Borrelia burgdorferi and Treponema pallidum: a comparison of functional genomics, environmental adaptations, and pathogenic mechanisms

Porcella, Stephen F.; Schwan, Tom G.

doi:10.1172/jci12484

Cited by 50 publications

(39 citation statements)

References 33 publications

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“…B burgdorferi does not produce true LPS, and genomic analysis has shown that LPS biosynthetic genes are absent (28). The recombinant proteins used in the current study contained LPS in quantities comprising 0.1-1.0% of total protein, presumably arising as a contaminant during production and purification.…”

Section: Discussionmentioning

confidence: 95%

“…This finding excludes more rapid elimination of OspB as an explanation for its failure to induce injury. It is also unlikely that differences in NF-B activation are involved, because all lipidated OSPs (OspA, OspB, and OspC) were able to activate this major inflammatory pathway in selected target cell populations, whereas the nonlipidated versions were not effective (6,27) (28). Expression of OSP gene products in the tick vector and the mammalian host has been studied previously (30).…”

Section: Discussionmentioning

confidence: 99%

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Outer surface lipoproteins ofBorrelia burgdorferivary in their ability to induce experimental joint injury

Batsford

Dunn

Mihatsch³

2004

Arthritis & Rheumatism

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Objective. To examine the ability of bacterial lipoproteins from the spirochete Borrelia burgdorferi to cause in vivo tissue injury (arthritis).Methods. Outer surface proteins (OSPs) from B burgdorferi were used in a rat model of antigen-induced allergic arthritis. Intraarticular challenge with recombinant OspA, OspB, and OspC in nonlipidated (peptide) and lipidated forms was performed in the left knee joint; the contralateral joint received buffer as control. Inflammation was monitored by technetium scintigraphy and histology.Results. Nonlipidated (peptide) OspA, OspB, and OspC did not induce arthritis; the only exception was polymerized OspA, which was tested in preimmunized rats. Lipidated OspA from 2 different strains and lipidated OspC induced severe arthritis, whereas lipidated OspB failed to induce injury. A synthetic analog of the OSP lipid modification, lipopeptide Pam 3 Cys-SerLys 4 -OH, either alone or coupled to bovine serum albumin, also failed to induce injury. Injury did not develop in control groups that were given the appropriate buffers or lipopolysaccharide. This showed that lipidated borrelial OSPs can be potent arthritogens but vary greatly with respect to their injury-inducing potential. The possession of a lipid modification is essential but is not sufficient to render an OSP arthritogenic.Conclusion. This is the first study to demonstrate that individual lipoproteins from B burgdorferi can induce experimental joint injury in vivo. These results may help elucidate the pathogenesis of Lyme arthritis and, above all, underline the importance of bacterial lipoproteins as major virulence factors.Lipoproteins are now being recognized as prime virulence factors of bacteria. For many decades this group of molecules played the role of poor relation to the lipopolysaccharides (LPS), but particularly the discovery that lipoproteins can act as ligands for the Toll-like receptor (TLR) complex has rekindled interest (1). In earlier studies, a number of naturally occurring bacterial lipoproteins and their synthetic lipopeptide analogs were shown to possess impressive biologic activities. The Braun protein, a prototype lipoprotein, can stimulate lymphocytes (2), and the corresponding synthetic lipopeptide is in fact now used as an adjuvant (3). Membrane lipoproteins and the corresponding lipopeptides from mycoplasma could induce mononuclear phagocytes to secrete cytokines; a particular lipopeptide from Mycoplasma fermentans, macrophage activating lipopeptide 2, was effective even at concentrations in the picogram range (4). The outer surface lipoproteins (OSPs) of Borrelia burgdorferi have been shown to exhibit similar stimulatory effects (5-8).Results of recent in vitro studies indicated that the lipid moiety plays a key role, and that the CD14/ TLR-2 receptors can be involved (9-11). Lipoproteins have been shown to be capable of inducing tissue injury in animals, mimicking certain common clinical manifestations of the corresponding infection in man. First, synthetic lipopeptide analogs of treponemal and...

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Outer surface lipoproteins ofBorrelia burgdorferivary in their ability to induce experimental joint injury

Batsford

Dunn

Mihatsch³

2004

Arthritis & Rheumatism

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“…Immunization of hosts against OspA protects against tick-borne infection by killing OspA-expressing spirochetes in the tick midgut during the initial stages of feeding (22). When spirochetes are transmitted to naïve hosts, they do not express OspA (24,30,40) and are therefore no longer vulnerable to OspA immunity (15). These dynamics are reflected in the sera of most patients and animals following tick-borne infection with B. burgdorferi.…”

