: This proposal will investigate the interactions between Borrelia burgdorferi and Ixodes scapularis ticks, in order to better understand Lyme disease pathogenesis. We will explore the hypothesis that the specific association between B. burgdorferi outer surface protein (Osp) A and the Tick Receptor for OspA (TROSPA) is required for the successful colonization of I. scapularis by the spirochete. We will focus on examining how OspA interacts with the arthropod vector because our published and preliminary studies demonstrate that OspA facilitates the adherence ofB. burgdorferi to the tick gut. The importance of OspA in the attachment of B. burgdorferi to the I. scapularis gut will be carefully examined. We will then identify, clone and characterize the TROSPA gene, express and purify TROSPA in recombinant form, and examine the interactions between OspA and TROSPA. In vitro and in vivo studies will then determine whether antibodies to TROSPA, or OspA peptides, can interfere with spirochete colonization of I. scapularis. Finally, we will assess the influence of B. burgdorferi on the expression of the TROSPA gene, exploring the hypothesis that B. burgdorferi upregulate TROSPA within the vector, in part to facilitate survival of the spirochete. The efforts on OspA and TROSPA will be the main focus of the grant proposal. It is also possible; however, that OspA is not the only B. burgdorferi ligand that interacts with I. scapuIaris, and we may consider other B. burgdorferi genes that are expressed within I. scapularis and that may associate with the vector as our research progresses. These studies will explore the intimate relationship between B. burgdorferi and I. scapularis - with an emphasis on OspA and TROSPA - leading to a greater appreciation of the B. burgdorferi lifecycle and new approaches to interfere with spirochete transmission.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI032947-12
Application #
6702214
Study Section
Special Emphasis Panel (ZRG1-TMP (02))
Program Officer
Baker, Phillip J
Project Start
1994-05-01
Project End
2008-04-30
Budget Start
2004-05-01
Budget End
2005-04-30
Support Year
12
Fiscal Year
2004
Total Cost
$408,750
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Wagemakers, Alex; Koetsveld, Joris; Narasimhan, Sukanya et al. (2016) Variable Major Proteins as Targets for Specific Antibodies against Borrelia miyamotoi. J Immunol 196:4185-95
Narasimhan, Sukanya; Fikrig, Erol (2015) Tick microbiome: the force within. Trends Parasitol 31:315-23
Narasimhan, Sukanya; Rajeevan, Nallakkandi; Liu, Lei et al. (2014) Gut microbiota of the tick vector Ixodes scapularis modulate colonization of the Lyme disease spirochete. Cell Host Microbe 15:58-71
Schuijt, Tim J; Bakhtiari, Kamran; Daffre, Sirlei et al. (2013) Factor Xa activation of factor V is of paramount importance in initiating the coagulation system: lessons from a tick salivary protein. Circulation 128:254-66
Qian, Feng; Wang, Xiaomei; Zhang, Lin et al. (2012) Age-associated elevation in TLR5 leads to increased inflammatory responses in the elderly. Aging Cell 11:104-10
Magnarelli, Louis A; Norris, Steven J; Fikrig, Erol (2012) Serum antibodies to whole-cell and recombinant antigens of Borrelia burgdorferi in cottontail rabbits. J Wildl Dis 48:12-20
Shaw, Albert C; Panda, Alexander; Joshi, Samit R et al. (2011) Dysregulation of human Toll-like receptor function in aging. Ageing Res Rev 10:346-53
Schuijt, Tim J; Coumou, Jeroen; Narasimhan, Sukanya et al. (2011) A tick mannose-binding lectin inhibitor interferes with the vertebrate complement cascade to enhance transmission of the lyme disease agent. Cell Host Microbe 10:136-46
Sukumaran, Bindu; Mastronunzio, Juliana E; Narasimhan, Sukanya et al. (2011) Anaplasma phagocytophilum AptA modulates Erk1/2 signalling. Cell Microbiol 13:47-61
Zhang, Lili; Zhang, Yue; Adusumilli, Sarojini et al. (2011) Molecular interactions that enable movement of the Lyme disease agent from the tick gut into the hemolymph. PLoS Pathog 7:e1002079

Showing the most recent 10 out of 21 publications