Structure and Function of the Circumsporozoite Protein

Summary

Principal Investigator: Photini Sinnis
Abstract: Plasmodium sporozoites make a remarkable journey from the mosquito midgut wall to the mammalian liver. It is the overall goal of this proposal to elucidate the role of the sporozoite's major surface protein, the circumsporozoite protein (CSP) in this journey. We have been studying the proteolytic processing of CSP and thus far, have found that processing occurs when sporozoites contact hepatocytes and is required for efficient invasion. Specifically, our data indicate that the amino-terminus of CSP masks the cell-adhesive domain in the carboxy-terminus and that proteolytic cleavage results in removal of the amino-terminus and exposure of this cell-adhesive domain. Overall our data suggest that CSP has two functional domains, each with distinct role(s) during the sporozoite's journey. The goal of this proposal is to continue our structure-function work on this important protein to define the role of each CSP domain in the mammalian host and to identify the protease responsible for CSP cleavage. The specific aims are: 1) To elucidate the phenotype of sporozoite mutants which expressed only the cleaved form of CSP in the dermis of the mammalian host. Using quantitative PCR, transcriptional profiling and confocal microscopy, we will determine whether N-terminal deletion mutants remain in the skin and begin their development there. 2) To determine the binding properties of each CSP domain by generating mutants in N-terminal residues that we have identified as having potential heparin-binding activity and using biochemical techniques to determine the binding partner of the TSR domain. 3) To identify the protease that cleaves CSP and determine its subcellular location in the sporozoite. These studies will be performed using conditional mutagenesis to delete candidate protease genes and using antisera to localize the proteases in sporozoites. Overall these studies will elucidate how CSP functions in the sporozoite[unreadable]s journey from mosquito to mammalian host and should open up new avenues for the control and prevention of malaria.
Funding Period: 2005-03-15 - 2015-02-28
more information: NIH RePORT

Top Publications

  1. pmc Transgenic Plasmodium berghei sporozoites expressing beta-galactosidase for quantification of sporozoite transmission
    Sabine Engelmann
    Department of Parasitology, Heidelberg University School of Medicine, INF 324, 69120 Heidelberg, Germany
    Mol Biochem Parasitol 146:30-7. 2006
  2. pmc What can we learn from an unnatural immune response?
    Brandy Lee Bennett
    Department of Medical Parasitology, New York University School of Medicine, New York, NY 10010, USA
    Trends Parasitol 26:319-21. 2010
  3. pmc The malaria circumsporozoite protein has two functional domains, each with distinct roles as sporozoites journey from mosquito to mammalian host
    Alida Coppi
    Department of Medical Parasitology, New York University School of Medicine, New York, NY 10010, USA
    J Exp Med 208:341-56. 2011
  4. pmc Evidence that mutant PfCRT facilitates the transmission to mosquitoes of chloroquine-treated Plasmodium gametocytes
    Andrea Ecker
    Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York 10032, USA
    J Infect Dis 203:228-36. 2011
  5. pmc Dendritic cells and hepatocytes use distinct pathways to process protective antigen from plasmodium in vivo
    Ian A Cockburn
    Johns Hopkins Malaria Research Institute and Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America
    PLoS Pathog 7:e1001318. 2011
  6. pmc Plasmodium protease ROM1 is important for proper formation of the parasitophorous vacuole
    Iset Medina Vera
    Departments of Medicine and of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, United States of America
    PLoS Pathog 7:e1002197. 2011
  7. pmc Extrahepatic exoerythrocytic forms of rodent malaria parasites at the site of inoculation: clearance after immunization, susceptibility to primaquine, and contribution to blood-stage infection
    Tatiana Voza
    Department of Medical Parasitology, New York University School of Medicine, New York, New York, USA
    Infect Immun 80:2158-64. 2012
  8. pmc Shedding of TRAP by a rhomboid protease from the malaria sporozoite surface is essential for gliding motility and sporozoite infectivity
    Ijeoma Ejigiri
    Department of Microbiology, New York University School of Medicine, New York, New York, United States of America
    PLoS Pathog 8:e1002725. 2012
  9. pmc Quantification of sporozoite invasion, migration, and development by microscopy and flow cytometry
    Photini Sinnis
    Department of Molecular Microbiology and Immunology, John Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
    Methods Mol Biol 923:385-400. 2013
  10. pmc The skin: where malaria infection and the host immune response begin
    Photini Sinnis
    Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
    Semin Immunopathol 34:787-92. 2012