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confidence: 99%

Immunoglobulin-Regulated Expression ofBorrelia burgdorferiOuter Surface Protein A In Vivo

et al. 2005

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Borrelia burgdorferi, the agent of Lyme disease, down-regulates outer surface protein A (OspA), which is abundantly expressed in ticks, during infection of the mammalian host. In this study we examined the signals that may be responsible for maintaining the OspA-negative state of spirochetes during infection. Transcription of ospA mRNA was found in tissues of C3H-severe combined immunodeficient (C3H-scid) mice, but not immunocompetent C3H mice, inoculated with cultured B. burgdorferi, tick-borne spirochetes, and host-adapted spirochetes. Transcription was more frequent at 4 weeks than at 1 week. Transcription was present at the host-tick interface as early as 24 h after tick attachment but declined at 48 and 72 h. Thus, ospA mRNA transcription in distant tissues and at later times in C3H-scid mice is probably due to up-regulation during infection. Adoptive lymphocyte transfer from naïve C3H mice to infected C3H-scid mice resulted in OspA seroconversion, confirming OspA expression in the host. Passive transfer of normal mouse serum, immunoglobulin M (IgM) from normal mouse serum, or IgG from normal mouse serum into infected C3H-scid mice resulted in down-regulation of ospA, but transfer of normal mouse serum depleted of immunoglobulin did not influence ospA mRNA transcription. Collectively, our results indicate that ospA mRNA transcription in the host is regulated by nonspecific immunoglobulin, which may be a natural antibody.

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“…Upon transmission, the spirochetes stay in the skin at the attachment site for several days and then disseminate throughout the vertebrate host (42). Early in infection, spirochetes express OspC but not OspA (11,30,37). In addition to these two lipoproteins that seem to be involved in adaptation to different environments, there is mounting evidence that genes encoding different antigens are differentially expressed or repressed in response to a variety of environmental cues during pathogen-tick-host interactions (7,8,13,22,26,27,32,38,39,41,44,45).…”

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confidence: 99%

Borrelia burgdorferi Population Kinetics and Selected Gene Expression at the Host-Vector Interface

et al. 2002

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By using real-time quantitative PCR, the population dynamics and gene transcription of Borrelia burgdorferi were examined in ticks and skin of mice during acquisition of the infection from mice by ticks and during transmission of the infection from ticks to mice. Population dynamics were determined by using a flaB DNA target. A quantitative analysis of flaB, ospA, ospC, dbpA, and arp transcription was also performed. The results revealed that both uninfected larval and nymphal Ixodes scapularis ticks acquired B. burgdorferi as early as 1 day after attachment and that the sizes of spirochete populations within ticks increased during feeding. In addition, all gene targets revealed that there was RNA transcription during feeding. Similar events occurred within infected nymphal ticks feeding on uninfected hosts. Transmission from infected nymphal ticks to mice could be detected within 1 day after attachment. Analysis of skin during the first 3 days after attachment of infected ticks revealed rising numbers of spirochetes but minimal gene transcription. In contrast, the skin of mice with established infections revealed static populations of spirochetes and active but stable transcription of flaB, ospC, dbpA, and arp. There were consistent reductions in the number of spirochetes in the skin at the tick attachment sites compared to the number of spirochetes in the skin at nontick sites, but there were no differences in gene expression between tick and nontick skin sites. Evidence of ospA transcription in skin could be found 1 day after tick attachment but not thereafter.Borrelia burgdorferi, the causative agent of Lyme disease, is transmitted to and acquired from its hosts by Ixodes spp. hard ticks. The principal Ixodes vectors include Ixodes ricinus in Europe, Ixodes persulcatus in Eastern Europe and Asia, and Ixodes scapularis and Ixodes pacificus in North America (35,43). Acquisition and transmission are processes that involve the tick, the host, and the pathogen in reciprocal interactions with one other. After attachment, ticks induce host local inflammatory responses and immune responses against components within their saliva. To counteract these responses, tick saliva also contains substances that suppress or divert host immune responses (31,46).In addition to these vector and host processes, B. burgdorferi undergoes dynamic changes within the vector during both acquisition and transmission and within vertebrate hosts after transmission. These changes include striking variations in antigen expression. For example, B. burgdorferi is limited to the midgut of resting (unfed) nymphal and adult ticks (5) and usually express outer surface protein A (OspA) and very rarely OspC (18). After ticks attach and begin feeding, the spirochetes rapidly multiply (12), down-regulate or shed OspA, and up-regulate OspC during their migration to the salivary glands (41). Upon transmission, the spirochetes stay in the skin at the attachment site for several days and then disseminate throughout the vertebrate host (42). Early in infect...

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Borrelia burgdorferi and Treponema pallidum: a comparison of functional genomics, environmental adaptations, and pathogenic mechanisms

Cited by 50 publications

References 33 publications

Outer surface lipoproteins ofBorrelia burgdorferivary in their ability to induce experimental joint injury

Outer surface lipoproteins ofBorrelia burgdorferivary in their ability to induce experimental joint injury

Immunoglobulin-Regulated Expression ofBorrelia burgdorferiOuter Surface Protein A In Vivo

Borrelia burgdorferi Population Kinetics and Selected Gene Expression at the Host-Vector Interface

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