitology. 1999 Oct;119 ( Pt 4):331-6
10581609
J Cell Sci. 2000 Oct;113 Pt 19:3419-26
10984433
Mol Biochem Parasitol. 2000 Sep;110(1):147-59
10989152
Proc Natl Acad Sci U S A. 2000 Oct 10;97(21):11516-21
11027351
Mol Biochem Parasitol. 2000 Oct;110(2):429-34
11071297
EMBO J. 2000 Nov 15;19(22):6030-40
11080150
Infect Immun. 2000 Dec;68(12):6618-23
11083773
Mol Biochem Parasitol. 2001 Feb;112(2):229-37
11223130
Vaccine. 2001 Mar 21;19(17-19):2309-14
11257353
Mol Biochem Parasitol. 2001 Apr 6;113(2):341-4
11295191
EMBO J. 2001 Aug 1;20(15):3975-83
11483501
Int J Parasitol. 2002 Jan;32(1):91-8
11796126
Chem Immunol. 2002;80:287-307
12058646
Parasitol Int. 2003 Mar;52(1):1-11
12543142
J Biol Chem. 2003 Feb 7;278(6):4184-93
12456678
Cell. 2004 Mar 5;116(5):661-70
15006349
Cell Microbiol. 2004 Jul;6(7):671-85
15186403
Infect Immun. 1984 Sep;45(3):775-7
6540756
Mol Biochem Parasitol. 1984 Oct;13(2):235-41
6151115
Mol Biochem Parasitol. 1985 Feb;14(2):127-39
4039406
J Exp Med. 1985 Nov 1;162(5):1460-76
2865324
Mol Biochem Parasitol. 1986 Aug;20(2):155-63
3528848
Science. 1986 Oct 31;234(4776):607-10
3532325
Proc R Soc Lond B Biol Sci. 1987 May 22;230(1261):443-58
2440053
Parasitol Res. 1987;73(6):500-6
3321042
Nature. 1988 May 5;333(6168):74-6
3283563
J Parasitol. 1988 Jun;74(3):432-9
3379524
Mol Biochem Parasitol. 1989 Mar 15;33(3):283-7
2468086
Parasitol Res. 1989;76(1):13-9
2695921
Exp Parasitol. 1990 Aug;71(2):229-35
2197114
Mol Biochem Parasitol. 1990 Nov;43(1):143-5
2290442
Exp Parasitol. 1991 Feb;72(2):145-56
2009919
Parasitol Res. 1991;77(3):230-6
2047369
J Protozool. 1992 Jul-Aug;39(4):449-54
1403980
Parasite Immunol. 1992 Sep;14(5):471-9
1437237
J Exp Med. 1993 Feb 1;177(2):505-10
8426118
Mol Biochem Parasitol. 1993 Jun;59(2):263-75
8341324
J Eukaryot Microbiol. 1993 Sep-Oct;40(5):569-76
8401470
Parasitology. 1993 Sep;107 ( Pt 3):225-31
8233585
Exp Parasitol. 1994 May;78(3):326-30
7909295
Parasitology. 1994 Jul;109 ( Pt 1):11-7
8058360
Parasitology. 1994 Nov;109 ( Pt 4):403-11
7800408
Mol Biochem Parasitol. 1994 Dec;68(2):189-96
7739665
Mol Biochem Parasitol. 1994 Dec;68(2):259-66
7739671
Eur J Cell Biol. 1996 Nov;71(3):270-6
8929565
Infect Immun. 1997 Mar;65(3):1109-13
9038325
Int J Parasitol. 1997 Feb;27(2):183-9
9088989
Mol Biochem Parasitol. 1997 Mar;85(1):131-4
9108555
Infect Immun. 1997 Jun;65(6):2260-4
9169761
Mol Biochem Parasitol. 1997 Jul;87(1):107-11
9233679