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Gern, Lise

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Gern, Lise
Affiliation principale
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Ancien.ne collaborateur.trice
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https://libra.unine.ch/handle/123456789/303

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  • Publication
    Métadonnées seulement
    Artificial-infection protocols allow immunodetection of novel Borrelia burgdorferi antigens suitable as vaccine candidates against Lyme disease
    (2003)
    Wallich, Reinhard
    ;
    Jahraus, Oliver
    ;
    Stehle, Thomas
    ;
    Tran, Thi Thanh Thao
    ;
    Brenner, Christiane
    ;
    Hofmann, Heidelore
    ;
    Gern, Lise 
    ;
    Simon, Markus M
    Vaccination with recombinant outer surface protein A (OspA) from Borrelia burgdorferi provides excellent antibody-mediated protection against challenge with the pathogen in animal models and in humans. However, the bactericidal antibodies are ineffective in the reservoir host, since OspA is expressed by spirochetes only in the vector, but rarely, if at all, in mammals. Using an artificially generated immune serum (anti-10(8) spirochetes) with high protective potential for prophylactic and therapeutic treatment, we have now isolated from an expression library of B. burgdorferi (strain ZS7) three novel genes, zs7.a36, zs7.a66 and zs7.a68. All three genes are located, together with ospA/B, on the linear plasmid lp54, and are expressed in vitro and in ticks. At least temporarily two of them, ZS7.A36 and ZS7.A66, are also expressed during infection. The respective natural antigens are poorly immunogenic in infected normal mice but elicited antibodies in Lyme disease patients. We show that recombinant preparations of ZS7.A36, ZS7.A66 and ZS7.A68 induce functional antibodies in rabbits capable of protecting immunodeficient mice against subsequent experimental infection. These findings suggest that all three recombinant antigens represent potential candidates for a 'second generation' vaccine to prevent and/or cure Lyme disease.
  • Publication
    Métadonnées seulement
    Resolution of experimental and tick-borne Borrelia burgdorferi infection in mice by passive, but not active immunization using recombinant OspC
    (1999)
    Zhong, Weimin
    ;
    Gern, Lise 
    ;
    Stehle, Thomas
    ;
    Museteanu, Crisan
    ;
    Kramer, Michael
    ;
    Wallich, Reinhard
    ;
    Simon, Markus M
    Vaccination with outer surface protein A (OspA) of Borrelia burgdorferi prevents subsequent infection and disease in both laboratory animals and humans with high efficacy. OspA-based immunity, however, does not affect established infection due to the loss of OspA expression in the vertebrate host. We show here that repeated passive transfer of mouse and/or rabbit immune sera to recombinant GST-OspC fusion protein resulted in a dose-dependent resolution (1) of fully established arthritis and carditis as well as infection in needle-challenged C.B-17 SCID and (2) of infection in both experimentally and tick-infected BALB/c mice. Unexpectedly, active immunization of disease-susceptible AKR/N mice with GST-OspC only led to prevention but not resolution of disease and infection, in spite of high serum titers of OspC-specific Ab and the expression of ospC in tissue-derived spirochetes. The data suggest that the efficacy of OspC antibody-mediated immunity depends on the immunological history of the recipient and/or environment-dependent regulation of OspC surface expression by spirochetes in vivo. The results encourage further attempts to develop therapeutic vaccination protocols against Lyme disease.
  • Publication
    Métadonnées seulement
    T helper cell priming of mice to Borrelia burgdorferi OspA leads to induction of protective antibodies following experimental but not tick-borne infection
    (1997)
    Zhong, Weimin
    ;
    Gern, Lise 
    ;
    Kramer, Michael
    ;
    Wallich, Reinhard
    ;
    Simon, Markus M
    Antibodies to the outer surface lipoprotein A (OspA) of Borrelia burgdorferi confer protection to SCID mice against subsequent tick-borne or experimental infection. However, OspA-specific antibodies are hardly detectable in naturally infected humans, dogs, hamsters and mice. This is most probably due to limited expression of OspA on spirochetes transmitted from the vector to the host. Here we have tested whether T cell priming of mice would lead to the induction of protective OspA-specific antibodies upon infection. It is shown that AKR/N mice, previously immunized with either a single T helper cell peptide of OspA, or a mixture of 27 peptides spanning the entire molecule, develop OspA-specific IgM or IgG antibodies, including those to a prominent protective B cell epitope of OspA, LA-2, within 7 days of infection with low doses (10(3)) of culture-derived spirochetes. In marked contrast, the same groups of pre-sensitized mice failed to generate any detectable OspA-specific antibodies after tick-borne infection for more than 40 days after infection. All mice, irrespective of their state of T cell immunity to OspA or the mode of infection, produced similar levels of OspC-specific IgM and IgG antibodies as early as day 14 after infection. None of the mice previously immunized with OspA peptides were protected against experimental infection, in spite of the appearance of protective antibodies. It is clear from these data that, in contrast to culture-derived spirochetes, the naturally transmitted pathogen fails to express OspA within the mammalian host at levels sufficient for induction of B cell responses, even in the presence of pre-activated T helper cells. Together with the fact that OspA-specific antibodies are mainly operative by eliminating spirochetes from the vector during infestation, the data suggest that OspA-vaccination for T helper cell immunity alone is not sufficient to prevent Lyme disease.
