Abstract
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.
Highlights
Lyme disease (LD) is a zoonotic bacterial infection caused by Borrelia burgdorferi that is transmitted to the host via the bite of an infected tick
We observed that the ears, hearts, tibiotarsal joints, and dura mater were culture-positive in all mice (n = 5), demonstrating that the infection had disseminated (Table 1). 1/5 brain samples were positive for spirochetes, and all blood cultures
The observation that both B31 and 297 colonized the dura mater suggests that these strains may not have differences in tropisms for central nervous system (CNS) tissues, and that the dura mater is potentially a general site of colonization for B. burgdorferi sensu stricto in a murine system
Summary
Lyme disease (LD) is a zoonotic bacterial infection caused by Borrelia burgdorferi that is transmitted to the host via the bite of an infected tick. If antibiotic treatment is delayed, the infection can disseminate resulting in systemic infection and inflammation that can include regions of the central nervous system (CNS) [1, 2]. Using NHPs, multiple investigators have shown that tick infestation or infection with inoculum doses exceeding 107 spirochetes, results in pleocytosis, lymphocytic meningitis, cranial neuritis and evidence of spirochetes in the CNS [3, 4]. Infection studies in NHPs suggest that B. burgdorferi spirochetes have a tropism for the leptomeninges, and that pathogen burden increases with immunosuppression [5]. Meningeal thickening due to inflammation has been reported in response to infection [6, 7]
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