Immunoglobulin-Regulated Expression of<i>Borrelia burgdorferi</i>Outer Surface Protein A In Vivo

Hodzic, Emir; Tunev, Stefan; Shao, Feng; Freet, Kim J.; Barthold, Stephen W.

doi:10.1128/iai.73.6.3313-3321.2005

Cited by 9 publications

(13 citation statements)

References 52 publications

(63 reference statements)

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“…To accomplish this, we processed three types of mouse tissue for immunohistochemical labeling of spirochetes during disease remission. We first examined archival tissue from a previous study (30) in which infected C3H-scid mice were immunologically reconstituted at 2 weeks of infection by intravenous adoptive transfer of 2 ϫ 10 7 splenocytes and 1 ϫ 10 7 lymph node cells from naïve C3H mice. At 4 and 6 weeks after adoptive transfer (6 and 8 weeks after infection), mice were necropsied.…”

Section: Induction Of Disease Remission and Tissue Spirochete Reductimentioning

confidence: 99%

“…The effect of treatment on spirochete numbers and gene expression in tissues was assessed in heart base, heart ventricular muscle, left tibiotarsus, and quadriceps muscle. These tissues were selected because heart base and tibiotarsus are sites with inflammation, whereas heart ventricular muscle and quadriceps muscle are tissues that are infected, but with minimal inflammation or no inflammation in C3H-scid mice (9,30). Tissue processing for DNA/RNA extraction precluded examination of heart base for carditis.…”

Section: Induction Of Disease Remission and Tissue Spirochete Reductimentioning

confidence: 99%

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Antibody-Mediated Disease Remission in the Mouse Model of Lyme Borreliosis

et al. 2006

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In the mouse model of Lyme borreliosis, the host immune response during infection with Borrelia burgdorferi results in the remission of carditis and arthritis, as well as global reduction of spirochete numbers in tissues, without elimination of infection (28). These events were recapitulated by passive transfer of immune serum from infected immunocompetent mice or T-cell-deficient mice to severe combined immunodeficient (SCID) mice. Previous studies have shown that immune serum is reactive against arthritis-related protein (Arp) and that Arp antiserum induces arthritis remission (16). However, although immune serum from T-cell-deficient mice induced disease remission, it was not reactive against Arp, suggesting that antibody to another antigen may be responsible. T-cell-deficient mouse immune serum was reactive to decorin binding protein A (DbpA). Therefore, DbpA antiserum was tested to determine its ability to induce disease remission in SCID mice. Antisera to Arp or DbpA induced both carditis and arthritis remission but did not significantly reduce spirochete numbers in tissues, based upon quantitative flaB DNA analysis, nor did treatment affect RNA levels of several genes, including arp and dbpA. Immunohistochemical labeling of spirochetes in hearts and joints during disease remission induced by adoptive transfer of lymphocytes, passive transfer of immune serum, or passive transfer of DbpA antiserum revealed that such treatment resulted in elimination of spirochetes from heart base and synovium but not vascular walls, tendons, or ligaments. These results suggest that Arp and DbpA antibodies may be active as disease-resolving components in immune serum but antibody against other antigens may be involved in reductions of spirochetes in tissues.Lyme borreliosis, caused by tick-borne Borrelia burgdorferi, has numerous clinical manifestations in humans, including arthritis and carditis, which undergo remission and periodic bouts of exacerbation over the course of months to years of persistent infection (42). Laboratory mice inoculated with B. burgdorferi also develop arthritis and carditis, which evolve over the course of three weeks and then undergo immunemediated remission and recurrence during persistent infection

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Section: Induction Of Disease Remission and Tissue Spirochete Reductimentioning

confidence: 99%

Section: Induction Of Disease Remission and Tissue Spirochete Reductimentioning

confidence: 99%

Antibody-Mediated Disease Remission in the Mouse Model of Lyme Borreliosis

et al. 2006

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“…When infected ticks feed again, the spirochetes multiply within the vector, downregulate the production of OspA and infect the host via the salivary glands of the tick. Nonspecific natural antibody in a host may be one signal that down regulates ospA expression (16). Mutants missing OspA and B are able to infect mice and cause disease (28).…”

