Rickettsial Immunity During Tick Transmission

Summary

Principal Investigator: JOAO PEDRA
Abstract: DESCRIPTION (provided by applicant): Prolonged feeding of ticks enables the transmission of several infectious agents to the mammalian host. Pathogen transmission by ticks is facilitated by the anti-inflammatory properties of tick saliva. While the extraordinary properties of tick saliva have been known for decades, the signaling mechanisms that lead to a more favorable environment for pathogen transmission remain elusive. The lack of such knowledge is problematic because it precludes the development of novel therapies for preventing infectious diseases. In this proposal, we will understand the complex interplay of a tick salivary protein, a pathogen and the vertebrate immune system. We hypothesize that sialostatin L2 - a tick salivary protein - modulates inflammasome activation and facilitates transmission of the rickettsial pathogen Anaplasma phagocytophilum to a mammalian host. The inflammasome promotes the maturation of inflammatory cytokines and is involved in host defense during infection. Our published and unpublished data show that the inflammasome is important for innate immunity against A. phagocytophilum. We also show that sialostatin L2 inhibits inflammasome activation. We will test our central hypothesis that sialostatin L2 facilitates transmission of the rickettsial pathogen A. phagocytophilum to a mammalian host by pursuing the following aims: (1) we will define signaling pathways that lead to inflammasome activation during A. phagocytophilum infection;and (2) we will characterize how sialostatin L2 inhibits inflammasome activation during tick transmission of A. phagocytophilum. The outcome of this proposal is significantly wide in scope. Ticks, mosquitoes, biting flies, fleas and blood feeding bugs have evolved salivary proteins to modulate host defense. Therefore, our findings may stimulate research into a diverse array of vector-host-pathogen associations resulting in new understandings of pathogenesis and immunity of vector-borne diseases. We envisage that deciphering how arthropod-borne pathogens colonize the mammalian host may lead to novel therapeutics against many arthropod borne diseases.
Funding Period: 2011-07-06 - 2016-06-30
more information: NIH RePORT

Top Publications

  1. pmc Tick salivary secretion as a source of antihemostatics
    Jindrich Chmelar
    Division of Vascular Inflammation, Diabetes and Kidney, Department of Medicine and Institute of Physiology, Technical University Dresden, 01307 Dresden, Germany
    J Proteomics 75:3842-54. 2012
  2. pmc Decoding the ubiquitin-mediated pathway of arthropod disease vectors
    Anthony Choy
    Institute for Integrative Genome Biology, Center for Disease Vector Research and Department of Entomology, University of California Riverside, Riverside, California, United States of America
    PLoS ONE 8:e78077. 2013
  3. pmc The E3 ubiquitin ligase XIAP restricts Anaplasma phagocytophilum colonization of Ixodes scapularis ticks
    Maiara S Severo
    Center for Disease Vector Research and Department of Entomology
    J Infect Dis 208:1830-40. 2013
  4. pmc The 'ubiquitous' reality of vector immunology
    Maiara S Severo
    Center for Disease Vector Research and Department of Entomology, University of California, Riverside, Riverside, CA 92521, USA
    Cell Microbiol 15:1070-8. 2013
  5. pmc Ixodes scapularis saliva mitigates inflammatory cytokine secretion during Anaplasma phagocytophilum stimulation of immune cells
    Gang Chen
    Center for Disease Vector Research and Department of Entomology, University of California Riverside, Riverside, CA 92521, USA
    Parasit Vectors 5:229. 2012
  6. pmc Anaplasma phagocytophilum dihydrolipoamide dehydrogenase 1 affects host-derived immunopathology during microbial colonization
    Gang Chen
    Department of Entomology and Center for Disease Vector Research, University of California Riverside, Riverside, California, USA
    Infect Immun 80:3194-205. 2012
  7. pmc Anaplasma phagocytophilum: deceptively simple or simply deceptive?
    Maiara S Severo
    Department of Entomology and Center for Disease Vector Research, 900 University Avenue, University of California Riverside, Riverside, CA 92521, USA
    Future Microbiol 7:719-31. 2012
  8. pmc The role of cystatins in tick physiology and blood feeding
    Alexandra Schwarz
    Laboratory of Genomics and Proteomics of Disease Vectors, Institute of Parasitology, Biology Centre, AS CR v v i, Ceske Budejovice, Czech Republic
    Ticks Tick Borne Dis 3:117-27. 2012
  9. pmc The Anopheles gambiae cE5, a tight- and fast-binding thrombin inhibitor with post-transcriptionally regulated salivary-restricted expression
    Raffaele Ronca
    Department of Structural and Functional Biology, Federico II University, Via Cinthia, 80126 Naples, Italy
    Insect Biochem Mol Biol 42:610-20. 2012
  10. pmc The tick salivary protein sialostatin L2 inhibits caspase-1-mediated inflammation during Anaplasma phagocytophilum infection
    Gang Chen
    Center for Disease Vector Research and Department of Entomology, University of California, Riverside, California, USA
    Infect Immun 82:2553-64. 2014

