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The Journal of Immunology, 2001, 167: 3029-3032.
Copyright © 2001 by The American Association of Immunologists

Cutting Edge

Cutting Edge: The Spirochetemia of Murine Relapsing Fever Is Cleared by Complement-Independent Bactericidal Antibodies1

Sean E. Connolly and Jorge L. Benach2

Center for Infectious Diseases, Department of Molecular Genetics and Microbiology, State University of New York, Stony Brook, NY 11794


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Abs are the major effectors of host defense against infections with Borrelia. Bactericidal murine mAbs and their Fabs destroy B. burgdorferi, the agent of Lyme disease, and relapsing fever Borrelia in the absence of complement. These in vitro observations led to the expansion of a search for functionally similar Abs in vivo. In this study, we demonstrate that functionally unique IgM Abs develop in vivo and are responsible for the elimination of spirochetemia in murine models of relapsing fever, without the assistance of complement. Mice deficient in the fifth or third component of complement can clear the spirochetemia, whereas B cell-deficient mice cannot. The B cell-deficient mice developed spirochetemia that was an order of magnitude higher and persisted for a longer period of time in comparison to the wild-type mice. Additionally, B cell-deficient mice passively immunized with immune IgM and with immune serum were protected from challenge.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The tick-borne Borrelioses comprise the agents of relapsing fever and Lyme disease. These spirochetes occur worldwide and produce diseases that share clinical characteristics. Organ-specific manifestations of Lyme disease and relapsing fever can be similar, particularly those involving the nervous system (1). Both diseases can also affect the joints and the heart, but Lyme disease lacks the marked and recurrent spirochetemia of relapsing fever (2). The spirochetemia of relapsing fever in patients and in murine models is characterized by a large first peak of organisms in the blood before their disappearance, only to be followed by several smaller peaks of spirochetemia. Antigenic variation of the organism is responsible for these recurrent, but much smaller, peaks of spirochetemia (3).

Abs are critical in the host response to infection with Borrelia. Passive immunization has been shown to be protective in experimental models (4, 5). Indeed, the current vaccine for Lyme disease depends on the action of Abs to kill the organisms in the gut of the vector ticks (6). The importance of Abs in controlling spirochetal infections was underscored with the discovery of an Ab with unique bactericidal properties. We found and characterized an IgG1-{kappa} murine mAb (CB2) to outer surface protein (Osp)3B of B. burgdorferi that was bactericidal in the absence of complement. This is a unique finding considering that typical destruction of bacteria is mediated by the action of complement-fixing Abs and the deposition of complement components, leading to lysis by the membrane attack complex of the latter stages of the complement cascade. Agglutination is not the manner of spirochete destruction by this Ab because its Fabs also have bactericidal activity (7, 8, 9). A similar bactericidal mAb to OspB was also reported, as well as a bactericidal Ab to B. hermsii, an agent of relapsing fever (10). These Abs are so effective in their bactericidal action that they have been used for selection of Borrelia mutants (7, 8, 9, 11, 12). Other complement-independent bactericidal Abs recognize epitopes in OspA, OspB, and p39 of B. burgdorferi (13, 14, 15), but the action of their Fabs was not studied.

Although the mechanism of action of these bactericidal Abs is not understood, some of their properties are known. The epitope recognized by CB2 (8) and another bactericidal Ab (11) maps to the carboxyl terminus of OspB and depends on a single lysine (Lys253) for binding and killing. The formation of an Ag (OspB)-Ab (CB2) complex leads to the lysis of the outer membrane of the bacterium (9). CB2 is not a catalytic Ab, but it appears to cause structural changes in OspB, as determined by limited proteolysis (16). Thus, the in vitro observations that mAbs can be bactericidal to two species of Borrelia, without the assistance of complement, led us to test the hypothesis that the clearance of in vivo relapsing fever spirochetemia is mediated by functionally similar bactericidal Abs.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Spirochetes and culture conditions

Patient-derived virulent relapsing fever Borrelia (17) was maintained in the laboratory through mouse-to-mouse passage at the time of the first, and highest, peak of spirochetemia.

