MHC class II-restricted responses mediated by CD4+ T lymphocytes are central to immune control of the tick-borne pathogens of the Family Anaplasmataceae. Priming and expansion of CD4+ T lymphocytes is required for development of high affinity neutralizing IgG antibodies directed against the bacterial surface and for efficient phagocyte activation leading to bacterial killing. The goal of the research is to identify the pathogen proteins that induce the T cell responses required for immunity. To date, only four T cell immunostimulatory molecules have been identified in Anaplasma marginale, the type species, and none in the related human pathogens within the Anaplasmataceae. We will address this knowledge gap using a comprehensive strategy to identify outer membrane proteins that prime naive CD4+ T lymphocytes and induce recall memory T cell responses of immunized and protected animals. In part 1 of the project, we propose to use a combination of biochemical fractionation of outer membranes combined with genomic analysis to identify the targets of the T cell response. At the conclusion of part 1, we expect to have identified novel outer membrane proteins bearing CD4+ T cell epitopes conserved among A. marginale strains. The presence of molecular and immunological orthologs among species in the Family Anaplasmataceae indicates that the research results should be broadly applicable and enhance understanding and control of human diseases. ? ? In part 2 of the project, we will examine the requirement for linked recognition of covalently associated outer membrane proteins in generating immunity. A. marginale outer membrane proteins are covalently linked by extensive disulfide bonding. How this covalent bonding affects generation of immunity is unknown. The observation that Major Surface Protein (MSP) 1a-specific CD4+ T cells provide help for B-lymphocytes to secrete antibody to the covalently bound MSPlb suggests that the native association of outer membrane proteins can be critical in inducing protective responses. We hypothesize that this """"""""linked recognition"""""""" of CD4+ T cell and B cell epitopes from different outer membrane proteins can be mimicked using chimeric multiple epitope constructs. At the conclusion of part 2, we expect to have determined if linked recognition between covalently bound outer membrane proteins, using MSPla and MSPlb as a model complex immunogen, can be represented by a chimeric epitope construct. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI053692-02S1
Application #
6892224
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Perdue, Samuel S
Project Start
2003-08-01
Project End
2008-01-31
Budget Start
2004-06-10
Budget End
2005-01-31
Support Year
2
Fiscal Year
2004
Total Cost
$26,091
Indirect Cost
Name
Washington State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
041485301
City
Pullman
State
WA
Country
United States
Zip Code
99164
Okagawa, Tomohiro; Konnai, Satoru; Deringer, James R et al. (2016) Cooperation of PD-1 and LAG-3 Contributes to T-Cell Exhaustion in Anaplasma marginale-Infected Cattle. Infect Immun 84:2779-90
Brown, Wendy C; Turse, Joshua E; Lawrence, Paulraj K et al. (2015) Loss of Immunization-Induced Epitope-Specific CD4 T-Cell Response following Anaplasma marginale Infection Requires Presence of the T-Cell Epitope on the Pathogen and Is Not Associated with an Increase in Lymphocytes Expressing Known Regulatory Cell Phenot Clin Vaccine Immunol 22:742-53
Turse, Joshua E; Scoles, Glen A; Deringer, James R et al. (2014) Immunization-induced Anaplasma marginale-specific T-lymphocyte responses impaired by A. marginale infection are restored after eliminating infection with tetracycline. Clin Vaccine Immunol 21:1369-75
Noh, Susan M; Turse, Joshua E; Brown, Wendy C et al. (2013) Linkage between Anaplasma marginale outer membrane proteins enhances immunogenicity but is not required for protection from challenge. Clin Vaccine Immunol 20:651-6
Brown, Wendy C (2012) Adaptive immunity to Anaplasma pathogens and immune dysregulation: implications for bacterial persistence. Comp Immunol Microbiol Infect Dis 35:241-52
Morse, Kaitlyn; Norimine, Junzo; Hope, Jayne C et al. (2012) Breadth of the CD4+ T cell response to Anaplasma marginale VirB9-1, VirB9-2 and VirB10 and MHC class II DR and DQ restriction elements. Immunogenetics 64:507-23
Palmer, Guy H; Brown, Wendy C; Noh, Susan M et al. (2012) Genome-wide screening and identification of antigens for rickettsial vaccine development. FEMS Immunol Med Microbiol 64:115-9
Morse, Kaitlyn; Norimine, Junzo; Palmer, Guy H et al. (2012) Association and evidence for linked recognition of type IV secretion system proteins VirB9-1, VirB9-2, and VirB10 in Anaplasma marginale. Infect Immun 80:215-27
Lockwood, Svetlana; Voth, Daniel E; Brayton, Kelly A et al. (2011) Identification of Anaplasma marginale type IV secretion system effector proteins. PLoS One 6:e27724
Agnes, Joseph T; Brayton, Kelly A; LaFollett, Megan et al. (2011) Identification of Anaplasma marginale outer membrane protein antigens conserved between A. marginale sensu stricto strains and the live A. marginale subsp. centrale vaccine. Infect Immun 79:1311-8

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