Experimental Infection of the Mouse Brain by a Relapsing Fever Borrelia Species: A Molecular Analysis

Cadavid, Diego; Bundoc, Virgilio; Barbour, Alan G.

doi:10.1093/infdis/168.1.143

Cited by 48 publications

(66 citation statements)

References 39 publications

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“…As confirmed by N-terminal sequencing, the f-Met was removed, probably by the E. coli methionyl aminopeptidase (48). For trypsin-treated S34VspA, the mass of the major peak was 17,739 Da, which corresponds to a predicted 17,700 Da protein starting with Ser 34 and ending with Lys 206 . The mass difference of 768 Da would also match the removal of 8 C-terminal amino acids, a predicted 792 Da.…”

Section: Resultsmentioning

confidence: 87%

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Structural Conservation of Neurotropism-associated VspA within the Variable Borrelia Vsp-OspC Lipoprotein Family

Zückert

Kerentseva

Lawson

et al. 2001

Journal of Biological Chemistry

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Vsp surface lipoproteins are serotype-defining antigens of relapsing fever spirochetes that undergo multiphasic antigenic variation to avoid the immune response. One of these proteins, VspA of Borrelia turicatae, is also associated with neurotropism in infected mice. Vsp proteins are highly polymorphic in sequence, which may relate to their specific antibody reactivities and host cell interactions. To determine whether sequence variations affect protein structure, we compared B. turicatae VspA with three related proteins: VspB of B. turicatae, Vsp26 of the relapsing fever agent Borrelia hermsii, and OspC of the Lyme disease spirochete Borrelia burgdorferi. Recombinant non-lipidated proteins were purified by affinity or ion exchange chromatography. Circular dichroism spectra revealed similar, highly ␣-helical secondary structures for all four proteins. In vitro assays demonstrated proteaseresistant, thermostable Vsp cores starting at a conserved serine at position 34 (Ser 34 ). All proteins aggregate as dimers in solution. In situ trypsin treatment and surface protein cross-linking showed that the native lipoproteins also form protease-resistant dimers. These findings indicate that Vsp proteins have a common compact fold and that their established functions are based on localized polymorphisms. Two forms of VspA crystals suitable for structure determination by x-ray diffraction methods have been obtained.

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Section: Resultsmentioning

confidence: 87%

“…The mass of undigested S34VspA was determined as a control, yielding a major peak of 18,507 Da. It corresponds to a protein starting with Ser 34 and ending with Asn 214 with a predicted size of 18,475 Da. As confirmed by N-terminal sequencing, the f-Met was removed, probably by the E. coli methionyl aminopeptidase (48).…”

Section: Resultsmentioning

confidence: 99%

Structural Conservation of Neurotropism-associated VspA within the Variable Borrelia Vsp-OspC Lipoprotein Family

Zückert

Kerentseva

Lawson

et al. 2001

Journal of Biological Chemistry

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“…3,7,11 Spirochetes were cultured as described. 12 Before infection, borrelia viability was assessed by microscopy and serotype identity was confirmed by Western blot with monoclonal antibodies. 7,11 …”

Section: Strains and Culture Conditionsmentioning

confidence: 99%

“…4 Mice were euthanized as described. 12 One half of brain and heart was snap-frozen for RNA extraction, whereas the other half was fixed in 4% paraformaldehyde for 6 hours at room temperature and paraffin-embedded.…”

Section: Mouse Infectionsmentioning

confidence: 99%

Role of Interleukin 10 during Persistent Infection with the Relapsing Fever Spirochete Borrelia turicatae

Gelderblom

Schmidt

Londoño

et al. 2007

The American Journal of Pathology

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Relapsing fever is an infection characterized by peaks of spirochetemia attributable to antibody selection against variable serotypes. In the absence of B cells, serotypes cannot be cleared, resulting in persistent infection. We previously identified differences in spirochetemia and disease severity during persistent infection of severe combined immunodeficiency mice with isogenic serotypes 1 (Bt1) or 2 (Bt2) of Borrelia turicatae. To investigate this further, we studied pathogen load, clinical disease, cytokine/chemokine production, and inflammation in mice deficient in B (Igh6 ؊/؊ ) or B and T (Rag1 ؊/؊ ) cells persistently infected with Bt1 or Bt2. The results showed that Igh6 ؊/؊ mice, despite lower spirochetemia, had a significantly aggravated disease course compared with Rag1 ؊/؊ mice. Measurement of cytokines revealed a significant positive correlation between pathogen load and interleukin (IL)-10 in blood, brain, and heart. Bt2-infected Rag1 ؊/؊ mice harbored the highest spirochetemia and, at the same time, displayed the highest IL-10 plasma levels. In the brain, Bt1, which was five times more neurotropic than Bt2, caused higher IL-10 production. Activated microglia were the main source of IL-10 in brain. IL-10 injected systemically reduced disease and spirochetemia. The results suggest IL-10 plays a protective role as a downregulator of inflammation and pathogen load during infection with relapsing fever spirochetes. (Am J

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“…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).…”

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

Liu¹,

Fitzgerald

Gran

et al. 2010

The Journal of Immunology

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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.

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Experimental Infection of the Mouse Brain by a Relapsing Fever Borrelia Species: A Molecular Analysis

Cited by 48 publications

References 39 publications

Structural Conservation of Neurotropism-associated VspA within the Variable Borrelia Vsp-OspC Lipoprotein Family

Structural Conservation of Neurotropism-associated VspA within the Variable Borrelia Vsp-OspC Lipoprotein Family

Role of Interleukin 10 during Persistent Infection with the Relapsing Fever Spirochete Borrelia turicatae

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

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