Mouse infection

Congenic mice of the strain B10.D2/oSnJ, deficient in C5 and the corresponding wild-type B10.D2/nSnJ strain were obtained from The Jackson Laboratory (Bar Harbor, ME) at ~3 wk of age (18), as were B cell-deficient B6.129S2 (IgH-/-) and wild-type control C57BL/6J mice (19). Mice deficient in C3 (20), on a mixed 129/B6 background, were the generous gift of Dr. H. W. Virgin IV (Washington University, St. Louis, MO). All complement-deficient and corresponding wild-type mice were housed in microisolator cages with free access to food and water. Cages of B cell-deficient mice were placed within laminar-flow biosafety cabinets.

The spirochetes used for inoculation were obtained from a C3H/HeN donor mouse at peak spirochetemia (21). Spirochete-rich plasma was obtained after centrifugation of citrated whole blood at 800 x g for 15 s. The plasma was centrifuged, and the resulting spirochete pellet was washed twice with serum-free Barbour-Stoenner-Kelley medium (Sigma, St. Louis, MO). Mice were inoculated s.c. with 2 x 104 spirochetes in 100 µl serum-free Barbour-Stoenner-Kelly medium, and the spirochetemia was monitored daily by dark-field microscopy (22). Peripheral blood smears were fixed in methanol and stained with modified Giemsa stain (Sigma). Mice were sacrificed by carbon dioxide inhalation, which was immediately followed by the collection of citrated whole blood via cardiac puncture. All animal procedures were done by protocols approved by the Institutional Review Board.

Detection of Abs

Washed Borrelia harvested from infected mice (as described above) and sham-citrated blood preparations from uninfected mice were electrophoresed on 12.5% SDS-PAGE gels under reducing conditions, and the gels were then transferred to nitrocellulose for immunoblotting. Infected and control mouse sera were diluted at 1/100 in Dulbecco’s PBS. Alkaline phosphatase-conjugated goat anti-mouse IgG ({gamma}-chain specific) and IgM (µ-chain specific) (Kirkegaard & Perry Laboratories, Gaithersburg, MD) were used as secondary Abs at their appropriate dilutions in Dulbecco’s PBS. Immunoblots were developed through reaction with 5-bromo-4-chloro-3-indolyl phosphate/nitroblue tetrazolium substrate (Kirkegaard & Perry Laboratories).

IgM purification

Using sera collected immediately after the clearance of the first peak of spirochetemia, IgM was purified by affinity chromatography using a mannan-binding protein column (Pierce, Rockford, IL). Once eluted from the column, the IgM was concentrated using Centricon-100 ultrafiltration units (Amicon, Beverly, MA), dialyzed against Dulbecco’s PBS, and pooled. Purity was assessed by immunoblotting.

Passive immunization

B cell-deficient mice were passively immunized daily with 50 µg purified IgM collected from complement-deficient mice after the clearance of the first peak of spirochetemia, 50 µg irrelevant murine monoclonal IgM (ICN Pharmaceuticals, Costa Mesa, CA), 200 µl normal mouse serum (Sigma), or 200 µl immune mouse serum, by i.p. injection beginning 2 days before and ending 4 days after s.c. challenge with 2 x 104 relapsing fever spirochetes. The daily passive immunization regimen was chosen to compensate for the ~20-h half-life of IgM (23), and the amount of serum given was based on the median concentration of serum IgM in mice. Spirochetemia was monitored daily for 10 days.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Complement components are not required to clear spirochetemia

The ability of C5-deficient mice to clear the spirochetemia caused by infection by relapsing fever as rapidly and completely as wild-type mice (Fig. 1Go) demonstrated that the terminal membrane attack complex of the classical, alternative, and mannan-binding lectin complement pathways is not involved in the removal of the spirochetes from the blood. Our findings with a patient-derived species of relapsing fever Borrelia in congenic mice confirm earlier observations in mice spontaneously deficient in C5 (24). C3-deficient mice were used to test for the role of earlier products of the complement cascade as possible opsonins in the clearance of the spirochetemia. The C3-deficient mice were equally efficient in clearing the spirochetemia as wild-type animals, indicating the lack of a discernible role for this pivotal complement component (Fig. 2Go). Furthermore, in both C3- and C5-deficient mice, subsequent peaks of spirochetemia proceeded as normally as their wild-type counterparts.



