Ixodes scapularis transmits important pathogens to humans, including the causative agent of Lyme disease, Borrelia burgdorferi. Lyme disease is the most commonly reported tick-borne disease in the United States. Tick salivary gland molecules are essential for modulating host innate and adaptive immune defenses and for transmission of infectious agents. Ixodes scapularis infestation polarizes host T lymphocyte cytokines to a Th2 profile while suppressing Th1 cytokines. Passively reconstituting suppressed cytokines provides protection against tick transmission of B. burgdorferi. This proposal is based on the hypothesis that reversal of I. scapularis induced Th2 polarization of host CD4+ T-cell responses will provide protection against tick transmission of B. burgdorferi. A well defined in vivo T-cell receptor (TCR) transgenic adoptive transfer model will be used to study the influence of infestation with pathogen-free and infected ticks as well as isolated tick salivary gland molecules on responses of naive CD4 T-cells to specific antigen.
The first aim i s to characterize the influence of infestation with pathogen-free and B. burgdorferi infected I. scapularis on the cytokine producing ability of TCR transgenic clonotypic T-cells specific for a model antigen, influenza hemagglutinin, on B10.D2 and BALB/c genetic backgrounds, which differ in their support of Th1 and Th2 responses. Second specific aim is to identify, isolate and characterize I. scapularis salivary gland molecules responsible for polarizing transgenic CD4 T-cells to a Th2 profile. Genes encoding reactive molecules will be cloned, recombinant forms expressed in a eukaryotic expression system and tested for activity.
The third aim i s to immunize with the recombinant forms of the reactive salivary gland molecules and determine whether tick induced cytokine polarization and B. burgdorferi transmission are blocked.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI062735-03
Application #
7171881
Study Section
Special Emphasis Panel (ZRG1-TMP (99))
Program Officer
Breen, Joseph J
Project Start
2005-02-01
Project End
2010-01-31
Budget Start
2007-02-01
Budget End
2008-01-31
Support Year
3
Fiscal Year
2007
Total Cost
$343,715
Indirect Cost
Name
University of Connecticut
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
Heinze, Dar M; Wikel, Stephen K; Thangamani, Saravanan et al. (2012) Transcriptional profiling of the murine cutaneous response during initial and subsequent infestations with Ixodes scapularis nymphs. Parasit Vectors 5:26
Thangamani, Saravanan; Higgs, Stephen; Ziegler, Sarah et al. (2010) Host immune response to mosquito-transmitted chikungunya virus differs from that elicited by needle inoculated virus. PLoS One 5:e12137
Krause, Peter J; Grant-Kels, Jane M; Tahan, Steven R et al. (2009) Dermatologic changes induced by repeated Ixodes scapularis bites and implications for prevention of tick-borne infection. Vector Borne Zoonotic Dis 9:603-10
Alarcon-Chaidez, F J; Boppana, V D; Hagymasi, A T et al. (2009) A novel sphingomyelinase-like enzyme in Ixodes scapularis tick saliva drives host CD4 T cells to express IL-4. Parasite Immunol 31:210-9
Boppana, V D; Thangamani, S; Adler, A J et al. (2009) SAAG-4 is a novel mosquito salivary protein that programmes host CD4 T cells to express IL-4. Parasite Immunol 31:287-95
Pagel Van Zee, J; Geraci, N S; Guerrero, F D et al. (2007) Tick genomics: the Ixodes genome project and beyond. Int J Parasitol 37:1297-305
Muller-Doblies, U U; Maxwell, S S; Boppana, V D et al. (2007) Feeding by the tick, Ixodes scapularis, causes CD4(+) T cells responding to cognate antigen to develop the capacity to express IL-4. Parasite Immunol 29:485-99
Geraci, Nicholas S; Spencer Johnston, J; Paul Robinson, J et al. (2007) Variation in genome size of argasid and ixodid ticks. Insect Biochem Mol Biol 37:399-408
Alarcon-Chaidez, Francisco; Ryan, Raymond; Wikel, Stephen et al. (2006) Confirmation of tick bite by detection of antibody to Ixodes calreticulin salivary protein. Clin Vaccine Immunol 13:1217-22