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

Abstract

Relapsing fever borreliosis is a multisystemic infection characterized primarily by bacteremia but can extend to the CNS. The incidence of CNS disease manifestations in humans depends on the infecting relapsing fever Borrelia species. In the murine model of Borrelia hermsii infection we found high incidence of distinct signs of CNS disease that ranged from a flaccid tail to complete paralysis of hind limbs. Infiltration of large number of T cells into the spinal cord of B. hermsii-infected mice and the upregulation of MHC class II and CD80 on infiltrating macrophages and on microglial cells suggested a role for T cell and Ag-presenting cell interactions in this pathogenesis. Indeed, B. hermsii infection did not induce CNS disease manifestations in T cell-deficient mice (TCR-β × δ−/−), although it resulted in bacteremia comparable to wild-type (Wt) level. Moreover, the infiltration of immune cells into the spinal cord of TCR-β × δ−/− mice was reduced and the resident microglial cells were not activated. Histopathological analysis of lumbar sections of the spinal cord confirmed severe inflammation in Wt but not in TCR-β × δ−/− mice. Induction of CNS disease was dependent on the B. hermsii strain as well as on the ability of the host to control bacteremia. Mice that are impaired in controlling B. hermsii, such as CD14−/− mice, exhibited more severe CNS disease than Wt mice. This study demonstrates that distinct neurologic disease manifestations develop during relapsing fever and that T cells play a critical role in the induction of neuropathogenesis.

A Disconnect between the Neurospirochetoses in Humans and Rodent Models of Disease

“…Likewise, experiments using direct inoculation of B. burgdorferi into the nervous system have not been pursued vigorously, except with NHP. Distinct signs of experimental CNS disease in mice that are less obvious than meningitis or encephalitis, such as flaccid tails or various degrees of limb paralysis, could be documented in mouse models, as was done in a recent study with B. hermsii [28]. For that matter, peripheral nervous system manifestations that may be more subtle or difficult to characterize need to be explored in mice as well.…”

Efficient B Cell Responses to Borrelia hermsii Infection Depend on BAFF and BAFFR but Not TACI

“…B. hermsii is a causative agent of tick-borne relapsing fever, which is endemic to the western United States (6). Experimental infections via needle inoculation in mice have been shown to recapitulate the key pathophysiological characteristics of the human disease (7)(8)(9)(10)(11)(12)(13)(14). B. hermsii infection is characterized by recurrent episodes of highlevel bacteremia (ϳ10 8 bacteria/ml blood), with each wave of bacteremia accompanied by a febrile episode.…”

Pathogenesis of Relapsing Fever

“…A neuroinvasive variant of B. turicatae had a lower fatality rate among experimentally infected mice than an isogenic variant with a lower potential for invasion of the brain (Cadavid et al, 1994;Pennington et al, 1997). Moreover, the noticeable neurological disease symptoms in certain cases of RF is aggravated by the massive influx of immune cells, including T cells that are important for neuropathogenesis (Liu et al, 2010).…”