Antigenic variation in rickettsial transmission

Summary

Principal Investigator: Guy Palmer
Abstract: The goals of the proposed research are to identify the epitope specificity and affinity required for immune control of antigenically-variant bacteria during acute and persistent infection and to determine whether this immune response is responsible for restricting pathogen genetic diversity in the mammalian reservoir host. This research addresses a fundamental gap in knowledge regarding control of bacterial pathogens in which the immune response is directed against both conserved and variable epitopes of outer membrane proteins. Tick-transmitted pathogens in the Family Anaplasmataceae (Order: Rickettsiales) cause acute febrile illness in animals and humans. During acute infection, cell-associated bacteremia reaches high, microscopically detectable levels and results in systemic disease. Importantly, ticks that feed on the mammalian host during this period of high-level bacteremia efficiently acquire the pathogen. Resolution of the acute high-level bacteremia requires CD4+ T lymphocytes and is associated with secretion of IFN-gamma and induction of neutralizing antibodies. This response does not completely clear the pathogen but the consequent persistent infection is controlled at low levels and the efficiency with which feeding ticks acquire the pathogen drops markedly. While studies have shown that persistence of Anaplasma spp. reflects emergence of organisms expressing structural and antigenic variants of the immunodominant outer membrane protein MSP2, how the immune response effectively controls the pathogen to low levels in face of this variation is unknown. In part 1 of the project, the epitope specificity and affinity of MSP2-specific CD4+ T cells associated with control of acute high-level bacteremia will be determined and whether induction of these responses prevents high-level bacteremia will be tested. In part 2, the epidemiological consequences of the gene conversion mechanism used to generate MSP2 variants and the effect of differential selection in the mammalian host versus tick vector will be examined. The generation of numerous complex MSP2 variants during infection of the mammalian host and the resulting immune responses are proposed to prevent tick-transmitted superinfection and thus restrict pathogen genotypic diversity. This hypothesis will be addressed using comprehensive identification of the variant population in the reservoir host and tick vector and testing whether immune responses against a broad array of variants prevents superinfection.
Funding Period: 1998-12-01 - 2008-11-30
more information: NIH RePORT

Top Publications

  1. ncbi Insights into mechanisms of bacterial antigenic variation derived from the complete genome sequence of Anaplasma marginale
    Guy H Palmer
    Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA 99164 7040, USA
    Ann N Y Acad Sci 1078:15-25. 2006
  2. pmc Anaplasma marginale infection with persistent high-load bacteremia induces a dysfunctional memory CD4+ T lymphocyte response but sustained high IgG titers
    Sushan Han
    Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA 99164 7040, USA
    Clin Vaccine Immunol 17:1881-90. 2010
  3. pmc Association of pathogen strain-specific gene transcription and transmission efficiency phenotype of Anaplasma marginale
    Joseph T Agnes
    Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA 99164 7040, USA
    Infect Immun 78:2446-53. 2010
  4. pmc Complete genome sequence of Anaplasma marginale subsp. centrale
    David R Herndon
    Animal Diseases Research Unit, Agricultural Research Service, U S Department of Agriculture, Pullman, Washington 99164, USA
    J Bacteriol 192:379-80. 2010
  5. pmc Identification of Anaplasma marginale type IV secretion system effector proteins
    Svetlana Lockwood
    School of Electrical Engineering and Computer Science, Washington State University, Pullman, Washington, United States of America
    PLoS ONE 6:e27724. 2011
  6. pmc Identification of Anaplasma marginale outer membrane protein antigens conserved between A. marginale sensu stricto strains and the live A. marginale subsp. centrale vaccine
    Joseph T Agnes
    Program in Vector Borne Diseases, Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA 99164 7040, USA
    Infect Immun 79:1311-8. 2011
