Share This Article:

Chronic Lyme Disease: Persistent Clinical Symptoms Related to Immune Evasion, Antibiotic Resistance and Various Defense Mechanisms of Borrelia burgdorferi

Full-Text HTML XML Download Download as PDF (Size:2574KB) PP. 252-260
DOI: 10.4236/ojmm.2014.44029    7,935 Downloads   22,319 Views   Citations

ABSTRACT

There are several factors involved in the ability of Borrelia burgdorferi to retain a persistent infection within a mammalian host. These factors of immune evasion include regulation of membrane proteins, variable epitopes of surface proteins, protection against the immune system through tick saliva, the ability to migrate to regions where it is not exposed to the immune system or antibiotics, invagination or invasion within various cells, pleomorphic forms, and the potential to produce biofilms. The window of conventional treatment for Lyme disease is short and has the potential to display different symptoms depending on the strain of Borrelia bugdorferi. These symptoms are dependent on the localization of Borrelia burgdorferi which correlates to the significance of diagnosing Lyme disease early to prevent such a spread throughout the body. Such complications of Borrelia burgdorferi may demand new clinical treatment discoveries for patient fighting the chronic form.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

Smith, A. , Oertle, J. and Prato, D. (2014) Chronic Lyme Disease: Persistent Clinical Symptoms Related to Immune Evasion, Antibiotic Resistance and Various Defense Mechanisms of Borrelia burgdorferi. Open Journal of Medical Microbiology, 4, 252-260. doi: 10.4236/ojmm.2014.44029.

