Mechanisms of mosquito midgut invasion by Plasmodium ookinetes

Summary

Principal Investigator: Marcelo Jacobs-Lorena
Abstract: ABSTRACT 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 is 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.
Funding Period: 1991-08-01 - 2013-11-30
more information: NIH RePORT

Top Publications

  1. pmc Effect of the antimicrobial peptide gomesin against different life stages of Plasmodium spp
    Cristina K Moreira
    Department of Molecular Microbiology, John Hopkins Bloomberg School of Public Health, Malaria Research Institute, 615 North Wolfe Street, Baltimore, MD 21205, USA
    Exp Parasitol 116:346-53. 2007
  2. pmc Multiple pathways for Plasmodium ookinete invasion of the mosquito midgut
    JOEL VEGA-RODRIGUEZ
    The W Harry Feinstone Department of Molecular Microbiology and Immunology, Malaria Research Institute, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205
    Proc Natl Acad Sci U S A 111:E492-500. 2014
  3. pmc Transgenic mosquitoes expressing a phospholipase A(2) gene have a fitness advantage when fed Plasmodium falciparum-infected blood
    Ryan C Smith
    Department of Molecular Microbiology and Immunology, Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America
    PLoS ONE 8:e76097. 2013
  4. pmc Enterobacter-activated mosquito immune responses to Plasmodium involve activation of SRPN6 in Anopheles stephensi
    Abraham G Eappen
    Department of Molecular Microbiology and Immunology, Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America
    PLoS ONE 8:e62937. 2013
  5. pmc Genetic approaches to interfere with malaria transmission by vector mosquitoes
    Sibao Wang
    Key Laboratory of Insect Developmental and Evolutionary Biology, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200032, China
    Trends Biotechnol 31:185-93. 2013
  6. pmc Regulation of anti-Plasmodium immunity by a LITAF-like transcription factor in the malaria vector Anopheles gambiae
    Ryan C Smith
    Department of Molecular Microbiology and Immunology, Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
    PLoS Pathog 8:e1002965. 2012
  7. pmc Wolbachia strain wAlbB enhances infection by the rodent malaria parasite Plasmodium berghei in Anopheles gambiae mosquitoes
    Grant L Hughes
    Department of Entomology, The Pennsylvania State University, University Park, PA, USA
    Appl Environ Microbiol 78:1491-5. 2012
  8. pmc Plasmodium ookinetes coopt mammalian plasminogen to invade the mosquito midgut
    Anil K Ghosh
    Department of Molecular Microbiology and Immunology, Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
    Proc Natl Acad Sci U S A 108:17153-8. 2011
  9. pmc Surface-expressed enolases of Plasmodium and other pathogens
    Anil Kumar Ghosh
    Department of Molecular Microbiology and Immunology, Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe Street, Baltimore, MD 21205, USA
    Mem Inst Oswaldo Cruz 106:85-90. 2011
  10. pmc Plasmodium sporozoite invasion of the mosquito salivary gland
    Anil Kumar Ghosh
    Johns Hopkins Bloomberg School of Public Health, Department of Molecular Microbiology and Immunology, Baltimore, MD 21205, USA
    Curr Opin Microbiol 12:394-400. 2009

