MOLECULAR MECHANISMS OF MSP2 VARIATION IN RICKETTSIAE

Summary

Principal Investigator: Anthony Barbet
Affiliation: University of Florida
Country: USA
Abstract: The objective of this proposal is to improve our understanding of the mechanisms of pathogenesis of tick- borne rickettsial pathogens that cause ehrlichiosis and anaplasmosis of humans and animals. These pathogens efficiently utilize a small genome (<1.5 Mb) to evade the immune response and establish persistent infection in the mammalian reservoir host, to colonize and replicate in the tick midgut and salivary glands, and to develop infectivity upon renewed feeding of the tick to effect onward transmission. MSP2 was initially defined in Anaplasma marginale and infections of cattle and ticks with this pathogen provide an excellent model for discovering the mechanisms used to modify the surface proteome. In the prior project period, we identified segmental gene conversion of single expression sites for MSP2, and a related surface paralogue MSP3, as a primary mechanism for generating surface diversity and demonstrated differential expression of operon-encoded proteins between the mammalian host and tick vector. A similar gene conversion mechanism is used by Anaplasma phagocytophilum to express a large repertoire of outer membrane proteins in human patients and studies by others support expression from multiple loci to generate surface diversity. Analysis of the A. marginale genome reveals a complex family of outer membrane protein genes related to msp2. This msp2 superfamily is comprised of 32 paralogues, comprising the two msp2 and msp3 operon-linked expression sites, a single msp4 gene locus, multiple msp2 and msp3 pseudogenes, and other uncharacterized msp2-1ike paralogues. We hypothesize that differential expression of these paralogues and recombination between them generates diversity in the pathogen surface and provides the ability of organisms to adapt to and persist in different hosts and cellular environments. The specific aims of the present proposal are: 1] Determine if msp2 superfamily genes are differentially expressed during infection of the mammalian and invertebrate hosts; 2] Determine the operon structure and generation of diversity within msp2 superfamily gene clusters; 3] Identify the mechanisms for differential regulation of the msp2 superfamily proteins in the mammalian and invertebrate hosts; and 4] Compare regulation of expression of msp2 superfamily proteins in A. marginale and A. phagocytophilum.
Funding Period: 1999-07-01 - 2008-12-31
more information: NIH RePORT

Top Publications

  1. pmc Complete genome sequencing of Anaplasma marginale reveals that the surface is skewed to two superfamilies of outer membrane proteins
    Kelly A Brayton
    Program in Vector Borne Diseases, Department of Veterinary Microbiology and Pathology, Washingston State University, Pullman, WA 99164 7040, USA
    Proc Natl Acad Sci U S A 102:844-9. 2005
  2. ncbi Distinctly different msp2 pseudogene repertoires in Anaplasma marginale strains that are capable of superinfection
    Jose Luis Rodriguez
    Program in Vector Borne Diseases, Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA 99164 7040, USA
    Gene 361:127-32. 2005
  3. pmc Interplay among coactivator-associated arginine methyltransferase 1, CBP, and CIITA in IFN-gamma-inducible MHC-II gene expression
    Eleni Zika
    Curriculum in Genetics and Molecular Biology, Lineberger Comprehensive Cancer Center, and Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA
    Proc Natl Acad Sci U S A 102:16321-6. 2005
  4. 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
  5. pmc Structure of the expression site reveals global diversity in MSP2 (P44) variants in Anaplasma phagocytophilum
    Anthony F Barbet
    Department of Infectious Diseases and Pathology, University of Florida, Gainesville, FL 32611 0880, USA, and Department of Clinical Microbiology, Kalmar County Hospital, Sweden
    Infect Immun 74:6429-37. 2006
  6. 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
  7. pmc Outer membrane protein sequence variation in lambs experimentally infected with Anaplasma phagocytophilum
    Erik G Granquist
    Department of Production Animal Clinical Sciences, Section of Small Ruminant Research, Norwegian School of Veterinary Science, Kyrkjevegen 332 334, Sandnes N 4325, Norway
    Infect Immun 76:120-6. 2008
  8. pmc In situ detection of Anaplasma spp. by DNA target-primed rolling-circle amplification of a padlock probe and intracellular colocalization with immunofluorescently labeled host cell von Willebrand factor
    Heather L Wamsley
    Department of Infectious Diseases and Pathology, University of Florida, College of Veterinary Medicine, Gainesville, Florida 32610, USA
    J Clin Microbiol 46:2314-9. 2008

Scientific Experts

Detail Information

Publications8

  1. pmc Complete genome sequencing of Anaplasma marginale reveals that the surface is skewed to two superfamilies of outer membrane proteins
    Kelly A Brayton
    Program in Vector Borne Diseases, Department of Veterinary Microbiology and Pathology, Washingston State University, Pullman, WA 99164 7040, USA
    Proc Natl Acad Sci U S A 102:844-9. 2005
    ....
  2. ncbi Distinctly different msp2 pseudogene repertoires in Anaplasma marginale strains that are capable of superinfection
    Jose Luis Rodriguez
    Program in Vector Borne Diseases, Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA 99164 7040, USA
    Gene 361:127-32. 2005
    ..This finding supports the hypothesis that the occurrence of superinfection reflects the differences in the msp2 repertoire and corresponding diversity of variants...
  3. pmc Interplay among coactivator-associated arginine methyltransferase 1, CBP, and CIITA in IFN-gamma-inducible MHC-II gene expression
    Eleni Zika
    Curriculum in Genetics and Molecular Biology, Lineberger Comprehensive Cancer Center, and Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA
    Proc Natl Acad Sci U S A 102:16321-6. 2005
    ..These results suggest functional and temporal relationships among CIITA, CARM1, and CBP for IFN-gamma induction of MHC-II...
  4. 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...
  5. pmc Structure of the expression site reveals global diversity in MSP2 (P44) variants in Anaplasma phagocytophilum
    Anthony F Barbet
    Department of Infectious Diseases and Pathology, University of Florida, Gainesville, FL 32611 0880, USA, and Department of Clinical Microbiology, Kalmar County Hospital, Sweden
    Infect Immun 74:6429-37. 2006
    ..These data suggest similar genetic mechanisms for A. phagocytophilum variation in all hosts but worldwide diversity of the MSP2 (P44) outer membrane protein...
  6. 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...
  7. pmc Outer membrane protein sequence variation in lambs experimentally infected with Anaplasma phagocytophilum
    Erik G Granquist
    Department of Production Animal Clinical Sciences, Section of Small Ruminant Research, Norwegian School of Veterinary Science, Kyrkjevegen 332 334, Sandnes N 4325, Norway
    Infect Immun 76:120-6. 2008
    ..phagocytophilum and the host immune system in naturally occurring persistent infections and provide an important comparison with enduring infections of cattle caused by A. marginale...
  8. pmc In situ detection of Anaplasma spp. by DNA target-primed rolling-circle amplification of a padlock probe and intracellular colocalization with immunofluorescently labeled host cell von Willebrand factor
    Heather L Wamsley
    Department of Infectious Diseases and Pathology, University of Florida, College of Veterinary Medicine, Gainesville, Florida 32610, USA
    J Clin Microbiol 46:2314-9. 2008
    ....