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Nod2 suppresses Borrelia burgdorferi mediated murine Lyme arthritis and carditis through the induction of tolerance.

Petnicki-Ocwieja T, DeFrancesco AS, Chung E, Darcy CT, Bronson RT, Kobayashi KS, Hu LT - PLoS ONE (2011)

Bottom Line: The internalization of Borrelia burgdorferi, the causative agent of Lyme disease, by phagocytes is essential for an effective activation of the immune response to this pathogen.In vitro stimulation of Nod2 deficient bone marrow derived macrophages (BMDM) resulted in decreased induction of multiple cytokines, interferons and interferon regulated genes compared with wild-type cells.However, B. burgdorferi infection of Nod2 deficient mice resulted in increased rather than decreased arthritis and carditis compared to control mice.

View Article: PubMed Central - PubMed

Affiliation: Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Boston, Massachusetts, United States of America.

ABSTRACT
The internalization of Borrelia burgdorferi, the causative agent of Lyme disease, by phagocytes is essential for an effective activation of the immune response to this pathogen. The intracellular, cytosolic receptor Nod2 has been shown to play varying roles in either enhancing or attenuating inflammation in response to different infectious agents. We examined the role of Nod2 in responses to B. burgdorferi. In vitro stimulation of Nod2 deficient bone marrow derived macrophages (BMDM) resulted in decreased induction of multiple cytokines, interferons and interferon regulated genes compared with wild-type cells. However, B. burgdorferi infection of Nod2 deficient mice resulted in increased rather than decreased arthritis and carditis compared to control mice. We explored multiple potential mechanisms for the paradoxical response in in vivo versus in vitro systems and found that prolonged stimulation with a Nod2 ligand, muramyl dipeptide (MDP), resulted in tolerance to stimulation by B. burgdorferi. This tolerance was lost with stimulation of Nod2 deficient cells that cannot respond to MDP. Cytokine patterns in the tolerance model closely paralleled cytokine profiles in infected Nod2 deficient mice. We propose a model where Nod2 has an enhancing role in activating inflammation in early infection, but moderates inflammation after prolonged exposure to the organism through induction of tolerance.

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Nod2 deficiency does not affect the control of B. burgdorferi burden.A) Three or four day old wild type (B6) and Nod2 deficient mice were injected subcutaneously with B. burgdorferi at 1×104 cells. Mice were sacrificed at 4 weeks post-infection. Bacterial loads in bladders (A) or hearts (B) were quantified by quantitative RT-qPCR for the bacterial ospA gene and normalized to copies of mouse nidogen. Values represent relative expression ± s.e.m. of three independent experiments, * p<0.05.
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pone-0017414-g007: Nod2 deficiency does not affect the control of B. burgdorferi burden.A) Three or four day old wild type (B6) and Nod2 deficient mice were injected subcutaneously with B. burgdorferi at 1×104 cells. Mice were sacrificed at 4 weeks post-infection. Bacterial loads in bladders (A) or hearts (B) were quantified by quantitative RT-qPCR for the bacterial ospA gene and normalized to copies of mouse nidogen. Values represent relative expression ± s.e.m. of three independent experiments, * p<0.05.

Mentions: To address the role of Nod2 in B. burgdorferi infection in vivo, wild type C57BL/6 and Nod2 deficient mice were subcutaneously infected with the spirochetes. The C57BL/6 genetic background is known to be resistant to B. burgdorferi induced arthritis. However, young mice of all species develop more severe arthritis than older mice and even young mice of the C57BL/6 background will develop detectable arthritis. The infant mouse model has been previously used to study other genetic knockout mice on a C57BL/6 background [45]. Age matched wild type and Nod2 deficient mice were infected with B. burgdorferi by subcutaneous injection. Mice were sacrificed at 4 weeks post-infection and we examined the numbers of B. burgdorferi in heart and bladder tissue by qPCR by measuring copies of B. burgdorferi recA (data not shown) and ospA (Figure 7) relative to mouse nidogen. Despite the immaturity of the immune system at the time of infection, the infection of mice with B. burgdorferi at a young age did not affect the bacterial burden in these mice when sampled at 3–4 weeks of age compared to mice infected as adults in previous studies (data not shown) [15]. Our analysis of bacterial burden showed a median decrease from 1190 copies of ospA in wild type mouse bladders down to 526 copies in Nod2 deficient bladders and from 11,550 copies in wild type hearts down to 4,475 copies in Nod2 deficient hearts (p = 0.0335 and 0.0155) (Figure 7). This suggests that Nod2 does not play a major role in reducing bacterial burden and may, in fact, hinder control of infection.