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  		FIGURE 1. C5 is not required to clear spirochetemia. The mean (± SD) course of spirochetemia in C5-deficient (•, n = 5) and wild-type mice ({blacktriangleup}, n = 5) after s.c. inoculation of 2 x 104 Borrelia. Both C5-deficient and wild-type mice cleared the spirochetemia rapidly after reaching peak, resulting in no visible spirochetes in the blood.

 


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  		FIGURE 2. C3 is not required to clear spirochetemia. The mean (± SD) course of spirochetemia in C3-deficient (•, n = 5) and wild-type ({blacktriangleup}, n = 5) after s.c. inoculation of 2 x 104 Borrelia. Both C3-deficient and wild-type mice cleared the spirochetemia rapidly after reaching peak, resulting in no visible spirochetes in the blood.

 
Coincident with the clearance of the first peak of spirochetemia and immediately thereafter, sera collected from mice deficient in C5 or C3, as well as from wild-type animals, revealed an exclusively IgM Ab response (Fig. 3Go). Ab levels in complement-deficient mice were the same as those in wild-type mice, as determined by ELISA (data not shown). There was no reactivity of the immune sera against equivalent sham-blood fractions obtained from uninfected mice (Fig. 3Go, lanes 3 and 6). Similarly, sera collected from uninfected mice did not show reactivity against Borrelial Ag at the serum dilutions used (data not shown).



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  		FIGURE 3. Igs produced in response to the infection. Western blot for postpeak IgM reactivity in serum from C5-deficient mice (lane 1), C5 wild-type mice (lane 2), and against sham control fractions from uninfected mice (lane 3). Both C5-deficient and wild-type mice exhibited similar reactivity against Borrelial Ags with a 35-kDa protein as the major immunogen. Western blot for IgM reactivity in serum from postpeak C3-deficient mice (lane 4), C3 wild-type mice (lane 5), and against sham control fractions from uninfected mice (lane 6). Both C3-deficient and wild-type mice exhibited similar reactivity against Borrelial Ags with a 39-kDa protein as the major immunogen. Postpeak sera did not show any IgG reactivity against the Borrelia in C5-deficient mice (lane 7), C5 wild-type mice (lane 8), and against sham control (lane 9). The C3-deficient mice also did not show any IgG reactivity against the Borrelia (data not shown). Molecular mass standards, in kDa, are shown on the left.

 
B cells are required to clear spirochetemia

B cell-deficient mice, generated through a targeted disruption in the IgM µ-chain, were used to verify the critical role of IgM Abs in the clearance of spirochetemia. Upon infection with 2 x 104 bacteria, these mice sustained a peak spirochetemia that was 40-fold higher (~4 x 108/ml) than the corresponding spirochetemia in wild-type controls (~107/ml), which lasted for 4–5 days (Figs. 4GoA and 5) as compared with the controls, in which the typical peak spirochetemia persisted for only 10–12 h (Fig. 4GoB). Furthermore, the B cell-deficient mice were unable to clear the infection from the blood and maintained a level of chronic spirochetemia for 30 days that was similar to the levels of peak spirochetemia obtained in wild-type mice (Fig. 4GoA, inset). There was no detectable IgM or IgG in the serum of the B cell-deficient mice, as determined by ELISA and Western blot (data not shown). Of note is that, despite the absence of Igs, spirochetemia in the B cell-deficient mice dropped by an order of magnitude to level off as a chronic blood infection.



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  		FIGURE 4. B cells are required to clear the spirochetemia. The mean (± SD) course of spirochetemia in B cell-deficient (A, •, n = 6) and wild-type (B, {blacktriangleup}, n = 6) after s.c. inoculation of 2 x 104 Borrelia. B cell-deficient mice developed spirochetemia that was >1 order of magnitude compared with that of the wild-type mice. These mice had a sustained peak spirochetemia for 4–5 days as opposed to wild-type controls, in which it typically lasted for ~10–12 h. Inset, The B cell-deficient mice were unable to clear the spirochetemia for 30 days, resulting in levels similar to the peak spirochetemia of wild-type mice.