Detail Information

Publications31

  1. pmc Transgenic Plasmodium berghei sporozoites expressing beta-galactosidase for quantification of sporozoite transmission
    Sabine Engelmann
    Department of Parasitology, Heidelberg University School of Medicine, INF 324, 69120 Heidelberg, Germany
    Mol Biochem Parasitol 146:30-7. 2006
    ..In addition, these sporozoites can be used to quantify sporozoites deposited in subcutaneous tissue during natural infection...
  2. pmc What can we learn from an unnatural immune response?
    Brandy Lee Bennett
    Department of Medical Parasitology, New York University School of Medicine, New York, NY 10010, USA
    Trends Parasitol 26:319-21. 2010
    ..Here we discuss some of these findings and highlight their importance to malaria vaccinology...
  3. pmc The malaria circumsporozoite protein has two functional domains, each with distinct roles as sporozoites journey from mosquito to mammalian host
    Alida Coppi
    Department of Medical Parasitology, New York University School of Medicine, New York, NY 10010, USA
    J Exp Med 208:341-56. 2011
    ..These data provide structure-function information relevant to malaria vaccine development...
  4. pmc Evidence that mutant PfCRT facilitates the transmission to mosquitoes of chloroquine-treated Plasmodium gametocytes
    Andrea Ecker
    Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York 10032, USA
    J Infect Dis 203:228-36. 2011
    ..Enhanced infectivity to mosquitoes may have been a key factor driving the worldwide spread of mutant pfcrt...
  5. pmc Dendritic cells and hepatocytes use distinct pathways to process protective antigen from plasmodium in vivo
    Ian A Cockburn
    Johns Hopkins Malaria Research Institute and Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America
    PLoS Pathog 7:e1001318. 2011
    ..Together, these results indicate that the presentation of epitopes to CD8+ T cells follows distinct pathways in DCs when the immune response is induced and in hepatocytes during the effector phase...
  6. pmc Plasmodium protease ROM1 is important for proper formation of the parasitophorous vacuole
    Iset Medina Vera
    Departments of Medicine and of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, United States of America
    PLoS Pathog 7:e1002197. 2011
    ..We propose a novel function for PyROM1 as a protease that promotes proper PV modification to allow parasite development and replication in a suitable environment within the mammalian host...
  7. pmc Extrahepatic exoerythrocytic forms of rodent malaria parasites at the site of inoculation: clearance after immunization, susceptibility to primaquine, and contribution to blood-stage infection
    Tatiana Voza
    Department of Medical Parasitology, New York University School of Medicine, New York, New York, USA
    Infect Immun 80:2158-64. 2012
    ..We took advantage of their resistance to primaquine to test whether they could initiate a blood-stage infection directly from the inoculation site, and our data indicate that these stages are not able to initiate malaria infection...
  8. pmc Shedding of TRAP by a rhomboid protease from the malaria sporozoite surface is essential for gliding motility and sporozoite infectivity
    Ijeoma Ejigiri
    Department of Microbiology, New York University School of Medicine, New York, New York, United States of America
    PLoS Pathog 8:e1002725. 2012
    ....
  9. pmc Quantification of sporozoite invasion, migration, and development by microscopy and flow cytometry
    Photini Sinnis
    Department of Molecular Microbiology and Immunology, John Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
    Methods Mol Biol 923:385-400. 2013
    ....
  10. pmc The skin: where malaria infection and the host immune response begin
    Photini Sinnis
    Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
    Semin Immunopathol 34:787-92. 2012
    ..The cellular, molecular, and immunological events that occur in the skin and associated lymph nodes are the topic of this review...
  11. pmc HIV nonnucleoside reverse transcriptase inhibitors and trimethoprim-sulfamethoxazole inhibit plasmodium liver stages
    Charlotte V Hobbs
    NIH NIAID Laboratory of Malaria Immunology and Vaccinology, Rockville, Maryland 20852, USA
    J Infect Dis 206:1706-14. 2012
    ....
  12. pmc Platelet factor 4 activity against P. falciparum and its translation to nonpeptidic mimics as antimalarials
    Melissa S Love
    Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA
