Abstract

- Understanding the capacity of the cellular immune response to clear Borrelia, the etiologic agent of Lyme disease, is essential to a proper understanding of the pathogenesis of this disorder. We know that both neutrophils and macrophages take up and kill Borrelia rapidly in vitro. Yet, intact spirochetes can be observed in skin and other tissues, and have been isolated from uninflamed peritoneal cavity despite the presence of resident macrophages. In order to examine the failure of phagocytes to clear the spirochetes in vivo, the killing mechanisms of phagocytes will be characterized. In situ microscopic examination of spirochete- phagocyte interactions, in situ hybridization and ex vivo RT-PCR of cytokine and other genes will be used to establish a profile of the macrophages' state of activation and deactivation. Different strains of Borrelia will be used to elucidate mechanisms of clearance versus persistence in vivo. Finally, it is proposed to use cDNA arrays to examine differences in host gene expression patterns during activation of neutrophils and macrophages by these types of Borrelia. These studies may provide the technical and conceptual basis for improvements in diagnostic and prognostic aspects of inflammatory diseases.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI043558-02
Application #
6163958
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Baker, Phillip J
Project Start
1999-03-15
Project End
2004-02-29
Budget Start
2000-03-01
Budget End
2001-02-28
Support Year
2
Fiscal Year
2000
Total Cost
$310,076
Indirect Cost

  Institution

Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520

  Publications

Malawista, Stephen E; de Boisfleury Chevance, Anne (2008) Clocking the Lyme spirochete. PLoS One 3:e1633
Malawista, Stephen E; de Boisfleury Chevance, Anne; van Damme, Jo et al. (2008) Tonic inhibition of chemotaxis in human plasma. Proc Natl Acad Sci U S A 105:17949-54
Montgomery, Ruth R; Booth, Carmen J; Wang, Xiaomei et al. (2007) Recruitment of macrophages and polymorphonuclear leukocytes in L:yme carditis. Infect Immun 75:613-20
Malawista, Stephen E; de Boisfleury Chevance, Anne (2007) Phagocytic function of human blood polymorphonuclear leukocytes in the presence of carrageenan, a potential vaginal microbicide. Inflammation 30:131-5
Malawista, Stephen E; Smith, Eileen O; Seibyl, John P (2006) Cryopreservable neutrophil surrogates: granule-poor, motile cytoplasts from polymorphonuclear leukocytes home to inflammatory lesions in vivo. Cell Motil Cytoskeleton 63:254-7
Montgomery, Ruth R; Schreck, Kimberly; Wang, Xiaomei et al. (2006) Human neutrophil calprotectin reduces the susceptibility of Borrelia burgdorferi to penicillin. Infect Immun 74:2468-72
Montgomery, Ruth R; Lusitani, Denise; De Boisfleury Chevance, Anne et al. (2004) Tick saliva reduces adherence and area of human neutrophils. Infect Immun 72:2989-94
Liu, Nengyin; Montgomery, Ruth R; Barthold, Stephen W et al. (2004) Myeloid differentiation antigen 88 deficiency impairs pathogen clearance but does not alter inflammation in Borrelia burgdorferi-infected mice. Infect Immun 72:3195-203
Malawista, Stephen E; de Boisfleury Chevance, Anne; Brown, Eric J et al. (2003) Chemotaxis of non-compressed blood polymorphonuclear leukocytes from an adolescent with severe leukocyte adhesion deficiency. Am J Hematol 73:115-20
Lusitani, Denise; Malawista, Stephen E; Montgomery, Ruth R (2003) Calprotectin, an abundant cytosolic protein from human polymorphonuclear leukocytes, inhibits the growth of Borrelia burgdorferi. Infect Immun 71:4711-6

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