 
Immune IgM and immune serum can protect B cell-deficient mice from infection

Passive immunization of B cell-deficient mice with purified IgM collected from complement-deficient mice immediately after the clearance of the first peak of spirochetemia conferred complete protection against challenge with 2 x 104 organisms. In addition, mice immunized with serum from wild-type mice that had developed and cleared the first peak of spirochetemia also provided complete protection against challenge. Control groups immunized with either normal mouse serum or irrelevant murine monoclonal IgM were not protected from the infection and developed high levels of spirochetemia within 4 days of challenge. These animals maintained the peak spirochetemia for several days and did not clear the organisms, again resulting in a persistent blood infection.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study used mice with single gene-product deficiencies to definitively demonstrate that specific bactericidal, complement-independent IgM Abs are required to clear the first and highest peak of spirochetemia in a murine model of relapsing fever. Production of IgM specific for the organisms can be first noted at the beginning of the clearance process and immediately thereafter. It is evident that neither early nor late complement components have a role in the clearance mechanism because neither C5- nor C3-deficient mice demonstrated clearance defects. Thus, there is a functional in vivo correlate to the complement-independent bactericidal mAbs characterized earlier in vitro for B. burgdorferi and B. hermsii (7, 8, 9, 11).

Both the increased levels and longer duration of spirochetemia in the B cell-deficient mice, as well as the ability to protect these mice against challenge by passive immunization with either purified immune IgM or immune serum, demonstrate the efficiency of the IgM response. Monoclonal IgM has also been effective in protecting passively and neutralizing relapsing fever Borrelia (25).

The B cell-deficient mice supported and survived levels of spirochetes in the bloodstream of ~4 x 108/ml for 4–5 days without any obvious ill effects. By all standards, this is a very high bacteremia that would readily kill these mice if infected with other organisms. Interestingly, the spirochetemia in the B cell-deficient mice did decrease to chronic levels in the absence of Ab pressure and remained at levels similar to first-peak levels in the wild-type mice for at least 1 mo. In the absence of Abs against the Borrelia, this decrease in spirochetemia could be due to self-regulating cell-division mechanisms of the spirochetes, or to incomplete cellular removal of the organisms from the blood.

The mechanisms for the removal of spirochetes from the bloodstream may use one or more pathways. Late complement components (C5) leading to lysis are not required for clearance. Early complement components (C3) that could opsonize the spirochetes for subsequent removal by phagocytic cells expressing complement receptors are also not participants for clearance. In the absence of specific receptors for IgM, combined with the lack of a role for complement, the exact mechanism for removal of the Ab-damaged Borrelia still needs to be worked out. Recently, a murine and human FcR for IgM and IgA was discovered in B cells and macrophages. Thus, this receptor, termed Fc {alpha}/µ, could be important in clearance of the spirochetes opsonized with IgM if these receptors are present in fixed macrophages (26). The Fc {alpha}/µ receptor could remove either opsonized and intact or opsonized and damaged spirochetes. However, in an earlier study, we documented the presence of spirochetal DNA by PCR in the blood of mice following clearance of live organisms (22). If the intact organisms were being removed from the blood by cells from the reticuloendothelial system with the Fc {alpha}/µ receptor, it would be unlikely that intact DNA would be returned to the bloodstream. This suggests that the Ab-mediated destruction of the spirochetes actually occurs in the blood.

In this study, we have identified an IgM-mediated, complement-independent clearance of the spirochetemia of relapsing fever. The IgM Ab response that was detected at the same time as the clearance of the spirochetemia protected B cell-deficient mice from challenge. To face this powerful clearance mechanism, it is not surprising that these spirochetes have developed sophisticated schemes for immune evasion, ranging from antigenic variation (3, 27) to the sequestration of exposed Ag by attached erythrocytes (28, 29). The polyclonal IgM that mediates the clearance of the spirochetemia and can protect B cell-deficient mice from challenge is functionally similar to the mAbs to other Borrelia species that are bactericidal in the absence of complement. Direct, complement-independent bactericidal action of Abs has been an overlooked but crucial mechanism of host defense as applied to infections with Borrelia, and perhaps to infections with other bacteria.



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  		FIGURE 5. A Giemsa-stained peripheral blood smear from a B cell-deficient mouse during peak spirochetemia, showing the massive spirochete load several days after inoculation.