Nod2 suppresses Borrelia burgdorferi mediated murine Lyme arthritis and carditis through the induction of tolerance.

Petnicki-Ocwieja T, DeFrancesco AS, Chung E, Darcy CT, Bronson RT, Kobayashi KS, Hu LT - PLoS ONE (2011)

Nod2 deficiency does not affect the control of B. burgdorferi burden.A) Three or four day old wild type (B6) and Nod2 deficient mice were injected subcutaneously with B. burgdorferi at 1×104 cells. Mice were sacrificed at 4 weeks post-infection. Bacterial loads in bladders (A) or hearts (B) were quantified by quantitative RT-qPCR for the bacterial ospA gene and normalized to copies of mouse nidogen. Values represent relative expression ± s.e.m. of three independent experiments, * p<0.05.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3046161&req=5

pone-0017414-g007: Nod2 deficiency does not affect the control of B. burgdorferi burden.A) Three or four day old wild type (B6) and Nod2 deficient mice were injected subcutaneously with B. burgdorferi at 1×104 cells. Mice were sacrificed at 4 weeks post-infection. Bacterial loads in bladders (A) or hearts (B) were quantified by quantitative RT-qPCR for the bacterial ospA gene and normalized to copies of mouse nidogen. Values represent relative expression ± s.e.m. of three independent experiments, * p<0.05.
Mentions: To address the role of Nod2 in B. burgdorferi infection in vivo, wild type C57BL/6 and Nod2 deficient mice were subcutaneously infected with the spirochetes. The C57BL/6 genetic background is known to be resistant to B. burgdorferi induced arthritis. However, young mice of all species develop more severe arthritis than older mice and even young mice of the C57BL/6 background will develop detectable arthritis. The infant mouse model has been previously used to study other genetic knockout mice on a C57BL/6 background [45]. Age matched wild type and Nod2 deficient mice were infected with B. burgdorferi by subcutaneous injection. Mice were sacrificed at 4 weeks post-infection and we examined the numbers of B. burgdorferi in heart and bladder tissue by qPCR by measuring copies of B. burgdorferi recA (data not shown) and ospA (Figure 7) relative to mouse nidogen. Despite the immaturity of the immune system at the time of infection, the infection of mice with B. burgdorferi at a young age did not affect the bacterial burden in these mice when sampled at 3–4 weeks of age compared to mice infected as adults in previous studies (data not shown) [15]. Our analysis of bacterial burden showed a median decrease from 1190 copies of ospA in wild type mouse bladders down to 526 copies in Nod2 deficient bladders and from 11,550 copies in wild type hearts down to 4,475 copies in Nod2 deficient hearts (p = 0.0335 and 0.0155) (Figure 7). This suggests that Nod2 does not play a major role in reducing bacterial burden and may, in fact, hinder control of infection.

Bottom Line: The internalization of Borrelia burgdorferi, the causative agent of Lyme disease, by phagocytes is essential for an effective activation of the immune response to this pathogen.In vitro stimulation of Nod2 deficient bone marrow derived macrophages (BMDM) resulted in decreased induction of multiple cytokines, interferons and interferon regulated genes compared with wild-type cells.However, B. burgdorferi infection of Nod2 deficient mice resulted in increased rather than decreased arthritis and carditis compared to control mice.

View Article: PubMed Central - PubMed

Affiliation: Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Boston, Massachusetts, United States of America.

ABSTRACT
The internalization of Borrelia burgdorferi, the causative agent of Lyme disease, by phagocytes is essential for an effective activation of the immune response to this pathogen. The intracellular, cytosolic receptor Nod2 has been shown to play varying roles in either enhancing or attenuating inflammation in response to different infectious agents. We examined the role of Nod2 in responses to B. burgdorferi. In vitro stimulation of Nod2 deficient bone marrow derived macrophages (BMDM) resulted in decreased induction of multiple cytokines, interferons and interferon regulated genes compared with wild-type cells. However, B. burgdorferi infection of Nod2 deficient mice resulted in increased rather than decreased arthritis and carditis compared to control mice. We explored multiple potential mechanisms for the paradoxical response in in vivo versus in vitro systems and found that prolonged stimulation with a Nod2 ligand, muramyl dipeptide (MDP), resulted in tolerance to stimulation by B. burgdorferi. This tolerance was lost with stimulation of Nod2 deficient cells that cannot respond to MDP. Cytokine patterns in the tolerance model closely paralleled cytokine profiles in infected Nod2 deficient mice. We propose a model where Nod2 has an enhancing role in activating inflammation in early infection, but moderates inflammation after prolonged exposure to the organism through induction of tolerance.

Show MeSH
Related in: MedlinePlus