Detail Information

Publications11

  1. pmc Tick salivary secretion as a source of antihemostatics
    Jindrich Chmelar
    Division of Vascular Inflammation, Diabetes and Kidney, Department of Medicine and Institute of Physiology, Technical University Dresden, 01307 Dresden, Germany
    J Proteomics 75:3842-54. 2012
    ..The resulting knowledge can be exploited for the isolation of novel antihemostatic agents. Here we review the tick salivary antihemostatics and their characterized functions at the molecular and cellular levels...
  2. pmc Decoding the ubiquitin-mediated pathway of arthropod disease vectors
    Anthony Choy
    Institute for Integrative Genome Biology, Center for Disease Vector Research and Department of Entomology, University of California Riverside, Riverside, California, United States of America
    PLoS ONE 8:e78077. 2013
    ..Taken together, these findings provide novel opportunities to study the interaction between a pathogen and an arthropod vector...
  3. pmc The E3 ubiquitin ligase XIAP restricts Anaplasma phagocytophilum colonization of Ixodes scapularis ticks
    Maiara S Severo
    Center for Disease Vector Research and Department of Entomology
    J Infect Dis 208:1830-40. 2013
    ..Taken together, our data define a role for ubiquitination during bacterial colonization of disease vectors. ..
  4. pmc The 'ubiquitous' reality of vector immunology
    Maiara S Severo
    Center for Disease Vector Research and Department of Entomology, University of California, Riverside, Riverside, CA 92521, USA
    Cell Microbiol 15:1070-8. 2013
    ..We also discuss scientific gaps in the literature and suggest that, similar to mammals, ubiquitin is a major regulator of immunity in medically important arthropods...
  5. pmc Ixodes scapularis saliva mitigates inflammatory cytokine secretion during Anaplasma phagocytophilum stimulation of immune cells
    Gang Chen
    Center for Disease Vector Research and Department of Entomology, University of California Riverside, Riverside, CA 92521, USA
    Parasit Vectors 5:229. 2012
    ..However, how I. scapularis saliva influences host cytokine secretion in the presence of the obligate intracellular rickettsial pathogen Anaplasma phagocytophilum remains elusive...
  6. pmc Anaplasma phagocytophilum dihydrolipoamide dehydrogenase 1 affects host-derived immunopathology during microbial colonization
    Gang Chen
    Department of Entomology and Center for Disease Vector Research, University of California Riverside, Riverside, California, USA
    Infect Immun 80:3194-205. 2012
    ..Taken together, these findings suggest the presence of different signaling pathways in neutrophils and macrophages during A. phagocytophilum invasion and highlight the importance of LPDA1 as an immunopathological molecule...
  7. pmc Anaplasma phagocytophilum: deceptively simple or simply deceptive?
    Maiara S Severo
    Department of Entomology and Center for Disease Vector Research, 900 University Avenue, University of California Riverside, Riverside, CA 92521, USA
    Future Microbiol 7:719-31. 2012
    ..We also discuss current scientific gaps in the knowledge of A. phagocytophilum biology for the purpose of exchanging research perspectives...
  8. pmc The role of cystatins in tick physiology and blood feeding
    Alexandra Schwarz
    Laboratory of Genomics and Proteomics of Disease Vectors, Institute of Parasitology, Biology Centre, AS CR v v i, Ceske Budejovice, Czech Republic
    Ticks Tick Borne Dis 3:117-27. 2012
    ..Finally, all the biochemically analyzed tick cystatins are powerful protease inhibitors, and some may be novel antigens for developing anti-tick vaccines and drugs of medical importance due to their stringent target specificity...
  9. pmc The Anopheles gambiae cE5, a tight- and fast-binding thrombin inhibitor with post-transcriptionally regulated salivary-restricted expression
    Raffaele Ronca
    Department of Structural and Functional Biology, Federico II University, Via Cinthia, 80126 Naples, Italy
    Insect Biochem Mol Biol 42:610-20. 2012
    ....
  10. pmc The tick salivary protein sialostatin L2 inhibits caspase-1-mediated inflammation during Anaplasma phagocytophilum infection
    Gang Chen
    Center for Disease Vector Research and Department of Entomology, University of California, Riverside, California, USA
    Infect Immun 82:2553-64. 2014
    ..Altogether, our data expand the knowledge of immunoregulatory pathways of tick salivary proteins and unveil an important finding in inflammasome biology. ..