Research Grants

Detail Information

Publications17

  1. pmc Effect of the antimicrobial peptide gomesin against different life stages of Plasmodium spp
    Cristina K Moreira
    Department of Molecular Microbiology, John Hopkins Bloomberg School of Public Health, Malaria Research Institute, 615 North Wolfe Street, Baltimore, MD 21205, USA
    Exp Parasitol 116:346-53. 2007
    ..These properties make gomesin an excellent candidate as a transmission blocking agent for the genetic engineering of mosquitoes...
  2. pmc Multiple pathways for Plasmodium ookinete invasion of the mosquito midgut
    JOEL VEGA-RODRIGUEZ
    The W Harry Feinstone Department of Molecular Microbiology and Immunology, Malaria Research Institute, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205
    Proc Natl Acad Sci U S A 111:E492-500. 2014
    ..berghei (SM1-sensitive and SM1-resistant) and Plasmodium falciparum ookinetes, suggesting that MP2 binds to a separate, universal receptor for midgut invasion. ..
  3. pmc Transgenic mosquitoes expressing a phospholipase A(2) gene have a fitness advantage when fed Plasmodium falciparum-infected blood
    Ryan C Smith
    Department of Molecular Microbiology and Immunology, Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America
    PLoS ONE 8:e76097. 2013
    ..In recent years, several proof-of-principle experiments have been performed that validate the idea that mosquitoes can be genetically modified to become refractory to malaria parasite development...
  4. pmc Enterobacter-activated mosquito immune responses to Plasmodium involve activation of SRPN6 in Anopheles stephensi
    Abraham G Eappen
    Department of Molecular Microbiology and Immunology, Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America
    PLoS ONE 8:e62937. 2013
    ..We conclude that AsSRPN6 is a vital component of the E. cloacae-mediated immune response that restricts Plasmodium development in the mosquito An. stephensi...
  5. pmc Genetic approaches to interfere with malaria transmission by vector mosquitoes
    Sibao Wang
    Key Laboratory of Insect Developmental and Evolutionary Biology, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200032, China
    Trends Biotechnol 31:185-93. 2013
    ..Here we consider both genetic manipulation strategies for rendering mosquitoes refractory to Plasmodium infection, and discuss challenges for the translation of laboratory findings to field applications...
  6. pmc Regulation of anti-Plasmodium immunity by a LITAF-like transcription factor in the malaria vector Anopheles gambiae
    Ryan C Smith
    Department of Molecular Microbiology and Immunology, Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
    PLoS Pathog 8:e1002965. 2012
    ..We conclude that LL3 is a transcription factor capable of modulating SRPN6 expression as part of the mosquito anti-Plasmodium immune response...
  7. pmc Wolbachia strain wAlbB enhances infection by the rodent malaria parasite Plasmodium berghei in Anopheles gambiae mosquitoes
    Grant L Hughes
    Department of Entomology, The Pennsylvania State University, University Park, PA, USA
    Appl Environ Microbiol 78:1491-5. 2012
    ....
  8. pmc Plasmodium ookinetes coopt mammalian plasminogen to invade the mosquito midgut
    Anil K Ghosh
    Department of Molecular Microbiology and Immunology, Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
    Proc Natl Acad Sci U S A 108:17153-8. 2011
    ....
  9. pmc Surface-expressed enolases of Plasmodium and other pathogens
    Anil Kumar Ghosh
    Department of Molecular Microbiology and Immunology, Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe Street, Baltimore, MD 21205, USA
    Mem Inst Oswaldo Cruz 106:85-90. 2011
    ..The therapeutic potential of targeting surface enolases of pathogens is discussed...
  10. pmc Plasmodium sporozoite invasion of the mosquito salivary gland
    Anil Kumar Ghosh
    Johns Hopkins Bloomberg School of Public Health, Department of Molecular Microbiology and Immunology, Baltimore, MD 21205, USA
    Curr Opin Microbiol 12:394-400. 2009
    ..Here we review recent progress towards the elucidation of invasion mechanisms...
  11. pmc Malaria parasite invasion of the mosquito salivary gland requires interaction between the Plasmodium TRAP and the Anopheles saglin proteins
    Anil K Ghosh
    Department of Molecular Microbiology and Immunology and Malaria Research Institute, Johns Hopkins School of Public Health, Baltimore, Maryland, United States of America
    PLoS Pathog 5:e1000265. 2009
    ..Together, the results suggest that saglin/TRAP interaction is crucial for salivary gland invasion by Plasmodium sporozoites...
  12. pmc Fitness of transgenic Anopheles stephensi mosquitoes expressing the SM1 peptide under the control of a vitellogenin promoter
    Chaoyang Li
    Johns Hopkins University, Bloomberg School of Public Health, Department of Molecular Microbiology and Immunology and Malaria Research Institute, 615 North Wolfe Street, Baltimore MD 21205, USA
    J Hered 99:275-82. 2008
    ..Thus, for transgenic mosquitoes released in the field to be effective in reducing malaria transmission, a driving mechanism will be required...
  13. pmc PbCap380, a novel oocyst capsule protein, is essential for malaria parasite survival in the mosquito
    Prakash Srinivasan
    Malaria Research Institute, Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, MD 20852, USA
    Cell Microbiol 10:1304-12. 2008
    ..As a result, mosquitoes infected with PbCap380(-) parasites do not transmit malaria. Targeting of the oocyst capsule may provide a new strategy for malaria control...
  14. pmc Plasmodium falciparum ookinetes require mosquito midgut chondroitin sulfate proteoglycans for cell invasion
    Rhoel R Dinglasan
    Department of Molecular Microbiology and Immunology, Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Baltimore, MD 21205, USA
    Proc Natl Acad Sci U S A 104:15882-7. 2007
    ..We provide evidence for the in vivo role of chondroitin sulfate proteoglycans in Plasmodium falciparum invasion of the midgut and insight into the molecular mechanisms mediating parasite-mosquito interactions...
  15. pmc Disruption of Plasmodium falciparum development by antibodies against a conserved mosquito midgut antigen
    Rhoel R Dinglasan
    Department of Molecular Microbiology and Immunology, Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Baltimore, MD 21205, USA
    Proc Natl Acad Sci U S A 104:13461-6. 2007
    ..These results advance our understanding of malaria parasite-mosquito host interactions and guide in the design of transmission-blocking vaccines...
  16. pmc Induction of actin gene expression in the mosquito midgut by blood ingestion correlates with striking changes of cell shape
    Ann Sodja
    Department of Biological Sciences, Wayne State University, Detroit, MI 48202, USA
    J Insect Physiol 53:833-9. 2007
    ..These changes correlate with the large increase of epithelial surface area needed to accommodate the blood meal. Actin gene expression, actin synthesis and cell morphology all return to the pre-feeding state by 24 h after blood intake...

Research Grants30

  1. New infection-related proteins of Plasmodium sporozoites and liver stages
    Stefan H I Kappe; Fiscal Year: 2013
    ..Identifying major liver stage-host hepatocyte interactions and elucidating their functional significance will reveal fundamental principles of malaria parasite liver infection and provide new avenues for preventive drug design. ..