  7. pmc Stability and tick transmission phenotype of gfp-transformed Anaplasma marginale through a complete in vivo infection cycle
    Susan M Noh
    Animal Disease Research Unit, Agriculture Research Service, US Department of Agriculture, Pullman, WA 99164 7030, USA
    Appl Environ Microbiol 77:330-4. 2011
  8. pmc Dermacentor andersoni transmission of Francisella tularensis subsp. novicida reflects bacterial colonization, dissemination, and replication coordinated with tick feeding
    Kathryn E Reif
    Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA 99164 7040, USA
    Infect Immun 79:4941-6. 2011
  9. pmc Expression of Anaplasma marginale ankyrin repeat-containing proteins during infection of the mammalian host and tick vector
    Solomon S Ramabu
    Department of Veterinary Microbiology and Pathology, and The Paul G Allen School for Global Animal Health, Washington State University, Pullman, Washington 99164 7040, USA
    Infect Immun 79:2847-55. 2011
  10. pmc Genome-wide screening and identification of antigens for rickettsial vaccine development
    Guy H Palmer
    Program in Vector Borne Diseases, Department of Veterinary Microbiology and Pathology and The Paul G Allen School for Global Animal Health, Washington State University, Pullman, WA 99164 7040, USA
    FEMS Immunol Med Microbiol 64:115-9. 2012

Detail Information

Publications36

  1. ncbi Insights into mechanisms of bacterial antigenic variation derived from the complete genome sequence of Anaplasma marginale
    Guy H Palmer
    Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA 99164 7040, USA
    Ann N Y Acad Sci 1078:15-25. 2006
    ..The resulting combinatorial diversity generates the number of variants both predicted and shown to emerge during persistence...
  2. pmc Anaplasma marginale infection with persistent high-load bacteremia induces a dysfunctional memory CD4+ T lymphocyte response but sustained high IgG titers
    Sushan Han
    Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA 99164 7040, USA
    Clin Vaccine Immunol 17:1881-90. 2010
    ..marginale infection. The failure to establish a strong memory T cell response during A. marginale infection likely contributes to bacterial persistence...
  3. pmc Association of pathogen strain-specific gene transcription and transmission efficiency phenotype of Anaplasma marginale
    Joseph T Agnes
    Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA 99164 7040, USA
    Infect Immun 78:2446-53. 2010
    ....
  4. pmc Complete genome sequence of Anaplasma marginale subsp. centrale
    David R Herndon
    Animal Diseases Research Unit, Agricultural Research Service, U S Department of Agriculture, Pullman, Washington 99164, USA
    J Bacteriol 192:379-80. 2010
    ..marginale strains. The comparison markedly narrows the number of outer membrane protein candidates for development of a safer inactivated vaccine and provides insight into the diversity among strains of senso lato A. marginale...
  5. pmc Identification of Anaplasma marginale type IV secretion system effector proteins
    Svetlana Lockwood
    School of Electrical Engineering and Computer Science, Washington State University, Pullman, Washington, United States of America
    PLoS ONE 6:e27724. 2011
    ..marginale by translocating effector proteins across its membrane into eukaryotic target cells. However, T4SS effector proteins have not been identified and tested in the laboratory until now...
  6. pmc Identification of Anaplasma marginale outer membrane protein antigens conserved between A. marginale sensu stricto strains and the live A. marginale subsp. centrale vaccine
    Joseph T Agnes
    Program in Vector Borne Diseases, Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA 99164 7040, USA
    Infect Immun 79:1311-8. 2011
    ..marginale and provides clear direction for development of a safer, more effective vaccine...
  7. pmc Stability and tick transmission phenotype of gfp-transformed Anaplasma marginale through a complete in vivo infection cycle
    Susan M Noh
    Animal Disease Research Unit, Agriculture Research Service, US Department of Agriculture, Pullman, WA 99164 7030, USA
    Appl Environ Microbiol 77:330-4. 2011
    ..Despite the lower levels of replication, ticks transmitted the transformant. Transformants can serve as valuable tools to dissect the molecular requirements of tick colonization and pathogen transmission...
