Myeloid differentiation antigen 88 deficiency impairs pathogen clearance but does not alter inflammation in Borrelia burgdorferi-infected mice

被引:120
作者
Liu, NY
Montgomery, RR
Barthold, SW
Bockenstedt, LK
机构
[1] Yale Univ, Anlyan Ctr, Sch Med, Dept Internal Med, New Haven, CT 06520 USA
[2] Univ Calif Davis, Sch Med, Ctr Comparat Med, Davis, CA 95616 USA
[3] Univ Calif Davis, Sch Vet Med, Ctr Comparat Med, Davis, CA 95616 USA
关键词
D O I
10.1128/IAI.72.6.3195-3203.2004
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 [免疫学];
摘要
The spirochete Borrelia burgdorferi causes acute inflammation in mice that resolves with the development of pathogen-specific adaptive immunity. B. burgdorferi lipoproteins activate innate immune cells via Toll-like receptor 2 (TLR2), but TLR2-deficient mice are not resistant to B. burgdorferi-induced disease, suggesting the involvement of other TLRs or non-TLR mechanisms in the induction of acute inflammation. For this study, we used mice that were deficient in the intracellular adapter molecule myeloid differentiation antigen 88 (MyD88), which is required for all TLR-induced inflammatory responses, to determine whether the interruption of this pathway would alter B. burgdorferi-induced disease. Infected MyD88(-/-) mice developed carditis and arthritis, similar to the disease in wild-type (WT) mice analyzed at its peak (days 14 and 28) and during regression (day 45). MyD88(-/-) macrophages produced tumor necrosis factor alpha only when spirochetes were opsonized, suggesting a role for B. burgdorferi-specific antibody in disease expression. MyD88(-/-) mice produced stronger pathogen-specific Th2-dependent immunoglobulin G1 (IgG1) responses than did WT mice, and their IgM titers remained significantly elevated through 90 days of infection. Despite specific antibodies, the pathogen burden was 250-fold higher in MyD88(-/-) mice than in WT mice 45 days after infection; by 90 days of infection, the pathogen burden had diminished substantially in MyD88(-/-) mice, but it was still elevated compared to that in WT mice. The elevated pathogen burden may be explained in part by the finding that. MyD88(-/-) peritoneal macrophages could ingest spirochetes but degraded them more slowly than WT macrophages. Our results show that MyD88-dependent signaling pathways are not required for B. burgdorferi-induced inflammation but are necessary for the efficient control of the pathogen burden by phagocytes.
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收藏
页码:3195 / 3203
页数:9
相关论文
共 45 条
[1]
Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function [J].
Adachi, O ;
Kawai, T ;
Takeda, K ;
Matsumoto, M ;
Tsutsui, H ;
Sakagami, M ;
Nakanishi, K ;
Akira, S .
IMMUNITY, 1998, 9 (01) :143-150
[2]
Mammalian Toll-like receptors [J].
Akira, S .
CURRENT OPINION IN IMMUNOLOGY, 2003, 15 (01) :5-11
[3]
Hyporesponsiveness to vaccination with Borrelia burgdorferi OspA in humans and in TLR1- and TLR2-deficient mice [J].
Alexopoulou, L ;
Thomas, V ;
Schnare, M ;
Lobet, Y ;
Anguita, J ;
Schoen, RT ;
Medzhitov, R ;
Fikrig, E ;
Flavell, RA .
NATURE MEDICINE, 2002, 8 (08) :878-884
[4]
Cell activation and apoptosis by bacterial lipoproteins through toll-like receptor-2 [J].
Aliprantis, AO ;
Yang, RB ;
Mark, MR ;
Suggett, S ;
Devaux, B ;
Radolf, JD ;
Klimpel, GR ;
Godowski, P ;
Zychlinsky, A .
SCIENCE, 1999, 285 (5428) :736-739
[5]
CARDITIS IN LYME-DISEASE SUSCEPTIBLE AND RESISTANT STRAINS OF LABORATORY MICE INFECTED WITH BORRELIA-BURGDORFERI [J].
ARMSTRONG, AL ;
BARTHOLD, SW ;
PERSING, DH ;
BECK, DS .
AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 1992, 47 (02) :249-258
[6]
BARBOUR AG, 1984, YALE J BIOL MED, V57, P521
[7]
Bart C. K., 1997, IND MARKET MANAG, V25, P1
[8]
LYME BORRELIOSIS IN GENETICALLY RESISTANT AND SUSCEPTIBLE MICE WITH SEVERE COMBINED IMMUNODEFICIENCY [J].
BARTHOLD, SW ;
SIDMAN, CL ;
SMITH, AL .
AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 1992, 47 (05) :605-613
[9]
Barthold SW, 1996, LAB INVEST, V74, P57
[10]
LYME BORRELIOSIS IN SELECTED STRAINS AND AGES OF LABORATORY MICE [J].
BARTHOLD, SW ;
BECK, DS ;
HANSEN, GM ;
TERWILLIGER, GA ;
MOODY, KD .
JOURNAL OF INFECTIOUS DISEASES, 1990, 162 (01) :133-138