Malaria continues to expand as a major public health threat throughout the world. The spread of drug resistant malaria and the lack of an effective vaccine make alternative and complementary approaches to malaria control increasingly important. The overall theme of this research program has been to develop mechanistic concepts of how to block malaria transmission by interfering with Plasmodium-mosquito molecular interactions within the mosquito midgut, particular at the ookinete-peritrophix matrix interface. The last project period showed that interfering with the function of Plasmodium chitinase(s) by antibody or chitinase gene deletion interfered with parasite infectivity for the mosquito. As part of ongoing efforts to continue delineating molecular mechanisms by which the Plasmodium ookinete invades the mosquito midgut we have identified a second P. gallinaceum ookinete-secreted chitinase, the only known ortholog of the P. falciparum chitinase, PfCHTI, and an ookinete-secreted plasmepsin, an aspartic protease that we hypothesize is involved working together with chitinase(s) to allow the ookinete to penetrate the peritrophic matrix within the mosquito midgut. The hypothesis underlying this application is that Plasmodium ookinetes secrete chitinases and plasmepsins that are both involved in invading the mosquito midgut, either additively or synergistically. This competitive renewal application has three specific aims: 1) To determine mechanisms by which the P. falciparum PfCHTI chitinase orthologue in P. gallinaceum, PgCHT2, facilitates ookinete penetration of the peritrophic matrix; 2) To identify the P. gallinaceum ookinete-produced protease that mediates activation of the P. gallinaceum chitinase PgCHT1; and 3) To determine the role of Plasmodium aspartic proteases (plasmepsins) in ookinete invasion1 of the mosquito midgut. This project will yield insight into basic biological processes of Plasmodium-mosquito midgut interactions, including the function of the P. falciparum chitinase, PfCHT1, and provide the scientific basis for developing novel potential approaches to interrupting malaria transmission at the vertebrate host-mosquito vector interface. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI045999-06A2
Application #
7033755
Study Section
Special Emphasis Panel (ZRG1-VB (01))
Program Officer
Rogers, Martin J
Project Start
2000-04-01
Project End
2011-01-31
Budget Start
2006-02-16
Budget End
2007-01-31
Support Year
6
Fiscal Year
2006
Total Cost
$380,891
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Gregory, James A; Li, Fengwu; Tomosada, Lauren M et al. (2012) Algae-produced Pfs25 elicits antibodies that inhibit malaria transmission. PLoS One 7:e37179
Patra, Kailash P; Vinetz, Joseph M (2012) New ultrastructural analysis of the invasive apparatus of the Plasmodium ookinete. Am J Trop Med Hyg 87:412-7
Isaacs, Alison T; Li, Fengwu; Jasinskiene, Nijole et al. (2011) Engineered resistance to Plasmodium falciparum development in transgenic Anopheles stephensi. PLoS Pathog 7:e1002017
Bounkeua, Viengngeun; Li, Fengwu; Chuquiyauri, Raul et al. (2011) Lack of molecular correlates of Plasmodium vivax ookinete development. Am J Trop Med Hyg 85:207-13
Bounkeua, Viengngeun; Li, Fengwu; Vinetz, Joseph M (2010) In vitro generation of Plasmodium falciparum ookinetes. Am J Trop Med Hyg 83:1187-94
Murai-Takeda, Ayano; Shibata, Hirotaka; Kurihara, Isao et al. (2010) NF-YC functions as a corepressor of agonist-bound mineralocorticoid receptor. J Biol Chem 285:8084-93
Li, Fengwu; Patra, Kailash P; Yowell, Charles A et al. (2010) Apical surface expression of aspartic protease Plasmepsin 4, a potential transmission-blocking target of the plasmodium ookinete. J Biol Chem 285:8076-83
McClean, Colleen M; Alvarado, Haydee Guerra; Neyra, Victor et al. (2010) Optimized in vitro production of Plasmodium vivax ookinetes. Am J Trop Med Hyg 83:1183-6
Takeo, Satoru; Hisamori, Daisuke; Matsuda, Shusaku et al. (2009) Enzymatic characterization of the Plasmodium vivax chitinase, a potential malaria transmission-blocking target. Parasitol Int 58:243-8
Bharti, Ajay R; Letendre, Scott L; Patra, Kailash P et al. (2009) Malaria diagnosis by a polymerase chain reaction-based assay using a pooling strategy. Am J Trop Med Hyg 81:754-7

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