  8. pmc Dermacentor andersoni transmission of Francisella tularensis subsp. novicida reflects bacterial colonization, dissemination, and replication coordinated with tick feeding
    Kathryn E Reif
    Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA 99164 7040, USA
    Infect Immun 79:4941-6. 2011
    ..The identification of specific genes and, more importantly, conserved pathways that function at the tick-pathogen interface will accelerate the development of new methods to block transmission...
  9. pmc Expression of Anaplasma marginale ankyrin repeat-containing proteins during infection of the mammalian host and tick vector
    Solomon S Ramabu
    Department of Veterinary Microbiology and Pathology, and The Paul G Allen School for Global Animal Health, Washington State University, Pullman, Washington 99164 7040, USA
    Infect Immun 79:2847-55. 2011
    ..Selection for divergence in Ank function among Anaplasma and Ehrlichia spp. is supported by both locus and allelic analyses of genes encoding orthologous proteins and their ankyrin motif compositions...
  10. pmc Genome-wide screening and identification of antigens for rickettsial vaccine development
    Guy H Palmer
    Program in Vector Borne Diseases, Department of Veterinary Microbiology and Pathology and The Paul G Allen School for Global Animal Health, Washington State University, Pullman, WA 99164 7040, USA
    FEMS Immunol Med Microbiol 64:115-9. 2012
    ....
  11. pmc Comparative genomics and transcriptomics of trait-gene association
    Sebastian Aguilar Pierle
    Program in Genomics, Department of Veterinary Microbiology and Pathology, Paul G, Allen School for Global Animal Health, Washington State University, Pullman, WA 99164 7040, USA
    BMC Genomics 13:669. 2012
    ..We combined DNA/RNA comparative genomic approaches using strains with different tick transmission phenotypes and identified genes that segregate with transmissibility...
  12. pmc Subdominant antigens in bacterial vaccines: AM779 is subdominant in the Anaplasma marginale outer membrane vaccine but does not associate with protective immunity
    Saleh M Albarrak
    Paul G Allen School for Global Animal Health, Washington State University, Pullman, Washington, United States of America
    PLoS ONE 7:e46372. 2012
    ..marginale and related bacterial pathogens...
  13. pmc Identification of multilocus genetic heterogeneity in Anaplasma marginale subsp. centrale and its restriction following tick-borne transmission
    David R Herndon
    Animal Diseases Research Unit, Agricultural Research Service, U S Department of Agriculture, Pullman, Washington, USA
    Infect Immun 81:1852-8. 2013
    ..These findings demonstrate the plasticity of an otherwise highly constrained genome and highlight the role of natural transmission cycles in shaping and maintaining the bacterial genome...
  14. pmc Transcriptional pathways associated with the slow growth phenotype of transformed Anaplasma marginale
    Sebastian Aguilar Pierle
    Program in Genomics, Department of Veterinary Microbiology and Pathology, Paul G Allen School for Global Animal Health, Washington State University, Pullman, WA 99164 7040, USA
    BMC Genomics 14:272. 2013
    ....
  15. pmc Protective immunity induced by immunization with a live, cultured Anaplasma marginale strain
    G Kenitra Hammac
    Program in Genomics, Department of Veterinary Microbiology and Pathology, Paul G Allen School for Global Animal Health, Washington State University, Pullman, WA 99164 7040, USA
    Vaccine 31:3617-22. 2013
    ..AmStM-GFP provided clinical protection, yielding a stable PCV and low bacteremia following challenge, whereas A. centrale only afforded partial clinical protection...
  16. pmc Linkage between Anaplasma marginale outer membrane proteins enhances immunogenicity but is not required for protection from challenge
    Susan M Noh
    Animal Disease Research Unit, Agricultural Research Service, U S Department of Agriculture, Pullman, Washington, USA
    Clin Vaccine Immunol 20:651-6. 2013
    ..Once protective antigens are identified, immunogenicity could be enhanced by cross-linking to allow a reduced immunogen dose or fewer booster vaccinations...
