: This project seeks to understand how microbial antigens that are selectively expressed in vivo, and in specific tissues, contribute to the genesis of protective host immune responses and can serve as rational targets for vaccines. Borrelia burgdorferi has been shown to preferentially express different genes during infection of the mammalian host and within distinct host tissues. Moreover, B. burgdorferi has a tropism for the skin, joints, heart and nervous system, and these organs/tissues are associated with particular clinical manifestations of Lyme disease, such as erythema migrans or Lyme arthritis. B. burgdorferi genes that are selectively expressed in vivo and in precise host tissues will be identified using 2 strategies. First, differential immunoscreening, a technique developed in our laboratory, will be used. In this approach, a B. burgdorferi expression library is probed with 2 sets of sera (for example, [a] sera from an infected host, and [b] sera from a host hyperimmunized with killed B. burgdorferi) to identify antigens that only react with [a], and may therefore be selectively expressed in vivo. Secondly, DECAL (Differential Expression analysis using a Custom Amplified Library), will be adapted to identify B. burgdorferi genes expressed in the host. In this strategy, prokaryotic ribosomal RNA is removed for a bacterial expression library, which can then be used for subtractive analysis of gene expression in host tissues. Then the immune responses to the host-specific B. burgdorferi antigens will be characterized. We will directly assess tissue-specific gene expression, by RT-PCR using patient specimens and also in an experimental murine model of Lyme borreliosis. Then we will correlate antigen-specific immune responses with the course of Lyme disease in patients and determine whether immune responses to tissue-specific antigens influence the course of infection and/or prevent specific clinical manifestations of disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI049200-04
Application #
6730623
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Baker, Phillip J
Project Start
2001-05-01
Project End
2006-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
4
Fiscal Year
2004
Total Cost
$327,000
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
Narasimhan, Sukanya; Schuijt, Tim J; Abraham, Nabil M et al. (2017) Modulation of the tick gut milieu by a secreted tick protein favors Borrelia burgdorferi colonization. Nat Commun 8:184
Silver, Adam C; Dunne, Dana W; Zeiss, Caroline J et al. (2013) MyD88 deficiency markedly worsens tissue inflammation and bacterial clearance in mice infected with Treponema pallidum, the agent of syphilis. PLoS One 8:e71388
Fikrig, Erol; Narasimhan, Sukanya; Neelakanta, Girish et al. (2009) Toll-like receptors 1 and 2 heterodimers alter Borrelia burgdorferi gene expression in mice and ticks. J Infect Dis 200:1331-40
Pal, Utpal; Dai, Jianfeng; Li, Xin et al. (2008) A differential role for BB0365 in the persistence of Borrelia burgdorferi in mice and ticks. J Infect Dis 197:148-55
Yang, Xiuli; Izadi, Hooman; Coleman, Adam S et al. (2008) Borrelia burgdorferi lipoprotein BmpA activates pro-inflammatory responses in human synovial cells through a protein moiety. Microbes Infect 10:1300-8
Yang, Xiaofeng F; Pal, Utpal; Alani, Sophie M et al. (2004) Essential role for OspA/B in the life cycle of the Lyme disease spirochete. J Exp Med 199:641-8
Liang, Fang Ting; Caimano, Melissa J; Radolf, Justin D et al. (2004) Borrelia burgdorferi outer surface protein (osp) B expression independent of ospA. Microb Pathog 37:35-40
Fikrig, Erol; Coyle, Patricia K; Schutzer, Steven E et al. (2004) Preferential presence of decorin-binding protein B (BBA25) and BBA50 antibodies in cerebrospinal fluid of patients with neurologic Lyme disease. J Clin Microbiol 42:1243-6
Liang, Fang Ting; Brown, Eric L; Wang, Tian et al. (2004) Protective niche for Borrelia burgdorferi to evade humoral immunity. Am J Pathol 165:977-85
Narasimhan, Sukanya; Caimano, Melissa J; Liang, Fang Ting et al. (2003) Borrelia burgdorferi transcriptome in the central nervous system of non-human primates. Proc Natl Acad Sci U S A 100:15953-8