Malaria kills an estimated 1-2 million people (mostly children) every year. For transmission to occur, Plasmodium, the causative agent of malaria, has to complete a complex developmental cycle in the mosquito. Only a small proportion of the parasites survive the entire cycle. Thus, the mosquito is a potential weak link that can be exploited for disease control. Invasion of the mosquito midgut by Plasmodium ookinetes is a crucial step, yet little is known about the molecular mechanisms that operate at this stage. We made two unexpected observations during the current grant period: 1) The surface of Plasmodium ookinetes (the form that invades the midgut) is lined with an enolase-like protein and 2) ookinetes can invade the midgut by more than one pathway, one that can be blocked by the SM1 peptide and another that cannot.
One aim of this proposal is to investigate, at the molecular level, the mechanism of midgut invasion.
Our first aim will address the following working hypothesis. Enolase expressed on the surface of midgut ookinetes captures plasminogen from the surrounding blood meal. A mosquito type II annexin on the surface of the midgut epithelium binds to both tissue type plasminogen activator (tPA) from the blood meal and to ookinete surface enolase. We hypothesize that this bridge facilitates both ookinete docking to the surface of the midgut epithelium and tPA activation of plasminogen into plasmin (a protease). The combination of these two separate but intimately entwined events results in successul midgut invasion.
Our second aim i s to identify P. berghei ookinete genes that are responsible for the different invasion pathways. This is the first comprehensive study of the mechanisms of Plasmodium invasion of the midgut epithelium. Knowledge generated by these studies may have important implications for the development of multivalent transmission-blocking vaccines.

Public Health Relevance

Malaria, AIDS and tuberculosis are three infectious diseases that cause the largest numbers of deaths worldwide. Of these, only malaria requires an intermediate vector for transmission to occur. Therefore, the mosquito vector is a potential weak point in the transmission cycle. A better understanding of parasite development in the mosquito may translate in the discovery of new strategies to fight this deadly disease.

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
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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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