 

   Footnotes
 
1 This study was funded by Grant AI-27044 from the National Institutes of Health and by a grant from the Mathers Foundation. Back

2 Address correspondence and reprint requests to Dr. Jorge L. Benach, Center for Infectious Diseases, Department of Molecular Genetics and Microbiology, State University of New York, Stony Brook, NY 11794-5120. E-mail address: jbenach{at}notes.cc.sunysb.edu Back

3 Abbreviation used in this paper: Osp, outer surface protein. Back

Received for publication June 28, 2001. Accepted for publication July 25, 2001.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Garcia-Monco, J. C., J. L. Benach. 1995. Lyme neuroborreliosis. Ann. Neurol. 37:691.[Medline]
  2. Southern, P., J. Sanford. 1969. Relapsing fever: a clinical and microbiological review. Medicine 48:129.
  3. Barbour, A. G.. 1990. Antigenic variation of a relapsing fever Borrelia species. Annu. Rev. Microbiol. 44:155.[Medline]
  4. Barthold, S. W., L. K. Bockenstedt. 1993. Passive immunizing activity of sera from mice infected with Borrelia burgdorferi. Infect. Immun. 61:4696.[Abstract/Free Full Text]
  5. Johnson, R. C., C. L. Kodner, M. E. Russell. 1986. Vaccination of hamsters against experimental infection with Borrelia burgdorferi. Zentralbl. Bakteriol. Mikrobiol. Hyg. [A] 263:45.
  6. Steere, A. C., V. K. Sikand, F. Meurice, D. L. Parenti, E. Fikrig, R. T. Schoen, J. Nowakowski, C. H. Schmid, S. Laukamp, C. Buscarino, D. S. Krause. 1998. Vaccination against Lyme disease with recombinant Borrelia burgdorferi outer-surface lipoprotein A with adjuvant: Lyme disease vaccine study group. N. Engl. J. Med. 339:209.[Abstract/Free Full Text]
  7. Coleman, J. L., R. C. Rogers, J. L. Benach. 1992. Selection of an escape variant of Borrelia burgdorferi by use of bactericidal monoclonal antibodies to OspB. Infect. Immun. 60:3098.[Abstract/Free Full Text]
  8. Coleman, J. L., R. C. Rogers, P. A. Rosa, J. L. Benach. 1994. Variations in the ospB gene of Borrelia burgdorferi result in differences in monoclonal antibody reactivity and in production of escape variants. Infect. Immun. 62:303.[Abstract/Free Full Text]
  9. Escudero, R., M. L. Halluska, P. B. Backenson, J. L. Coleman, J. L. Benach. 1997. Characterization of the physiological requirements for the bactericidal effects of a monoclonal antibody to OspB of Borrelia burgdorferi by confocal microscopy. Infect. Immun. 65:1908.[Abstract]
  10. Sadziene, A., M. Jonsson, S. Bergstrom, R. K. Bright, R. C. Kennedy, A. G. Barbour. 1994. A bactericidal antibody to Borrelia burgdorferi is directed against a variable region of the OspB protein. Infect. Immun. 62:2037.[Abstract/Free Full Text]
  11. Sadziene, A., A. G. Barbour, P. A. Rosa, D. D. Thomas. 1993. An OspB mutant of Borrelia burgdorferi has reduced invasiveness in vitro and reduced infectivity in vivo. Infect. Immun. 61:3590.[Abstract/Free Full Text]
  12. Backenson, P. B., J. L. Coleman, J. L. Benach. 1995. Borrelia burgdorferi shows specificity of binding to glycosphingolipids. Infect. Immun. 63:2811.[Abstract]
  13. Aydintug, M. K., Y. Gu, M. T. Philipp. 1994. Borrelia burgdorferi antigens that are targeted by antibody-dependent, complement-mediated killing in the rhesus monkey. Infect. Immun. 62:4929.[Abstract/Free Full Text]
  14. Ma, J., C. Gingrich-Baker, P. M. Franchi, P. Bulger, R. T. Coughlin. 1995. Molecular analysis of neutralizing epitopes on outer surface proteins A and B of Borrelia burgdorferi. Infect. Immun. 63:2221.[Abstract]
  15. Scriba, M., J. S. Ebrahim, T. Schlott, H. Eiffert. 1993. The 39-kilodalton protein of Borrelia burgdorferi: a target for bactericidal human monoclonal antibodies. Infect. Immun. 61:4523.[Abstract/Free Full Text]
  16. Katona, L. I., S. Ayalew, J. L. Coleman, J. L. Benach. 2000. A bactericidal monoclonal antibody elicits a change in its antigen, OspB of Borrelia burgdorferi, that can be detected by limited proteolysis. J. Immunol. 164:1425.[Abstract/Free Full Text]
