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 successful 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI031478-19
Application #
7992411
Study Section
Vector Biology Study Section (VB)
Program Officer
Costero, Adriana
Project Start
1991-08-01
Project End
2013-11-30
Budget Start
2010-12-01
Budget End
2011-11-30
Support Year
19
Fiscal Year
2011
Total Cost
$488,435
Indirect Cost
Name
Johns Hopkins University
Department
Microbiology/Immun/Virology
Type
Schools of Public Health
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Smith, Ryan C; Barillas-Mury, Carolina; Jacobs-Lorena, Marcelo (2015) Hemocyte differentiation mediates the mosquito late-phase immune response against Plasmodium in Anopheles gambiae. Proc Natl Acad Sci U S A 112:E3412-20
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 109:644-61

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