A Novel Mouse Model Of Neuroborreliosis

Lyme disease (LD) is a tick-borne infection caused by Borrelia burgdorferi (Bb) that has a global impact and a high incidence in the United States. If not treated with antibiotics during the early stages of the disease within the first few weeks of infection, patients usually develop musculoskeletal symptoms and neurological complications that can include neurocognitive and neuropsychiatric manifestations. For many, regardless of the stage of the disease or duration of the infection, antibiotic treatment with oral or intravenous antibiotics is curative. Nevertheless, up to 20% of individuals that receive antibiotic treatment during late-stage infection do not find relief from their symptoms, despite multiple rounds of antibiotic therapy. Collectively, the symptoms that persist after antibiotic treatment are called Refractory Lyme arthritis (RLA) when symptoms are predominantly rheumatologic, or post-treatment Lyme Disease syndrome (PTLDS) when symptoms are predominantly neurologic, neuropsychiatric and/or neurocognitive. Neither of the syndromes is mutually exclusive. Currently there is no FDA approved treatment for PTLDS, and although autoimmune etiologies have been proposed, a definitive causal mechanism has not been identified. A major limitation in our understanding of neurologic LD and its associated syndrome PTLDS is the lack of a suitable mouse model for modeling neurologic Bb infection. In section 1, we provide background on LD and summarize the hypotheses and approaches that we took in our research. In section 2, we review T cell and dendritic cell contributions to inflammation in RLA, to underscore what is known about complications of LD. Section 2 closes with a brief discussion of PTLDS and neuroborreliosis, to emphasize the questions that are currently understudied in LD. In section 3, we present a novel mouse model of neuroborreliosis that results from Bb infection of C3H/HeN mice, using the North American CSF-tropic strain of Bb, Bb 297, and an intradermal route of inoculation. We demonstrate that intradermal infection with Bb 297 results in persistent infection of the meninges and the brain, that CD4+ T cells accumulate in the brain during early and late-stage LD, and that both persistent infection and neuroimmune changes are temporally associated with significant behavioral deficits in nociception, mobility, and movement. In section 4 we provide a discussion of the implications of the research that we have performed

A Murine Model of Lyme Disease Demonstrates That Borrelia burgdorferi Colonizes the Dura Mater and Induces Inflammation in the Central Nervous System

Lyme disease, which is caused by infection with Borrelia burgdorferi and related species, can lead to inflammatory pathologies affecting the joints, heart, and nervous systems including the central nervous system (CNS). Inbred laboratory mice are effective models for characterizing B. burgdorferi infection kinetics and host immune responses in joints and heart tissues; however, similar studies are lacking in the CNS of these animals. Here we characterize the kinetics of B. burgdorferi colonization and associated immune responses in the CNS of infected C3H mice during early and subacute infection. B. burgdorferi colonized the dura mater following needle or tick challenge, and induced expression of inflammatory cytokines and a robust IFN response as well as histopathological changes. A sterile IFN response in the absence of B. burgdorferi or inflammatory cytokines was unique to the brain parenchyma, and could provide insights into the mechanism of inflammatory CNS pathology associated with this important pathogen

Borrelia burgdorferi Adhere to Blood Vessels in the Dura Mater and are Associated with Increased Meningeal T Cells during Murine Disseminated Borreliosis

Borrelia burgdorferi, the causative agent of Lyme disease, is a vector-borne bacterial infection that is transmitted through the bite of an infected tick. If not treated with antibiotics during the early stages of infection, disseminated infection can spread to the central nervous system (CNS). In non-human primates (NHPs) it has been demonstrated that the leptomeninges are among the tissues colonized by B. burgdorferi spirochetes. Although the NHP model parallels aspects of human borreliosis, a small rodent model would be ideal to study the trafficking of spirochetes and immune cells into the CNS. Here we show that during early and late disseminated infection, B. burgdorferi infects the meninges of intradermally infected mice, and is associated with concurrent increases in meningeal T cells. We found that the dura mater was consistently culture positive for spirochetes in transcardially perfused mice, independent of the strain of B. burgdorferi used. Within the dura mater, spirochetes were preferentially located in vascular regions, but were also present in perivascular, and extravascular regions, as late as 75 days post-infection. At the same end-point, we observed significant increases in the number of CD3+ T cells within the pia and dura mater, as compared to controls. Flow cytometric analysis of leukocytes isolated from the dura mater revealed that CD3+ cell populations were comprised of both CD4 and CD8 T cells. Overall, our data demonstrate that similarly to infection in peripheral tissues, spirochetes adhere to the dura mater during disseminated infection, and are associated with increases in the number of meningeal T cells. Collectively, our results demonstrate that there are aspects of B. burgdorferi meningeal infection that can be modelled in laboratory mice, suggesting that mice may be useful for elucidating mechanisms of meningeal pathogenesis by B. burgdorferi

Tarih-i Hayrullah Efendi, Devlet-i Aliye-i Osmaniye tarihi

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Tarih-i Hayrullah Efendi, Devlet-i Aliye-i Osmaniye tarihi

Yayın Tarihi İç Kapakta “1289 H.”, Ketebe Kaydında İse “ Gurre-İ Muharrem 1290”Dir. Ön Ve Arka Cildler Bezemelidir

A murine model of Lyme disease demonstrates that Borrelia burgdorferi colonizes the dura mater and induces inflammation in the central nervous system.