  • Publication
    Accès libre
    T helper cell priming of mice to Borrelia burgdorferi Osp A leads to induction of protective antibodies following experimental but not tickborne infection
    Zhong, Weimin
    ;
    Gern, Lise 
    ;
    Kramer, Michael
    ;
    Wallich, Reinhard
    ;
    Simon, Markus M
    Antibodies to the outer surface lipoprotein A (Osp A) of Borrelia burgdorferi confer protection to SCID mice against subsequent tick-borne or experimental infection. However, Osp A-specific antibodies are hardly detectable in naturally infected humans, dogs, hamsters and mice. This is most probably due to limited expression of Osp A on spirochetes transmitted from the vector to the host. Here we have tested whether T cell priming of mice would lead to the induction of protective Osp A-specific antibodies upon infection. It is shown that AKR/N mice, previously immunized with either a single T helper cell peptide of Osp A, or a mixture of 27 peptides spanning the entire molecule, develop Osp A-specific IgM or IgG antibodies, including those to a prominent protective B cell epitope of Osp A, LA-2, within 7 days of infection with low doses (103) of culture-derived spirochetes. In marked contrast, the same groups of pre-sensitized mice failed to generate any detectable Osp A-specific antibodies after tick-borne infection for more than 40 days after infection. All mice, irrespective of their state of T cell immunity to OspA or the mode of infection, produced similar levels of Osp C-specific IgM and IgG antibodies as early as day 14 after infection. None of the mice previously immunized with Osp A peptides were protected against experimental infection, in spite of the appearance of protective antibodies. It is clear from these data that, in contrast to culture-derived spirochetes, the naturally transmitted pathogen fails to express Osp A within the mammalian host at levels sufficient for induction of B cell responses, even in the presence of pre-activated T helper cells. Together with the fact that Osp A-specific antibodies are mainly operative by eliminating spirochetes from the vector during infestation, the data suggest that Osp A-vaccination for T helper cell immunity alone is not sufficient to prevent Lyme disease.
  • Publication
    Accès libre
    Resolution of experimental and tick-borne Borrelia burgdorferi infection in mice by passive, but not active immunization using recombinant OspC
    Zhong, Weimin
    ;
    Gern, Lise 
    ;
    Stehle, Thomas
    ;
    Museteanu, Crisan
    ;
    Kramer, Michael
    ;
    Wallich, Reinhard
    ;
    Simon, Markus M
    Vaccination with outer surface protein A (OspA) of Borrelia burgdorferi prevents subsequent infection and disease in both laboratory animals and humans with high efficacy. OspA-based immunity, however, does not affect established infection due to the loss of OspA expression in the vertebrate host. We show here that repeated passive transfer of mouse and/or rabbit immune sera to recombinant GST-OspC fusion protein resulted in a dose-dependent resolution (1) of fully established arthritis and carditis as well as infection in needle-challenged C.B-17 SCID and (2) of infection in both experimentally and tick-infected BALB/c mice. Unexpectedly, active immunization of disease-susceptible AKR/N mice with GST-OspC only led to prevention but not resolution of disease and infection, in spite of high serum titers of OspC-specific Ab and the expression of ospC in tissue-derived spirochetes. The data suggest that the efficacy of OspC antibody-mediated immunity depends on the immunological history of the recipient and/or environment-dependent regulation of OspC surface expression by spirochetes in vivo. The results encourage further attempts to develop therapeutic vaccination protocols against Lyme disease.
  • Publication
    Accès libre
    Protective immunization with plasmid DNA containing the outer surface lipoprotein A gene of Borrelia burgdorferi is independent of an eukaryotic promoter
    Simon, Markus M
    ;
    Gern, Lise 
    ;
    Hauser, Pierre
    ;
    Zhong, Weimin
    ;
    Nielsen, Peter J
    ;
    Kramer, Michael D
    ;
    Brenner, Christiane
    ;
    Wallich, Reinhard
    Plasmid DNA encoding the outer surface lipoprotein A (OspA) of Borrelia burgdorferi under the control of either strong eukaryotic/viral or its own bacterial promoter was injected intramuscularly (m. tibialis anterior) or intradermally into BALB/c and AKR/N mice. OspA-specific antibodies and OspA-reactive T helper 1 cells (Th1) were induced only with those plasmids containing the ospA structural gene including its own regulatory control region immediately upstream. In the absence of the ospA promoter, no or only marginal immune responses to ospA were obtained, even when strong eukaryotic promoter/enhancer elements were present. Together with the finding that the ospA promoter is active in a mouse B- lymphoma line, the data suggest that spirochetes are able to express at least part of their genes in the mammalian environment. Mice previously vaccinated with the relevant ospA plasmid DNA were protected against subsequent experimental challenge with a virulent strain of B. burgdorferi, as measured by the appearance of antibodies to a prominent protective epitope (LA-2) and the failure to re- isolate spirochetes from ear biopsies. In addition, C.B-17 severe-combined immunodeficient mice could be protected against infection by passive transfer of immune sera from ospA plasmid DNA-inoculated normal mice. Protective LA-2- related antibody titers obtained after repeated immunization persisted for 200 days and longer. This simple procedure of immunization using plasmid DNA consisting of a prokaryotic gene under the control of its own promoter holds great promise for the development of alternative subunit vaccines against bacterial infections, including Lyme disease. In addition, the availability of this novel prokaryotic promoter element now allows the study of the basis for the differential expression of bacterial genes in prokaryotic and eukaryotic environments.