Dataset Information

Proteomic analysis of three Borrelia burgdorferi sensu lato species and disseminating clones: relevance for Lyme vaccine design.

ABSTRACT: Lyme borreliosis is first characterized by a cutaneous inflammation, the erythema migrans, and if dissemination occurs after an infected tick bite cutaneous, nervous and articular manifestations appear. Although antibiotic treatments are efficient in the early stage of the infection, a significant number of patients develop disseminated manifestations due to unnoticed or absence of erythema migrans, or to inappropriate treatment. Vaccine could be an efficient approach to decrease Lyme disease incidence. We have developed a proteomic approach based on a Ge-LC-MS/MS strategy to identify new vaccine candidates. We analyzed a disseminating clone and the associated wild type strain for each major pathogenic Borrelia species: B. burgdorferi sensu stricto, B. garinii and B. afzelii. We managed to identify proteins specific and common to the disseminating clones of the 3 main species. In parallel, we used a spectral counting strategy in order to identify up-regulated proteins common to the clones. Thus, we identified 40 proteins that are potentially involved in bacterial virulence and could be of interest in the development of a new vaccine.

INSTRUMENT(S): ion trap

ORGANISM(S): Borrelia Burgdorferi 297

SUBMITTER: Schnell Gilles

LAB HEAD: Laurence Sabatier

PROVIDER: PXD000876 | Pride | 2015-02-16

REPOSITORIES: Pride

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Publications

Proteomic analysis of three Borrelia burgdorferi sensu lato native species and disseminating clones: relevance for Lyme vaccine design.

Schnell Gilles G Boeuf Amandine A Jaulhac Benoît B Boulanger Nathalie N Collin Elody E Barthel Cathy C De Martino Sylvie S Ehret-Sabatier Laurence L

Proteomics 20150204 7

Lyme borreliosis is the most important vector-borne disease in the Northern hemisphere. It is caused by Borrelia burgdorferi sensu lato bacteria transmitted to humans by the bite of hard ticks, Ixodes spp. Although antibiotic treatments are efficient in the early stage of the infection, a significant number of patients develop disseminated manifestations (articular, neurological, and cutaneous) due to unnoticed or absence of erythema migrans, or to inappropriate treatment. Vaccine could be an ef ...[more]

PMID: 25475896

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Project description:Chemokines and cytokines are key signaling molecules that orchestrate the trafficking of immune cells, direct them to sites of tissue injury and inflammation and modulate their states of activation and effector cell function. We have measured, using a multiplex-based approach, the levels of 58 immune mediators and 7 acute phase markers in sera derived from of a cohort of patients diagnosed with acute Lyme disease and matched controls. This analysis identified a cytokine signature associated with the early stages of infection and allowed us to identify two subsets (mediator-high and mediator-low) of acute Lyme patients with distinct cytokine signatures that also differed significantly (p<0.0005) in symptom presentation. In particular, the T cell chemokines CXCL9 (MIG), CXCL10 (IP-10) and CCL19 (MIP3B) were coordinately increased in the mediator-high group and levels of these chemokines could be associated with seroconversion status and elevated liver function tests (p=0.027 and p=0.021 respectively). There was also upregulation of acute phase proteins including CRP and serum amyloid A. Consistent with the role of CXCL9/CXCL10 in attracting immune cells to the site of infection, CXCR3+ CD4 T cells are reduced in the blood of early acute Lyme disease (p=0.01) and the decrease correlates with chemokine levels (p=0.0375). The levels of CXCL9/10 did not relate to the size or number of skin lesions but elevated levels of serum CXCL9/CXCL10 were associated with elevated liver enzymes levels. Collectively these results indicate that the levels of serum chemokines and the levels of expression of their respective chemokine receptors on T cell subsets may prove to be informative biomarkers for Lyme disease and related to specific disease manifestations. A total of 65 immune and inflammatory mediators were profiled in serum samples derived from early Lyme disease patients and age- and sex-matched controls. These samples have been generated as part of a prospective cohort study that includes a well-defined cohort of patients with acute Lyme disease enrolled from a Lyme endemic area of the mid-Atlantic United States. Only patients with untreated, confirmed early Lyme disease manifesting an active EM skin lesion at the time of enrollment, as defined by CDC case criteria are eligible. Patients with a history of prior Lyme disease or the presence of confounding preexisting medical conditions associated with prolonged fatigue, pain or neurocognitive symptoms are excluded. Controls are nonhospitalized age- and sex-matched and have no prior history of Lyme disease or any exclusionary medical conditions including lack of inflammatory disorders.

Project description:The alternative sigma factor RpoS plays a central role in the critical host-adaptive response of the Lyme disease spirochete, Borrelia burgdorferi. We previously identified bbd18 as a negative regulator of RpoS but could not inactivate bbd18 in wild-type spirochetes. In the current study we employed an inducible bbd18 gene to demonstrate the essential nature of BBD18 for viability of wild-type spirochete viability in vitro and at a unique point in vivo. Transcriptomic analyses of BBD18 depleted cells demonstrated global induction of RpoS-dependent genes prior to lysis, with the absolute requirement for BBD18, both in vitro and in vivo, circumvented by deletion of rpoS. The increased expression of plasmid prophage genes and the presence of phage particles in the supernatants of lysing cultures indicate that RpoS regulates phage lysis-lysogeny decisions. Through this work we identify a mechanistic link between endogenous transducing prophages and the RpoS-dependent adaptive response of the Lyme disease spirochete. The alternative sigma factor RpoS plays a central role in the critical host-adaptive response of the Lyme disease spirochete, Borrelia burgdorferi. We previously identified bbd18 as a negative regulator of RpoS but could not inactivate bbd18 in wild-type spirochetes. In the current study we employed an inducible bbd18 gene to demonstrate the essential nature of BBD18 for viability of wild-type spirochete viability in vitro and at a unique point in vivo. Transcriptomic analyses of BBD18 depleted cells demonstrated global induction of RpoS-dependent genes prior to lysis, with the absolute requirement for BBD18, both in vitro and in vivo, circumvented by deletion of rpoS. The increased expression of plasmid prophage genes and the presence of phage particles in the supernatants of lysing cultures indicate that RpoS regulates phage lysis-lysogeny decisions. Through this work we identify a mechanistic link between endogenous transducing prophages and the RpoS-dependent adaptive response of the Lyme disease spirochete.

Dataset Information

Proteomic analysis of three Borrelia burgdorferi sensu lato species and disseminating clones: relevance for Lyme vaccine design.

Publications

Proteomic analysis of three Borrelia burgdorferi sensu lato native species and disseminating clones: relevance for Lyme vaccine design.

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