Lyme disease, which is caused by infection with Borrelia burgdorferi and related species, can lead to inflammatory pathologies affecting the joints, heart, and nervous systems including the central nervous system (CNS). Inbred laboratory mice have been used to define the kinetics of B. burgdorferi infection and host immune responses in joints and heart, however similar studies are lacking in the CNS of these animals. A tractable animal model for investigating host-Borrelia interactions in the CNS is key to understanding the mechanisms of CNS pathogenesis. Therefore, we characterized the kinetics of B. burgdorferi colonization and associated immune responses in the CNS of mice during early and subacute infection. Using fluorescence-immunohistochemistry, intravital microscopy, bacterial culture, and quantitative PCR, we found B. burgdorferi routinely colonized the dura mater of C3H mice, with peak spirochete burden at day 7 post-infection. Dura mater colonization was observed for several Lyme disease agents including B. burgdorferi, B. garinii, and B. mayonii. RNA-sequencing and quantitative RT-PCR showed that B. burgdorferi infection was associated with increased expression of inflammatory cytokines and a robust interferon (IFN) response in the dura mater. Histopathologic changes including leukocytic infiltrates and vascular changes were also observed in the meninges of infected animals. In contrast to the meninges, we did not detect B. burgdorferi, infiltrating leukocytes, or large-scale changes in cytokine profiles in the cerebral cortex or hippocampus during infection; however, both brain regions demonstrated similar changes in expression of IFN-stimulated genes as observed in peripheral tissues and meninges. Taken together, B. burgdorferi is capable of colonizing the meninges in laboratory mice, and induces localized inflammation similar to peripheral tissues. A sterile IFN response in the absence of B. burgdorferi or inflammatory cytokines is unique to the brain parenchyma, and provides insight into the potential mechanisms of CNS pathology associated with this important pathogen

Temperature-Dependent Three-Dimensional Anisotropy of the Magnetoresistance in WTe

Extremely large magnetoresistance (XMR) was recently discovered in WTe2, triggering extensive research on this material regarding the XMR origin. Since WTe2 is a layered compound with metal layers sandwiched between adjacent insulating chalcogenide layers, this material has been considered to be electronically two-dimensional (2D). Here we report two new findings on WTe2: (1) WTe2 is electronically 3D with a mass anisotropy as low as 2, as revealed by the 3D scaling behavior of the resistance RðH; θÞ ¼ RðεθHÞ with εθ ¼ ðcos2θ þ γ−2sin2θÞ1=2, θ being the magnetic field angle with respect to the c axis of the crystal and γ being the mass anisotropy and (2) the mass anisotropy γ varies with temperature and follows the magnetoresistance behavior of the Fermi liquid state. Our results not only provide a general scaling approach for the anisotropic magnetoresistance but also are crucial for correctly understanding the electronic properties of WTe2, including the origin of the remarkable “turn-on” behavior in the resistance versus temperature curve, which has been widely observed in many materials and assumed to be a metalinsulator transition

Dura mater is colonized by spirochetes during disseminated borreliosis.

<p>Dura mater is colonized by spirochetes during disseminated borreliosis.</p

T cells in dura mater are CD4 and CD8 T cells.

<p>(A-C) Representative flow cytometric density plots showing gating strategy for the identification of CD4+ and CD8+ T cell subsets in the spleen (A) and dura mater (B-C). (A) CD3+ T cells (left), and CD4+ / CD8+ subsets (right) in splenocytes of control mice. (B/C) CD3+ T cells and CD4+/CD8+ subsets in dura mater of (B) control mice, and (C) <i>B</i>. <i>burgdorferi</i> infected mice. Prior to analysis all samples were gated on singlets using FSC-A vs FSC-H, and live cells were identified using Aqua amine reactive dye.</p

<i>B</i>. <i>burgdorferi</i> infects brain infrequently.

<p>Quantitative PCR of DNA isolated from brain and heart tissue isolated from mice infected with B31 MI-16 (blue symbols) or 297 (red symbols) as indicated. Copies/well for each biological replicate are shown for the <i>B</i>. <i>burgdorferi flaB</i> target sequence (circles), as well as mouse <i>β-actin</i> reference target (triangles). Horizontal lines indicate mean normalized <i>flaB</i>/10⁷ <i>β-actin</i> ± SD for each group. Dashed line indicates lower limit of detection. Samples with no detectable <i>flaB</i> signal are denoted by the symbol N.</p