  17. Anda, P., W. Sanchez-Yebra, M. del Mar Vitutia, E. Perez Pastrana, I. Rodriguez, N. S. Miller, P. B. Backenson, J. L. Benach. 1996. A new Borrelia species isolated from patients with relapsing fever in Spain. Lancet 348:162.[Medline]
  18. Ooi, Y. M., H. R. Colten. 1979. Genetic defect in secretion of complement C5 in mice. Nature 282:207.[Medline]
  19. Kitamura, D., K. Rajewsky. 1992. Targeted disruption of µ chain membrane exon causes loss of heavy-chain allelic exclusion. Nature 356:154.[Medline]
  20. Circolo, A., G. Garnier, W. Fukuda, X. Wang, T. Hidvegi, A. J. Szalai, D. E. Briles, J. E. Volanakis, R. A. Wetsel, H. R. Colten. 1999. Genetic disruption of the murine complement C3 promoter region generates deficient mice with extrahepatic expression of C3 mRNA. Immunopharmacology 42:135.[Medline]
  21. Garcia-Monco, J. C., N. S. Miller, P. B. Backenson, P. Anda, J. L. Benach. 1997. A mouse model of Borrelia meningitis after intradermal injection. J. Infect. Dis. 175:1243.[Medline]
  22. Gebbia, J. A., J. C. Garcia-Monco, J. L. Degen, T. H. Bugge, J. L. Benach. 1999. The plasminogen activation system enhances brain and heart invasion in murine relapsing fever borreliosis. J. Clin. Invest. 103:81.[Medline]
  23. Vieira, P., K. Rajewsky. 1988. The half-lives of serum immunoglobulins in adult mice. Eur. J. Immunol. 18:313.[Medline]
  24. Jr Newman, K., R. C. Johnson. 1981. In vivo evidence that an intact lytic complement pathway is not essential for successful removal of circulating Borrelia turicatae from mouse blood. Infect. Immun. 31:465.[Abstract/Free Full Text]
  25. Barbour, A. G., V. Bundoc. 2001. In vitro and in vivo neutralization of the relapsing fever agent Borrelia hermsii with serotype-specific immunoglobulin M antibodies. Infect. Immun. 69:1009.[Abstract/Free Full Text]
  26. Shibuya, A., N. Sakamoto, Y. Shimizu, K. Shibuya, M. Osawa, T. Hiroyama, H. J. Eyre, G. R. Sutherland, Y. Endo, T. Fujita, et al 2000. Fc {alpha}/µ receptor mediates endocytosis of IgM-coated microbes. Nat. Immunol. 1:441.[Medline]
  27. Coffey, E. M., W. C. Eveland. 1967. Experimental relapsing fever initiated by Borrelia hermsi. II. Sequential appearance of major serotypes in the rat. J. Infect. Dis. 117:29.[Medline]
  28. Shamaei-Tousi, A., P. Martin, A. Bergh, N. Burman, T. Brannstrom, S. Bergstrom. 1999. Erythrocyte-aggregating relapsing fever spirochete Borrelia crocidurae induces formation of microemboli. J. Infect. Dis. 180:1929.[Medline]
  29. Shamaei-Tousi, A., O. Collin, A. Bergh, S. Bergstrom. 2001. Testicular damage by microcirculatory disruption and colonization of an immune-privileged site during Borrelia crocidurae infection. J. Exp. Med. 193:995.[Abstract/Free Full Text]



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[Abstract] [Full Text] [PDF]

Home page
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[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
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[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
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J. Immunol., February 15, 2005; 174(4): 2084 - 2091.
[Abstract] [Full Text] [PDF]

Home page
 Infect. Immun.Home page
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[Abstract] [Full Text] [PDF]

Home page
 Infect. Immun.Home page
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New Concepts in Antibody-Mediated Immunity
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[Full Text] [PDF]

Home page
 J. Immunol.Home page
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[Abstract] [Full Text] [PDF]

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[Abstract] [Full Text] [PDF]

Home page
 Infect. Immun.Home page
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Effect of Complement Component C3 Deficiency on Experimental Lyme Borreliosis in Mice
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[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
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