References

[1] Li, H., Dunn, J.J., Luft, B.J. and Lawson, C.L. (1997) Crystal Structure of Lyme Disease Antigen Outer Surface Protein A Complexed with an Fab. Proceedings of the National Academy of Sciences of the United States of America, 94, 3584-3589.
http://dx.doi.org/10.1073/pnas.94.8.3584
[2] Wilske, B., Preac-Mursic, V., Jauris, S., et al. (1993) Immunological and Molecular Polymorphisms of OspC, an Immunodominant Major Outer Surface Protein of Borrelia burgdorferi. Infection and Immunity, 61, 2182-2191.
[3] Norris, S.J., Carter, C.J., Howell, J.K. and Barbour, A.G. (1992) Lowpassage-Associated Proteins of Borrelia burgdorferi B31: Characterization and Molecular Cloning of OspD, a Surface-Exposed, Plasmid-Encoded Lipoprotein. Infection and Immunity, 60, 4662-4672.
[4] Lam, T.T., Nguyen, T.P., Montgomery, R.R., Kantor, F.S., Fikrig, E. and Flavell, R.A. (1994) Outer Surface Proteins E and F of Borrelia burgdorferi, the Agent of Lyme Disease. Infection and Immunity, 62, 290-298.
[5] Barbour, A.G. (1988) Antigenic Variation of Surface Proteins of Borrelia Species. Clinical Infectious Diseases, 10, S399-S402.
http://dx.doi.org/10.1093/cid/10.Supplement_2.S399
[6] Marconi, R.T., Samuels, D.S. and Garon, C.F. (1993) Transcriptional Analyses and Mapping of the OspC Gene in Lyme Disease Spirochetes. Journal of Bacteriology, 175, 926-932.
[7] Jauris-Heipke, S., Liegl, G., Preac-Mursic, V., et al. (1995) Molecular Analysis of Genes Encoding Outer Surface Protein C (OspC) of Borrelia burgdorferi Sensu Lato: Relationship to ospA Genotype and Evidence of Lateral Gene Exchange of ospC. Journal of Clinical Microbiology, 33, 1860-1866.
[8] Wilske, B., Jauris-Heipke, S., Lobentanzer, R., et al. (1995) Phenotypic Analysis of Outer Surface Protein C (OspC) of Borrelia burgdorferi Sensu Lato by Monoclonal Antibodies: Relationship to Genospecies and OspA Serotype. Journal of Clinical Microbiology, 33, 103-109.
[9] Hefty, P.S., Jolliff, S.E., Caimano, M.J., Wikel, S.K. and Akins, D.R. (2002) Changes in Temporal and Spatial Patterns of Outer Surface Lipoprotein Expression Generate Population Heterogeneity and Antigenic Diversity in the Lyme Disease Spirochete, Borrelia burgdorferi. Infection and Immunity, 70, 3468-3478.
http://dx.doi.org/10.1128/IAI.70.7.3468-3478.2002
[10] Wallich, R., Brenner, C., Kramer, M.D. and Simon, M.M. (1995) Molecular Cloning and Immunological Characterization of a Novel Linear-Plasmid-Encoded Gene, pG, of Borrelia burgdorferi Expressed Only in Vivo. Infection and Immunity, 63, 3327-3335.
[11] Ma, Y. and Weis, J.J. (1993) Borrelia burgdorferi Outer Surface Lipoproteins OspA and OspB Possess B-Cell Mitogenic and Cytokine-Stimulatory Properties. Infection and Immunity, 61, 3843-3853.
[12] Takayama, K., Rothenberg, R.J. and Barbour, A.G. (1987) Absence of Lipopolysaccharide in the Lyme Disease Spirochete, Borrelia burgdorferi. Infection and Immunity, 55, 2311-2313.
[13] Barbour, A.G., Tessier, S.L. and Todd, W.J. (1983) Lyme Disease Spirochetes and Ixodid Tick Spirochetes Share a Common Surface Antigenic Determinant Defined by a Monoclonal Antibody. Infection and Immunity, 41, 795-804.
[14] Pal, U. and Fikrig, E. (2003) Adaptation of Borrelia burgdorferi in the Vector and Vertebrate Host. Microbes and Infection, 5, 659-666.
http://dx.doi.org/10.1016/S1286-4579(03)00097-2
[15] Schwan, T.G., Piesman, J., Golde, W.T., Dolan, M.C. and Rosa, P.A. (1995) Induction of an Outer Surface Protein on Borrelia burgdorferi during Tick Feeding. Proceedings of the National Academy of Sciences of the United States of America, 92, 2909-2913.
