The plasminogen activation system enhances brain and heart invasion in murine relapsing fever borreliosis

Gebbia, Joseph A.; Moncó, Juan Carlos García; Degen, Jay L.; Bugge, Thomas H.; Benach, Jorge L.

doi:10.1172/jci5171

Cited by 102 publications

(112 citation statements)

References 54 publications

(42 reference statements)

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“…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.…”

Section: Discussionsupporting

confidence: 55%

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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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Section: Discussionsupporting

confidence: 55%

“…The major agents of RF in North America, Borrelia hermsii and B. turicatae, are transmitted to humans by bites from infected ticks (5). Rodents are natural reservoirs of tick-borne RF Borreliae and the murine model of RF borreliosis recapitulates a number of pathophysiologic aspects of the human disease (3,6,7).…”

mentioning

confidence: 99%

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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“…The resistance to trypsin and plasmin might also serve the spirochetes in their vertebrate hosts. After host plasminogen acquisition and activation, surface bound plasmin facilitates the dissemination of bacteria in the tick and fosters heart and brain invasion in infected mice (56,57).…”

Section: Discussionmentioning

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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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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“…The subsequent activation of plasminogen to plasmin may contribute to the virulence of these microorganisms (13). However, during bacterial arthritis, plasmin may also be of importance in the host defense by degrading deleterious bacteria or ECM components during tissue repair (14). The PA system thus appears to play dual, but contrasting, roles during bacterial arthritis, enhancing both bacterial invasion and host defense.…”

mentioning

confidence: 99%

Protective effects of plasmin(ogen) in a mouse model of Staphylococcus aureus–induced arthritis

Guo¹,

Li²,

Hagström³

et al. 2008

Arthritis & Rheumatism

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Objective. To assess the functional roles of plasmin in a murine model of Staphylococcus aureus-induced bacterial arthritis.Methods. Bacterial arthritis was induced in plasminogen-deficient (Plg -/-) and wild-type (Plg ؉/؉ ) littermates by local injection of 1 ؋ 10 6 colony-forming units of S aureus into the knee joints. Human plasminogen was administered to Plg -/-mice on days 0-7 or days 7-14. Antibiotic treatment was administered to Plg -/-mice on days 7-14. Bacteria counts and histologic, immunohistochemical, and Western blot analyses were performed.Results. In Plg ؉/؉ mice, S aureus counts had declined within 2 days, and by day 28 the bacteria had been completely eliminated. However, S aureus was still detectable in all injected joints from Plg -/-mice, and bacteria counts were 27 times higher than the amount injected on day 0. The extent of macrophage and neutrophil recruitment to the infected joints was comparable for Plg ؉/؉ and Plg -/-mice on days 1, 7, and 14. The activation of these inflammatory cells appeared to be impaired in Plg -/-mice, however. Treatment of Plg -/-mice with antibiotic (cloxacillin) resulted in successful killing of the bacteria, but the necrotic tissue remained in the infected joints. When human plasminogen was given intravenously to Plg -/-mice daily for 7 days, bacterial clearance was greatly improved as compared with their untreated counterparts, and the amount of necrotic tissue in the joint cavity was dramatically reduced. The expression of interleukin 6 (IL-6) and IL-10 was higher in Plg ؉/؉ mice than in Plg -/-mice during bacterial arthritis.Conclusion. Our findings indicate that plasmin plays a pluripotent role in protecting against S aureusinduced arthritis by activating inflammatory cells, killing bacteria, removing necrotic tissue, and enhancing cytokine expression.Staphylococcus aureus is the microorganism most frequently associated with bacterial arthritis (1,2), which results in synovial inflammation, cartilage and bone destruction, and eventually, joint deformity (3). The plasminogen activator (PA) system is a general proteolytic system that has been suggested to play an important role in the development of different types of arthritis (4-6). Plasminogen can be activated to the broadspectrum protease plasmin by either of the 2 physiologic PAs, tissue-type PA (tPA) or urokinase-type PA (uPA). In addition to its function in fibrinolysis, plasmin(ogen) plays a role in degradation of the extracellular matrix (ECM) and in tissue remodeling during many physiologic and pathologic processes, such as wound healing (7), tumor cell invasion, angiogenesis, and rheumatoid arthritis (RA) (8). There is some evidence that plasmin can also induce proinflammatory responses independently of its proteolytic properties (9).A number of pathogenic microorganisms have been shown to bind plasminogen (10-12). The subsequent activation of plasminogen to plasmin may contribute to the virulence of these microorganisms (13). However, during bacterial arthritis, plasmin may also be of importance...

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The plasminogen activation system enhances brain and heart invasion in murine relapsing fever borreliosis

Cited by 102 publications

References 54 publications

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

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

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

Protective effects of plasmin(ogen) in a mouse model of Staphylococcus aureus–induced arthritis

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