  17. pmc Identification of Rhipicephalus microplus genes that modulate the infection rate of the rickettsia Anaplasma marginale
    Ricardo F Mercado-Curiel
    Program in Vector Borne Diseases, Department of Veterinary Microbiology and Pathology and Paul G Allen School for Global Animal Health, Washington State University, Pullman, Washington, United States of America
    PLoS ONE 9:e91062. 2014
    ..Identifying vector genes and subsequent determination of the encoded functions are initial steps in discovery of new targets for inhibiting pathogen development and subsequent transmission. ..
  18. pmc Identification of Anaplasma marginale proteins specifically upregulated during colonization of the tick vector
    Solomon S Ramabu
    Program in Vector Borne Diseases, Department of Veterinary Microbiology and Pathology and School for Global Animal Health, Washington State University, Pullman, Washington 99164 7040, USA
    Infect Immun 78:3047-52. 2010
    ....
  19. pmc The immunization-induced antibody response to the Anaplasma marginale major surface protein 2 and its association with protective immunity
    Susan M Noh
    Animal Disease Research Unit, Agricultural Research Service, U S Department of Agriculture, Pullman, WA 99164 7030, USA
    Vaccine 28:3741-7. 2010
    ....
  20. pmc Differential expression and sequence conservation of the Anaplasma marginale msp2 gene superfamily outer membrane proteins
    Susan M Noh
    Program in Vector borne Diseas, Department of Microbiology and Pathology, Washington State University, Pullman, WA 99164 6630, USA
    Infect Immun 74:3471-9. 2006
    ..Maries strain and Florida strain genomes...
  21. ncbi Characterization of WC1 co-receptors on functionally distinct subpopulations of ruminant gamma delta T cells
    Aric N Rogers
    Program in Molecular and Cellular Biology, University of Massachusetts, Amherst, MA 01003, USA
    Cell Immunol 239:151-61. 2006
    ..1(+)/WC1.2(-) and WC1.2(+)/WC1.1(-)) both had complex 2-D patterns, virtually all spots associated with WC1.2(+)/WC1.1(-) cells bore the WC1.2 epitope, distinguishing them from the WC1.1(+) cells...
  22. ncbi Immune control of Babesia bovis infection
    Wendy C Brown
    Program in Vector borne Disease, Department of Veterinary Microbiology and Pathology, College of Veterinary Medicine, Washington State University, Pullman, WA 99164 7040, USA
    Vet Parasitol 138:75-87. 2006
    ..The availability of an annotated B. bovis genome will, for the first time, enable identification of non-immunodominant proteins that may stimulate protective immunity...
  23. pmc Characterization of a phenotypically unique population of CD13+ dendritic cells resident in the spleen
    Yan Zhuang
    Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, 99164 7040, USA
    Clin Vaccine Immunol 13:1064-9. 2006
    ..Upon cytokine-induced maturation, splenic DCs both efficiently present antigen in the stimulation of allogeneic lymphocyte proliferation and recall antigen-specific responses...
  24. ncbi Quantitation of Anaplasma marginale major surface protein (MSP)1a and MSP2 epitope-specific CD4+ T lymphocytes using bovine DRB3*1101 and DRB3*1201 tetramers
    Junzo Norimine
    Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA 99164 7040, USA
    Immunogenetics 58:726-39. 2006
    ..This novel technology should be useful to track the fate of antigen-specific CD4+ T-cell responses in cattle after immunization or infection with persistent pathogens, such as A. marginale, that modulate the host immune response...
  25. pmc Selection for simple major surface protein 2 variants during Anaplasma marginale transmission to immunologically naïve animals
    Guy H Palmer
    Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA 99164 7040, USA
    Infect Immun 75:1502-6. 2007
    ..However, these mosaics have a selective advantage only in the presence of adaptive immunity and are rapidly replaced by simple variants following transmission...
  26. pmc Maintenance of antibody to pathogen epitopes generated by segmental gene conversion is highly dynamic during long-term persistent infection
    Yan Zhuang
    Program in Vector Borne Diseases and Immunology, Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, Washington 99164 7040, USA
    Infect Immun 75:5185-90. 2007
    ..The results unify the genetic potential of segmental gene conversion with escape from antibody recognition and identify immunological effects of variant mosaic structure...
