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.
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.
|Baia-da-Silva, Djane Clarys; Alvarez, Luis Carlos Salazar; Lizcano, Omaira Vera et al. (2018) The role of the peritrophic matrix and red blood cell concentration in Plasmodium vivax infection of Anopheles aquasalis. Parasit Vectors 11:148|
|Wang, Sibao; Dos-Santos, André L A; Huang, Wei et al. (2017) Driving mosquito refractoriness to Plasmodium falciparum with engineered symbiotic bacteria. Science 357:1399-1402|
|Orfano, Alessandra S; Nacif-Pimenta, Rafael; Duarte, Ana P M et al. (2016) Species-specific escape of Plasmodium sporozoites from oocysts of avian, rodent, and human malarial parasites. Malar J 15:394|
|Goodman, Christopher D; Siregar, Josephine E; Mollard, Vanessa et al. (2016) Parasites resistant to the antimalarial atovaquone fail to transmit by mosquitoes. Science 352:349-53|
|McLean, Kyle Jarrod; Jacobs-Lorena, Marcelo (2016) Genetic Control Of Malaria Mosquitoes. Trends Parasitol 32:174-176|
|Ruiz, A; Pérez, D; Muñoz, M C et al. (2015) Targeting essential Eimeria ninakohlyakimovae sporozoite ligands for caprine host endothelial cell invasion with a phage display peptide library. Parasitol Res 114:4327-31|
|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|
|Smith, Ryan C; Jacobs-Lorena, Marcelo (2015) Malaria parasite Pfs47 disrupts JNK signaling to escape mosquito immunity. Proc Natl Acad Sci U S A 112:1250-1|
|Vega-Rodriguez, Joel; Perez-Barreto, Davinia; Ruiz-Reyes, Antonio et al. (2015) Targeting molecular interactions essential for Plasmodium sexual reproduction. Cell Microbiol 17:1594-604|
|Ferrer, Patricia; Vega-Rodriguez, Joel; Tripathi, Abhai K et al. (2015) Antimalarial iron chelator FBS0701 blocks transmission by Plasmodium falciparum gametocyte activation inhibition. Antimicrob Agents Chemother 59:1418-26|
Showing the most recent 10 out of 34 publications