http://dx.doi.org/10.1073/pnas.92.7.2909
[16] De Silva, A.M., Telford III, S.R., Brunet, L.R., Barthold, S.W. and Fikrig, E. (1996) Borrelia burgdorferi OspA Is an Arthropod-Specific Transmission-Blocking Lyme Disease Vaccine. Journal of Experimental Medicine, 183, 271-275.
http://dx.doi.org/10.1084/jem.183.1.271
[17] Barthold, S.W., Fikrig, E., Bockenstedt, L.K. and Persing, D.H. (1995) Circumvention of Outer Surface Protein A Immunity by Host-Adapted Borrelia burgdorferi. Infection and Immunity, 63, 2255-2261.
[18] Gilmore Jr., R.D. and Piesman, J. (2000) Inhibition of Borrelia burgdorferi Migration from the Midgut to the Salivary Glands Following Feeding by Ticks on OspC-Immunized Mice. Infection and Immunity, 68, 411-414.
http://dx.doi.org/10.1128/IAI.68.1.411-414.2000
[19] Fingerle, V., Hauser, U., Liegl, G., Petko, B., Preac-Mursic, V. and Wilske, B. (1995) Expression of Outer Surface Proteins A and C of Borrelia burgdorferi in Ixodes ricinus. Journal of Clinical Microbiology, 33, 1867-1869.
[20] Ohnishi, J., Piesman, J. and De Silva, A.M. (2001) Antigenic and Genetic Heterogeneity of Borrelia burgdorferi Populations Transmitted by Ticks. Proceedings of the National Academy of Sciences of the United States of America, 98, 670-675.
http://dx.doi.org/10.1073/pnas.98.2.670
[21] Barbour, A.G. and Restrepo, B.I. (2000) Antigenic Variation in Vector-Borne Pathogens. Emerging Infectious Diseases, 6, 449-457.
http://dx.doi.org/10.3201/eid0605.000502
[22] Hastey, C.J., Elsner, R.A., Barthold, S.W. and Baumgarth, N. (2012) Delays and Diversions Mark the Development of B Cell Responses to Borrelia burgdorferi Infection. Journal of Immunology, 188, 5612-5622.
http://dx.doi.org/10.4049/jimmunol.1103735
[23] Zhang, J.R., Hardham, J.M., Barbour, A.G. and Norris, S.J. (1997) Antigenic Variation in Lyme Disease Borreliae by Promiscuous Recombination of VMP-Like Sequence Cassettes. Cell, 89, 275-285.
http://dx.doi.org/10.1016/S0092-8674(00)80206-8
[24] Anguita, J., Thomas, V., Samanta, S., Persinski, R., Hernanz, C., Barthold, S.W. and Fikrig, E. (2001) Borrelia burgdorferi Induced Inflammation Facilitates Spirochete Adaptation and Variable Major Protein-Like Sequence Locus Recombination. Journal of Immunology, 167, 3383-3390.
http://dx.doi.org/10.4049/jimmunol.167.6.3383
[25] Liang, F.T., Jacobs, M.B. and Philipp, M.T. (2001) C-Terminal Invariable Domain of VlsE May Not Serve as Target for Protective Immune Response against Borrelia burgdorferi. Infection and Immunity, 69, 1337-1343.
http://dx.doi.org/10.1128/IAI.69.3.1337-1343.2001
[26] Zhang, J.R. and Norris, S.J. (1998) Gentic Variation of the Borrelia burgdorferi Gene VlsE Involves Cassette Specific, Segmental Gene Conversion. Infection and Immunity, 66, 3698-3704.
[27] Mcdowell, J.V., Sung, S.Y., Hu, L.T. and Marconi, R.T. (2002) Evidence that the Variable Regions of the Central Domain of VlsE Are Antigenic during Infection with Lyme Disease Spirochetes. Infection and Immunity, 70, 4196-4203.
http://dx.doi.org/10.1128/IAI.70.8.4196-4203.2002
[28] Schuijt, T.J., Hovius, J.W., Van Burgel, N.D., Ramamoorthi, N., Fikrig, E. and Van Dam, A.P. (2008) The Tick Salivary Protein Salp15 Inhibits the Killing of Serum-Sensitive Borrelia burgdorferi Sensu Lato Isolates. Infection and Immunity, 76, 2888-2894.
http://dx.doi.org/10.1128/IAI.00232-08
[29] Henningson, A.J., Ernerudh, J., Sandholm, K., Carlsson, S.A., Granlund, H., Jansson, C., et al. (2007) Complement Activation in Lyme Neuroborreliosis—Increased Levels of C1q and C3a in Cerebrospinal Fluid Indicate Complement Activation in the CNS. Journal of Neuroimmunology, 183, 200-207.