    Cell Host Microbe 12:815-23. 2012
    ..Lead smHDPs also reduced parasitemia in a murine malaria model. Thus, identifying host molecules that control parasite growth can further the development of related molecules with therapeutic potential...
  13. pmc A host GPCR signaling network required for the cytolysis of infected cells facilitates release of apicomplexan parasites
    Melanie G Millholland
    Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
    Cell Host Microbe 13:15-28. 2013
    ..Importantly, an orally bioavailable PKC inhibitor prolonged survival in an experimental cerebral malaria model...
  14. pmc A key role for lipoic acid synthesis during Plasmodium liver stage development
    Brie Falkard
    Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY, USA
    Cell Microbiol 15:1585-604. 2013
    ..This study also highlights the potential of exploiting lipid metabolism pathways for the design of genetically attenuated sporozoite vaccines. ..
  15. pmc Structure-based design of novel small-molecule inhibitors of Plasmodium falciparum
    Sandhya Kortagere
    Center for Molecular Parasitology, Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, Pennsylvania, USA
    J Chem Inf Model 50:840-9. 2010
    ....
  16. pmc Plasmodium sporozoite-host interactions from the dermis to the hepatocyte
    Ijeoma Ejigiri
    Department of Medical Parasitology, New York University School of Medicine, New York, NY 10010, USA
    Curr Opin Microbiol 12:401-7. 2009
    ..Recent advances in our understanding of sporozoite biology in the dermal inoculation site, the role of cell traversal and the mechanism by which sporozoites productively invade hepatocytes will be highlighted in this review...
  17. pmc The fatty acid biosynthesis enzyme FabI plays a key role in the development of liver-stage malarial parasites
    Min Yu
    Department of Microbiology, Columbia University, New York, NY 10032, USA
    Cell Host Microbe 4:567-78. 2008
    ..These data illuminate key differences between liver- and blood-stage parasites in their requirements for host versus de novo synthesized fatty acids, and create new prospects for stage-specific antimalarial interventions...
  18. pmc Antimalarial activity of allicin, a biologically active compound from garlic cloves
    Alida Coppi
    Department of Medical Parasitology, New York University School of Medicine, 341 East 25th Street, New York, NY 10010, USA
    Antimicrob Agents Chemother 50:1731-7. 2006
    ..Together, these experiments demonstrate that the same cysteine protease inhibitor can target two different life cycle stages in the vertebrate host...
  19. pmc Plasmodium sporozoites trickle out of the injection site
    Lucy Megumi Yamauchi
    Department of Medical Parasitology, New York University School of Medicine, 341 East 25th Street, New York, NY 10010, USA
    Cell Microbiol 9:1215-22. 2007
    ..These findings indicate that there is ample time for host and parasite to interact at the inoculation site and are of relevance to the pre-erythrocytic stage malaria vaccine effort...
  20. pmc Furuncular myiasis caused by Dermatobia hominis in a returning traveler
    Ramanath Bhandari
    Department of Medical Parasitology, New York University School of Medicine, New York, New York 10010, USA
    Am J Trop Med Hyg 76:598-9. 2007
    ..The case is unique because the primary care physician obtained magnetic resonance images. The images, however, do not show any characteristic features that assist in diagnosis...
  21. pmc A long and winding road: the Plasmodium sporozoite's journey in the mammalian host
    Photini Sinnis
    Department of Medical Parasitology, New York University School of Medicine, 341 East 25th Street, New York, NY 10010, United States
    Parasitol Int 56:171-8. 2007
    ..Here we review our current knowledge of the molecular and cellular basis of this journey, which begins in the skin and ends in the hepatocyte...
  22. pmc Mosquito heparan sulfate and its potential role in malaria infection and transmission
    Photini Sinnis
    Department of Medical Parasitology, New York University School of Medicine, New York, New York 10010, USA
    J Biol Chem 282:25376-84. 2007
    ..The heparan sulfate isolated from the whole mosquito binds to circumsporozoite protein, suggesting a role within the mosquito for infection and transmission of the Plasmodium parasite...
  23. ncbi Apolipoprotein E-derived antimicrobial peptide analogues with altered membrane affinity and increased potency and breadth of activity
