The mammalian host response to borrelia infection

Abstract

Tick-borne relapsing fever (RF) and Lyme disease (LD) are spirochetal infections of humans caused by different Borrelia species in endemic areas throughout the world. Our laboratory is studying the response of mammalian hosts to borrelia infection in RF and LD. For this, we use mice and non-human primates infected with B. burgdorferi sensu stricto strain N40 (N40) and the Oz1 strain of Borrelia turicatae (Bt), agents of LD and RF in North America, respectively. Our results have revealed that outbred non-human primates are significantly less susceptible than outbred mice to persistent infection with N40. In contrast, the majority of mice inoculated with the RF agent B. turicatae clear the infection, with the notable exception of residual brain or blood infection in up to 25% of cases. Little if any tissue injury occurs in immunocompetent animals with either LD or RF. In contrast, impairment of specific antibody production results in significant tissue injury, most notably in the heart, in both LD and RF. The inflammatory infiltrate is rich in plasma cells, activated macrophages and T cells, and there is significant deposition of antibody and complement, including membrane attack complex, in inflamed tissues and spirochetes. Significant loss of cardiomyocytes with apoptosis and caspase activation was observed in the heart of immunosuppressed non-human primates infected with N40 and in B cell-deficient mice infected with B. turicatae. Unlike the heart, the brain of B cell-deficient mice infected with B. turicatae showed prominent microglial activation but no detectable tissue injury. Tissues from immunosuppressed non-human primates infected with N40 produce large amounts of immunoglobulin and the B cell chemokine CXCL13, both of which significantly correlate with the spirochetal load. We conclude that the main response of mammalian hosts in LD and RF is the production of specific antibody to clear the infection. Failure of this response leads to persistent infection, which can lead to tissue injury, most notably in the heart.

Induction of Distinct Neurologic Disease Manifestations during Relapsing Fever Requires T Lymphocytes

“…In contrast to all the RF models described to date, we have found that during B. hermsii infection in immunocompetent mice, neurologic disease manifestations occur as early as 9 d postinfection and persist at least for 2 wk. Furthermore, we have shown that the infiltration of spinal cord predominantly involves CD4 + T cells, distinguishing the current findings from any of those previously reported (3,13,14).…”

“…Examination of the spinal cord revealed a severe infiltration of immune cells in the lumbar sections. We have identified T cells as the essential contributors for the induction of the CNS disease, distinguishing the current findings from those previously described studies in RF (3,4,13,14,29). Although the B. hermsii infection-associated neurologic symptoms were remarkably similar to those of classical EAE, Luxol fast blue staining of spinal cord sections did not reveal demyelination (data not shown), a hallmark of EAE, indicating that B. hermsii-induced CNS pathogenesis is different from classical EAE.…”

“…In the B. turicatae infection model, SCID mice exhibit a high incidence of vestibular dysfunction indicating that T cells are not required for the induction of this CNS disease manifestation (14). In the B. crocidurae RF model, macrophages are the most dominant cell type among the infiltrating immune cells in the brain (4,29).…”

“…For example, in the epidemic form of RF due to B. recurrentis, the incidence of CNS complications can be as high as 40%. The murine models for neurologic involvement during RF are characterized mainly by the presence of bacteria in the CNS and/or meningitis (4,(12)(13)(14).…”

Bacterial Lipoproteins Can Disseminate from the Periphery to Inflame the Brain

“…For this we measured transcription of three genes that we have shown before are significantly up-regulated in the brain during infection with Bt1: the membrane glycoprotein of microglia/macrophages F4/80, 3,4 the cytokine IL-10, 27,28 and the B cell chemokine CXCL13. 4,29,30 For this groups of uninfected C3H/HeJ mice were injected intraperitoneally with 100 g/kg of Eu-LVsp1 or Eu-albumin, and changes in gene transcription were measured 18 hours later by using TaqMan RT-PCR. The results showed upregulation in the brain of all three genes examined with Eu-LVsp1 compared with Eu-albumin: the fold difference was 1.5 for F4/80 (P ϭ 0.02), 1.9 for CXCL13 (P ϭ 0.048), and 4.9 for IL-10 (P ϭ 0.01).…”