Among the three major infectious disease killers in the world - AIDS, tuberculosis and malaria - malaria is unique in that it requires an intermediate insect vector (the Anopheles mosquito) for transmission to occur. This absolute requirement provides novel opportunities to develop strategies to control the spread of disease. In the mosquito, a major bottleneck in parasite numbers occurs in the midgut, making the midgut stages of the parasite cycle especially vulnerable to interference. The goal of the present project is to define the molecular mechanisms operating during the Plasmodium ookinete invasion of the mosquito midgut.
The aims i nclude the following. 1) Further characterize the recently discovered plasminogen-mediated mechanism of ookinete midgut invasion. Key molecules involved in activation of plasminogen into active plasmin on the ookinete surface, will be further defined. In addition, luminal matrix components targeted by the ookinete-associated plasmin will be defined. 2) During the current project period we discovered that the 12-amino acid peptide MP2, binds tightly to the luminal surface of the mosquito midgut while blocking ookinete invasion. With the same strategy previously used for a different blocking peptide (SM1) we will identify the putative midgut receptor to which MP2 binds and identify the ookinete protein that interacts with this receptor. Characterization of this new parasite-mosquito pathway for midgut invasion might provide important new tools to interfere with malaria transmission. 3) We have previously found that the rodent malaria P. berghei can invade the mosquito midgut by more than one pathway, one that is sensitive to SM1 peptide blocking and the other that is not. We will investigate whether or not field isolates of the human parasites P. falciparum and P. vivax display differential sensitivities to inhibition by the SM1 and MP2 peptides. These findings may have important implications for the implementation of transmission-blocking strategies to control malaria.

Public Health Relevance

Successful development of the malaria parasite in its mosquito vector is an absolute requirement for the spread of disease. This project examines a critical step - parasite invasion of the mosquito midgut - that may provide the basis for the development of novel intervention approaches.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Vector Biology Study Section (VB)
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Costero, Adriana
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Johns Hopkins University
Schools of Public Health
United States
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Vega-Rodríguez, Joel; Ghosh, Anil K; Kanzok, Stefan M et al. (2014) Multiple pathways for Plasmodium ookinete invasion of the mosquito midgut. Proc Natl Acad Sci U S A 111:E492-500
Smith, Ryan C; Vega-Rodríguez, Joel; Jacobs-Lorena, Marcelo (2014) The Plasmodium bottleneck: malaria parasite losses in the mosquito vector. Mem Inst Oswaldo Cruz 0:
Wang, Sibao; Jacobs-Lorena, Marcelo (2013) Genetic approaches to interfere with malaria transmission by vector mosquitoes. Trends Biotechnol 31:185-93
Smith, Ryan C; Kizito, Christopher; Rasgon, Jason L et al. (2013) Transgenic mosquitoes expressing a phospholipase A(2) gene have a fitness advantage when fed Plasmodium falciparum-infected blood. PLoS One 8:e76097
Eappen, Abraham G; Smith, Ryan C; Jacobs-Lorena, Marcelo (2013) Enterobacter-activated mosquito immune responses to Plasmodium involve activation of SRPN6 in Anopheles stephensi. PLoS One 8:e62937
Hughes, Grant L; Vega-Rodriguez, Joel; Xue, Ping et al. (2012) Wolbachia strain wAlbB enhances infection by the rodent malaria parasite Plasmodium berghei in Anopheles gambiae mosquitoes. Appl Environ Microbiol 78:1491-5
Ghosh, Anil Kumar; Jacobs-Lorena, Marcelo (2011) Surface-expressed enolases of Plasmodium and other pathogens. Mem Inst Oswaldo Cruz 106 Suppl 1:85-90
Ghosh, Anil K; Coppens, Isabelle; Gardsvoll, Henrik et al. (2011) Plasmodium ookinetes coopt mammalian plasminogen to invade the mosquito midgut. Proc Natl Acad Sci U S A 108:17153-8
Ghosh, Anil K; Devenport, Martin; Jethwaney, Deepa et al. (2009) Malaria parasite invasion of the mosquito salivary gland requires interaction between the Plasmodium TRAP and the Anopheles saglin proteins. PLoS Pathog 5:e1000265
Ghosh, Anil Kumar; Jacobs-Lorena, Marcelo (2009) Plasmodium sporozoite invasion of the mosquito salivary gland. Curr Opin Microbiol 12:394-400

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