  27. pmc Identification of midgut and salivary glands as specific and distinct barriers to efficient tick-borne transmission of Anaplasma marginale
    Massaro W Ueti
    Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA 99164 7040, USA
    Infect Immun 75:2959-64. 2007
    ..These results establish that there are at least two specific barriers to efficient tick-borne transmission, the midgut and salivary glands, and highlight the complexity of the pathogen-tick interaction...
  28. pmc Tick-borne transmission of two genetically distinct Anaplasma marginale strains following superinfection of the mammalian reservoir host
    Christina K Leverich
    Department of Veterinary Microbiology and Pathology, Program in Vector Borne Diseases, School for Global Animal Health, Washington State University, Pullman, Washington 99164 7040, USA
    Infect Immun 76:4066-70. 2008
    ..marginale strain capable of superinfecting the mammalian host can subsequently be cotransmitted and become established within the host population despite the presence of an existing established strain...
  29. pmc Unraveling the immune regulatory mechanisms imposed by Anaplasma
    Wendy C Brown
    Vet J 175:10-1. 2008
  30. pmc Composition of the surface proteome of Anaplasma marginale and its role in protective immunity induced by outer membrane immunization
    Susan M Noh
    Animal Disease Research Unit, Agriculture Research Service, U S Department of Agriculture, Pullman, WA 99164 7030, USA
    Infect Immun 76:2219-26. 2008
    ..Furthermore, the data support that remodeling of the surface proteome accompanies the transition between mammalian and arthropod hosts and identify novel targets for blocking transmission...
  31. pmc Superinfection as a driver of genomic diversification in antigenically variant pathogens
    James E Futse
    Program in Vector Borne Diseases, College of Veterinary Medicine, Washington State University, Pullman, WA 99164, USA
    Proc Natl Acad Sci U S A 105:2123-7. 2008
    ....
  32. pmc Rapid deletion of antigen-specific CD4+ T cells following infection represents a strategy of immune evasion and persistence for Anaplasma marginale
    Sushan Han
    Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA 99164, USA
    J Immunol 181:7759-69. 2008
    ..Thus, infection of cattle with A. marginale leads to the rapid loss of Ag-specific T cells and immunologic memory, which may be a strategy for this pathogen to modulate the immune response and persist...
  33. pmc Independence of Anaplasma marginale strains with high and low transmission efficiencies in the tick vector following simultaneous acquisition by feeding on a superinfected mammalian reservoir host
    Maria F B M Galletti
    Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA 99164 USA
    Infect Immun 77:1459-64. 2009
    ..These results support the idea that the strain predominance in regions of endemicity is mediated by the intrinsic transmission efficiency of specific strains regardless of occurrence of superinfection...
  34. pmc Quantitative differences in salivary pathogen load during tick transmission underlie strain-specific variation in transmission efficiency of Anaplasma marginale
    Massaro W Ueti
    Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA 99164 7040, USA
    Infect Immun 77:70-5. 2009
    ....
  35. pmc Generation of antigenic variants via gene conversion: Evidence for recombination fitness selection at the locus level in Anaplasma marginale
    James E Futse
    Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, 99164, USA
    Infect Immun 77:3181-7. 2009
    ..Identification of highly fit variants provides targets for vaccines that will prevent the high-level bacteremia associated with acute disease...
  36. pmc Global transcriptional analysis reveals surface remodeling of Anaplasma marginale in the tick vector
    G Kenitra Hammac
    Program in Genomics, Department of Veterinary Microbiology and Pathology, Paul G, Allen School for Global Animal Health, Washington State University, Pullman, WA 99164 7040, USA
    Parasit Vectors 7:193. 2014
    ..Differential gene transcription, especially of potential vaccine candidates, is of interest in Anaplasma marginale, the tick-borne causative agent of bovine anaplasmosis...