    Bridie A Kelly
    Faculty of Life Sciences, The Mill, The University of Manchester, UK
    FEBS J 274:4511-25. 2007
    ....
  24. pmc Heparan sulfate proteoglycans provide a signal to Plasmodium sporozoites to stop migrating and productively invade host cells
    Alida Coppi
    Department of Medical Parasitology, 341 East 25th Street, New York University School of Medicine, New York, NY 10010, USA
    Cell Host Microbe 2:316-27. 2007
    ..These findings explain how sporozoites retain their infectivity for an organ that is far from their site of entry...
  25. pmc The Plasmodium TRAP/MIC2 family member, TRAP-Like Protein (TLP), is involved in tissue traversal by sporozoites
    Cristina K Moreira
    Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10021, USA
    Cell Microbiol 10:1505-16. 2008
    ..These results indicate a role of TLP in cell traversal by sporozoites...
  26. pmc High mobility group protein HMGB2 is a critical regulator of plasmodium oocyst development
    Mathieu Gissot
    Department of Medicine and of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461, USA
    J Biol Chem 283:17030-8. 2008
    ..Therefore, sexual stage protein expression appears to be both transcriptionally and translationally regulated with Plasmodium HMGB2 acting as an important regulator of malaria sexual stage gene expression...
  27. ncbi The skin stage of malaria infection: biology and relevance to the malaria vaccine effort
    Photini Sinnis
    Department of Medical Parasitology, New York University School of Medicine, 341 East 25th Street, New York, NY 10010, USA
    Future Microbiol 3:275-8. 2008
    ....
  28. pmc Attenuated Plasmodium yoelii lacking purine nucleoside phosphorylase confer protective immunity
    Li Min Ting
    Department of Medicine and Microbiology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA
    Nat Med 14:954-8. 2008
    ..They also suggest a strategy for the development of attenuated nontransmissible metabolic mutants as blood-stage malaria vaccine strains...
  29. pmc HIV protease inhibitors inhibit the development of preerythrocytic-stage plasmodium parasites
    Charlotte V Hobbs
    NYU School of Medicine, Dept of Pediatrics, Div of Infectious Disease, 550 First Ave, 8W New Bellevue, NY, NY 10010, USA
    J Infect Dis 199:134-41. 2009
    ..We found that lopinavir/ritonavir had a dose-dependent effect on liver-stage parasite development. Given that sub-Saharan Africa is where the HIV/AIDS pandemic intersects with malaria, these results merit analysis in clinical settings...
  30. ncbi Vaccination with live Plasmodium yoelii blood stage parasites under chloroquine cover induces cross-stage immunity against malaria liver stage
    Elodie Belnoue
    Department of Immunology, Centre National de la Recherche Scientifique, Institut Cochin, Universite Paris Descartes, Paris, France
    J Immunol 181:8552-8. 2008
    ....
  31. doi Model for In Vivo Assessment of Humoral Protection against Malaria Sporozoite Challenge by Passive Transfer of Monoclonal Antibodies and Immune Serum
    Brandon K Sack
    Seattle Biomedical Research Institute, Seattle, Washington, USA
    Infect Immun 82:808-17. 2014
    ..falciparum challenge model. Together, these models constitute unique and sensitive in vivo methods to assess serum-transferable protection against Plasmodium sporozoite challenge. ..

Research Grants30

  1. Molecular Analysis of the PfEMP1 Binding Activity
    JOSEPH DOUGLAS SMITH; Fiscal Year: 2013
    ..These studies will contribute to a detail characterization of the cytoadhesive properties of P. falciparum infected erythrocytes and enable a greater understanding of the molecular basis of malaria pathogenesis. ..
  2. An Effector Memory T Cell-Inducing Subunit Vaccine against Malaria
    Klaus J Früh; Fiscal Year: 2013
    ..knowlesi sporozoites. Upon completion of this exploratory project, we will thus know whether a TEM-inducing vaccine can improve the level and duration of sterilizing immunity induced by subunit vaccines against malaria parasites. ..
  3. Comparative Biology of Tissue Repair, Regeneration and Aging
    Kevin Strange; Fiscal Year: 2013
    ..The proposed COBRE will greatly enhance MDIBL's growth and development, which in turn will contribute to the continued growth and enhancement of the biomedical research infrastructure in Maine. ..
  4. Endothelial Injury and Repair: CardioPulmonary Vascular Biology COBRE
    SHARON IRENE SMITH ROUNDS; Fiscal Year: 2013
    ..abstract_text> ..