Spinal cord involvement in the nonhuman primate model of Lyme disease

Abstract

Lyme borreliosis is a multisystemic disease caused by infection with various genospecies of the spirochete Borrelia burgdorferi. The organs most often affected are the skin, joints, the heart, and the central and peripheral nervous systems. Multiple neurological complications can occur, including aseptic meningitis, encephalopathy, facial nerve palsy, radiculitis, myelitis, and peripheral neuropathy. To investigate spinal cord involvement in the nonhuman primate (NHP) model of Lyme borreliosis, we inoculated 25 adult Macaca mulatta with B. burgdorferi sensu strictu strains N40 by needle (N ¼ 9) or by tick (N ¼ 4) or 297 by needle (N ¼ 2), or with B. burgdorferi genospecies garinii strains Pbi (N ¼ 4), 793 (N ¼ 2), or Pli (N ¼ 4) by needle. Immunosuppression either transiently (TISP) or permanently (IS) was used to facilitate establishment of infection. Tissues and fluids were collected at necropsy 7-24 weeks later. Hematoxylin and eosin staining was used to study inflammation, and immunohistochemistry and digital image analysis to measure inflammation and localize spirochetes. The spirochetal load and C1q expression were measured by TaqMan RT-PCR. The results showed meningoradiculitis developed in only one of the 25 NHP's examined, TISP NHP 321 inoculated with B. garinii strain Pbi. Inflammation was localized to nerve roots, dorsal root ganglia, and leptomeninges but rarely to the spinal cord parenchyma itself. T cells and plasma cells were the predominant inflammatory cells. Significantly increased amounts of IgG, IgM, and C1q were found in inflamed spinal cord. Taqman RT-PCR found spirochetes in the spinal cord only in IS-NHP's, mostly in nerve roots and ganglia rather than in the cord parenchyma. C1q mRNA expression was significantly increased in inflamed spinal cord. This is the first comprehensive study of spinal cord involvement in Lyme borreliosis.

Steroid use in Lyme disease-associated facial palsy is associated with worse long-term outcomes

“…Evidence has demonstrated that oral corticosteroids may delay recovery in Guillain‐Barré syndrome . In NHP models of neuroborreliosis, corticosteroid monotherapy was found to increase spirochetal load in neural tissues and impair anti‐ B. burgdorferi isotype switching, resulting in higher IgM and lower IgG levels in the serum of immunocompromised animals as compared to infected immunocompetent controls . These findings provide possible explanations for the failure of corticosteroids to improve neuropathy symptoms in LD, and for why patients who received concurrent corticosteroids in the present study demonstrated worse long‐term facial outcomes as compared to those who received antibiotics alone.…”

“…In contrast to Bell palsy, direct infection of the facial nerve is unlikely to play a major pathophysiologic role in LDFP because the spirochete is rarely found in neural tissues . The peripheral neuropathy of LD is a mononeuropathy multiplex with electrophysiology and biopsy findings consistent with an axonal neuropathy .…”

“…First, the inflammatory infiltrate seen in peripheral nerves in patients with LD contains a high proportion of plasma cells whose primary function is immunoglobulin production. Antibody and complement deposition have been demonstrated in neural tissue from humans and NHPs with neuroborreliosis . Serum of patients with LD has been shown to contain IgM antibodies to B. burgdorferi that cross‐react with human axonal antigens, and higher levels of antiganglioside IgM antibodies have been shown in serum of patients with neuroborreliosis as compared to those with predominantly cutaneous and articular involvement .…”

Possible role of glial cells in the onset and progression of Lyme neuroborreliosis

“…This dose was found to be safe in studies involving intrathecal inoculation of Treponema pallidum , another spirochete, in rhesus macaques [ 30 ]. Similar inoculum doses were used previously in the rhesus monkey [ 31 - 34 ]. To monitor CNS inflammation following inoculation, CSF (0.5–1.0 ml) and serum (5 ml of blood) were collected on a weekly basis for 4 weeks, and then once every two weeks until the end of the study for each animal.…”

Interaction of the Lyme Disease Spirochete Borrelia burgdorferi with Brain Parenchyma Elicits Inflammatory Mediators from Glial Cells as Well as Glial and Neuronal Apoptosis

“…24 Lyme disease signs and disease progression in the rhesus macaque are similar to those of human Lyme disease, which makes the use of this model both appropriate and valuable. [25][26][27][28][29][30][31][32] Observations from human Lyme neuroborreliosis patients as well as studies in rhesus monkeys suggest that inflammation plays an important role in disease pathogenesis. We therefore hypothesized that B. burgdorferi spirochetes cause inflammation in the CNS by inducing cytokines, chemokines, and other immune mediators in glial cells.…”