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confidence: 99%

Infection of Mice with Lyme Disease Spirochetes Constitutively Producing Outer Surface Proteins A and B

et al. 2007

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Outer surface protein A (OspA) of the Lyme disease spirochete is primarily produced in the tick vector. OspA, which is a receptor for attaching spirochetes to the tick gut, is down regulated as the spirochetes leave the tick and enter the mammalian host. Although OspA is not a major antigen produced in the mammal, the protein appears to be produced under some conditions and production has been linked to more severe disease. A Lyme disease vaccine based on recombinant OspA has been approved for human use. However, the vaccine is no longer available, in part because of fears that OspA causes arthritis in people. To further understand the consequences of OspA production in the host, we created a Borrelia burgdorferi mutant that was unable to down regulate OspA. C3H/HeN mice infected with this mutant developed a specific anti-OspA immune response, and the spirochetes were unable to persist in these mice. In contrast, immunodeficient SCID mice were persistently infected with the mutant. We conclude that spirochetes producing OspA and B from the flaB promoter in immunocompetent mice stimulate an immune response that clear the bacteria without any signs of disease development in the mice.The Lyme disease spirochete Borrelia burgdorferi produces an array of outer surface lipoproteins (Osps). While some of the lipoproteins are chromosomally produced, the majority are produced on extrachromosomal plasmids. As many as 91, or 14.5%, of the genes encoded on plasmids are putative lipoproteins (7). Many plasmid-encoded lipoproteins are differentially expressed in the tick vector or the vertebrate host, indicating that they function at specific stages in the life cycle of the spirochete. The function of several lipoproteins has been studied using genetic and biochemical approaches, but there still remains much to be learned about these proteins.OspA and B are two proteins encoded by a single operon on linear plasmid 54 (lp54). These two surface proteins are produced in abundance by spirochetes grown in culture. OspA, in particular, has been the focus of study because the gene encoding OspA was among the first B. burgdorferi genes to be cloned and a recombinant OspA vaccine has been approved for use in people and animals. However, the vaccine is no longer available, in part because of fears that the protein or an immune response against the protein could induce arthritis. OspA is differentially produced during the natural transmission cycle of the spirochete. When spirochetes first enter a tick, OspA is upregulated and the protein is required for tick colonization. OspA serves as a ligand for tethering spirochetes to a receptor in the tick gut (20). When infected ticks feed again, the spirochetes multiply within the vector, downregulate the production of OspA and infect the host via the salivary glands of the tick. Nonspecific natural antibody in a host may be one signal that down regulates ospA expression (16). Mutants missing OspA and B are able to infect mice and cause disease (28).There is conflicting data about the role of ...

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“…One signal for downregulation of ospA in the tick is a natural antibody that is acquired during the blood meal (Belperron and Bockenstedt 2001). In contrast, ospA is transcribed in immunodeficient C3H-scid mice, and it has been found that passive transfer of normal mouse serum in infected C3H-scid mice results in ospA downregulation (Hodzic et al 2005). OspA also tends to be expressed in the context of inflammation (Crowley and Huber 2003).…”

Section: Discussionmentioning

confidence: 99%

Assessment of Transcriptional Activity ofBorrelia burgdorferiand Host Cytokine Genes During Early and Late Infection in a Mouse Model

Hodzic

Shao

Barthold³

2013

Vector-Borne and Zoonotic Diseases

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Differential gene expression by Borrelia burgdorferi spirochetes during mammalian infection facilitates their dissemination as well as immune evasion. Modulation of gene transcription in response to host immunity has been documented with the outer surface protein C, but the influence of transcription of other genes is largely unknown. A low-density array (LDA) was developed to study transcriptional activity of 43 B. burgdorferi genes and 19 host genes that may be involved in various host-agent interactions. Gene transcription in heart, joint, and muscle tissue was compared in immunocompetent C3H and immunodeficient C3H-scid mice during early (3 weeks) and late (2 months) B. burgdorferi infection. Among all tissue types, levels of relative transcription of over 80% of B. burgdorferi genes tested were one-to nine-fold less in C3H mice compared to C3H-scid mice. At the later time point, all genes were transcribed in C3H-scid mice, whereas transcription of 16 genes out of 43 tested was not detected in analyzed tissues of C3H mice. Our data suggest that during infection of immunocompetent mice, a majority of B. burgdorferi genes tested are downregulated in response to acquired host immunity. LDA revealed variable patterns of host gene expression in different tissues and at different intervals in infected mice. Higher levels of relative expression for IL-10 during both early and late infection were detected in heart base, and it was unchanged in the tibiotarsal joint. Comparative analysis of B. burgdorferi and host genes transcriptional activity revealed that increased flaB mRNA during early infection was followed by increases of CCL7, CCL8, interleukin-10 (IL-10), and tumor necrosis factor-a (TNF-a) in all assessed tissue types. LDA represents a valuable approach for sensitive and quantitative gene transcription profiling and for understanding Lyme borreliosis.

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Immunoglobulin-Regulated Expression ofBorrelia burgdorferiOuter Surface Protein A In Vivo

Cited by 9 publications

References 52 publications

Antibody-Mediated Disease Remission in the Mouse Model of Lyme Borreliosis

Antibody-Mediated Disease Remission in the Mouse Model of Lyme Borreliosis

Infection of Mice with Lyme Disease Spirochetes Constitutively Producing Outer Surface Proteins A and B

Assessment of Transcriptional Activity ofBorrelia burgdorferiand Host Cytokine Genes During Early and Late Infection in a Mouse Model

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