Long-term intrathecal infusion of outer surface protein C from Borrelia burgdorferi causes axonal damage.

Lyme neuroborreliosis (LNB) is the most frequent tick-borne infectious disease of the central nervous system. In acute LNB and the rare chronic state of infection, patients can experience cognitive deficits such as attention and memory disturbances. During LNB, single compounds of Borrelia burgdorferi sensu lato are released into the subarachnoid space.To investigate the pathogenesis of neurologic dysfunction in LNB, we determined that the outer surface protein C (OspC), a major virulence factor of B. burgdorferi, stimulated mouse microglial cells in a dose-dependent manner to release nitric oxide (EC50 = 0.24 mg/L) in vitro. To mimic pathophysiologic conditions of long-term release of this bacterial component in vivo, we treated C57BL/6 mice with recombinant OspC from Borrelia garinii or buffer by intraventricular infusion and tested them for behavioral deficits. After 4weeks, brains were examined by routine histology and immunohistochemistry. Assessment of spatial learning and memory of treated mice during OspC exposure did not reveal significant differences from controls. Continuous exposure to intrathecal B. burgdorferi OspC led to activation of microglia and axonal damage without demonstrable cognitive impairment in experimental mice. These results suggest that long-term intrathecal exposure to OspC resulted in axonal damage that may underlie the neurologic manifestations in chronic LNB.

Outer surface lipoproteins of Borrelia burgdorferi vary in their ability to induce experimental joint injury.

OBJECTIVE: To examine the ability of bacterial lipoproteins from the spirochete Borrelia burgdorferi to cause in vivo tissue injury (arthritis). METHODS: Outer surface proteins (OSPs) from B burgdorferi were used in a rat model of antigen-induced allergic arthritis. Intraarticular challenge with recombinant OspA, OspB, and OspC in nonlipidated (peptide) and lipidated forms was performed in the left knee joint; the contralateral joint received buffer as control. Inflammation was monitored by technetium scintigraphy and histology. RESULTS: Nonlipidated (peptide) OspA, OspB, and OspC did not induce arthritis; the only exception was polymerized OspA, which was tested in preimmunized rats. Lipidated OspA from 2 different strains and lipidated OspC induced severe arthritis, whereas lipidated OspB failed to induce injury. A synthetic analog of the OSP lipid modification, lipopeptide Pam(3)Cys-Ser-Lys(4)-OH, either alone or coupled to bovine serum albumin, also failed to induce injury. Injury did not develop in control groups that were given the appropriate buffers or lipopolysaccharide. This showed that lipidated borrelial OSPs can be potent arthritogens but vary greatly with respect to their injury-inducing potential. The possession of a lipid modification is essential but is not sufficient to render an OSP arthritogenic. CONCLUSION: This is the first study to demonstrate that individual lipoproteins from B burgdorferi can induce experimental joint injury in vivo. These results may help elucidate the pathogenesis of Lyme arthritis and, above all, underline the importance of bacterial lipoproteins as major virulence factors.

Neuroborreliosis: central nervous system involvement.

Despite rapid dissemination of Borrelia burgdorferi throughout the body following initial inoculation, the clinical manifestations of this illness tend to involve specific organ systems preferentially. The nervous system, in particular, is frequently affected; involvement usually follows one of several distinct patterns. Most commonly, patients develop a lymphocytic meningitis, radiculoneuritis or cranial neuropathy, occurring singly or in combination. Patients with radicular involvement often have a myelopathic component as well. At the other extreme, rare patients will develop focal inflammation of the central nervous system, an encephalomyelitis, that appears to involve white matter more often than grey. More commonly, patients may develop cognitive and memory impairment-a mild encephalopathy. In some patients this may represent a subtle form of encephalomyelitis, while in others it is probably a "toxic-metabolic" effect of systemic infection. Disease variability among patients probably is the result of multiple factors, including bacterial strain differences in virulence and organotropism, inoculum size, host immunity, and simultaneous co-infection with other tick-borne organisms. Accurate diagnosis remains somewhat problematic. The cerebrospinal fluid is almost always abnormal in the presence of active CNS infection. Intrathecal production of specific antibody can be demonstrated in over 90% of patients with meningitis or frank inflammatory encephalomyelitis; in patients with a milder encephalopathy this is less consistently observed. In most instances, diagnosis relies on a combination of demonstration of a specific immune response, and clinical judgment. In patients in whom the diagnosis is secure, appropriate antimicrobial therapy is highly effective in the vast majority of cases, although if there has been significant structural damage to the CNS, some residua may remain.