Research Grants30

  1. The Role of Mosquito Saliva in Chikungunya Virus Transmission and Dissemination
    Saravanan Thangamani; Fiscal Year: 2013
    ..The proposed work on an increasingly important pathogen, using innovative approaches and methodologies, represents a significant contribution to our knowledge base on this subject. ..
  2. 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. ..
  3. Endothelial Injury and Repair: CardioPulmonary Vascular Biology COBRE
    SHARON IRENE SMITH ROUNDS; Fiscal Year: 2013
    ..abstract_text> ..
  4. Pacific NorthWest Regional Center of Excellence (PNWRCE)
    Jay A Nelson; Fiscal Year: 2013
    ..pseudomallei host pathogen response during both the septicemic as well as the intracellular phases of the disease. ..
  5. Southeast Regional Centers of Excellence for Biodefense &Emerging Infectious Di
    Philip Frederick Sparling; Fiscal Year: 2013
    ..SERCEB brings new investigators to the biodefense effort through a combination of educational programs, support of innovative new projects, and the synergistic interactions among its world-class investigators. ..
  6. New England Regional Center of Excellence in Biodefense and Emerging Infectious D
    Dennis L Kasper; Fiscal Year: 2013
    ..NERCE will also continue its Developmental Projects program and Career Development in Biodefense program in an effort to initiate new research efforts and to attract new investigators to this field. ..
  7. Middle Atlantic Regional Center for Excellence for Biodefense and Emerging Infect
    MYRON MAX LEVINE; Fiscal Year: 2013
    ..abstract_text> ..
  8. Northeast Biodefense Center
    W Ian Lipkin; Fiscal Year: 2013
    ..As a Center based in a School of Public Health and a State Department of Health, the NBC has a firm commitment to and practical understanding of Emergency Preparedness. ..
  9. LIPID AND LIPOPROTEIN METABOLISM IN ATHEROSCLEROSIS
    Alan M Fogelman; Fiscal Year: 2013
    ..These six Projects will be supported by four cores and together will form a highly interactive and synergistic Program Project that is focused on lipid and lipoprotein metabolism in atherosclerosis. ..
  10. Molecular Analyses and Interventions for Biodefense and Emerging Pathogens
    Olaf Schneewind; Fiscal Year: 2013
    ..Research and training at the GLRCE is governed by a mechanism involving ongoing review of scientific excellence and translational goals, inter-institutional advisory boards and external scientific advisory bodies. ..
  11. Regulation of Mucosal Immunity by Pro- and Anti-inflammatory Salivary Defensins
    Michael E Selsted; Fiscal Year: 2013
    ..Taken together, these studies will provide new insights into the unique features of immunity in the oral cavity of rhesus monkeys, thereby guiding preclinical approaches to SIV and HIV vaccine development. ..
  12. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..