http://dx.doi.org/10.1016/j.jneuroim.2006.10.022
[30] Zipfel, P.F. and Skerka, C. (1999) FHL-1/Reconectin: A Human Complement and Immune Regulator with Cell-Adhesive Function. Trends in Immunology, 20, 135-140.
http://dx.doi.org/10.1016/S0167-5699(98)01432-7
[31] Kraiczy, P., Skerka, C., Brade, V. and Zipfel, P.F. (2001) Further Characterization of Complement Regulator-Acquiring Surface Proteins of Borrelia burgdorferi. Infection and Immunity, 69, 7800-7809.
http://dx.doi.org/10.1128/IAI.69.12.7800-7809.2001
[32] Zipfel, P.F., Skerka, C., Hellwage, J., Jokiranta, S.T., Meri, S., Brade, V., et al. (2002) Factor H Family Proteins: On Complement, Microbes and Human Diseases. Biochemical Society Transactions, 30, 971-978.
[33] Akins, D.R., Caimano, M.J., Yang, X., Cerna, F., Norgard, M.V. and Radolf, J.D. (1999) Molecular and Evolutionary Analysis of Borrelia burgdorferi 297 Circular Plasmid-Encoded Lipoproteins with OspE- and OspF-Like Leader Peptides. Infection and Immunity, 67, 1526-1532.
[34] Alitalo, A., Meri, T., Ramo, L., Sakari Jokiranta, T., Heikkilä, T., Seppälä, I.J.T., et al. (2001) Complement Evasion by Borrelia burgdorferi: Serum-Resistant Strains Promote C3b Inactivation. Infection and Immunity, 69, 3685-3691. http://dx.doi.org/10.1128/IAI.69.6.3685-3691.2001
[35] Sung, S.Y., Mcdowell, J.V., Carlyon, J.A. and Marconi, R.T. (2000) Mutation and Recombination in the Upstream Homology Box-Flanked OspE-Related Genes of the Lyme Disease Spirochetes Result in the Development of New Antigenic Variants during Infection. Infection and Immunity, 68, 1319-1327.
http://dx.doi.org/10.1128/IAI.68.3.1319-1327.2000
[36] Stevenson, B., Bono, J.L., Schwan, T.G. and Rosa, P. (1998) Borrelia burgdorferi erp Proteins Are Immunogenic in Mammals Infected by Tick Bite, and Their Synthesis Is Inducible in Cultured Bacteria. Infection and Immunity, 66, 2648-2654.
[37] Hellwage, J., Meri, T., Heikkila, T., Alitalo, A., Panelius, J., Lahdenne, P., et al. (2001) The Complement Regulator Factor H Binds to the Surface Protein OspE of Borrelia burgdorferi. Journal of Biological Chemistry, 276, 8427-8435.
[38] Ramamoorthi, N., Narasimhan, S., Pal, U., Bao, F., Yang, X.F.F., Fish, D., et al. (2005) The Lyme Disease Agent Exploits a Tick Protein to Infect the Mammalian Host. Nature, 436, 573-577.
http://dx.doi.org/10.1038/nature03812
[39] Anguita, J., Ramamoorthi, N., Hovius, J.W., Das, S., Thomas, V., Persinski, R., et al. (2002) Salp15, an Ixodes scapularis Salivary Protein, Inhibits CD4+ T Cell Activation. Immunity, 16, 849-859.
http://dx.doi.org/10.1016/S1074-7613(02)00325-4
[40] Juncadella, I.J., Garg, R., Ananthnarayanan, S.K., Yengo, C.M. and Anguita, J. (2007) T-Cell Signaling Pathways Inhibited by the Tick Saliva Immunosuppressor, Salp15. FEMS Immunology & Medical Microbiology, 49, 433-438.
http://dx.doi.org/10.1111/j.1574-695X.2007.00223.x
[41] Kubes, M., Kocáková, P., Slovák, M., Sláviková, M., Fuchsberger, N. and Nuttal, P.A. (2002) Heterogeneity in the Effect of Different Ixodid Tick Species on Human Natural Killer Cell Activity. Parasite Immunology, 24, 23-28.
http://dx.doi.org/10.1046/j.0141-9838.2001.00434.x
[42] Hovius, J.W., De Jong, M.A., Den Dunnen, J., Litjens, M., Fikrig, E., van der Poll, T., et al. (2008) Salp15 Binding to DC-SIGN Inhibits Cytokine Expression by Impairing both Nucleosome Remodeling and mRNA Stabilization. PLoS Pathogens, 4.
[43] Montgomery, R.R., Lusitani, D., De Boisfleurychevance, A. and Malawista, S.E. (2004) Tick Saliva Reduces Adherence and Area of Human Neutrophils. Infection and Immunity, 72, 2989-2994.
http://dx.doi.org/10.1128/IAI.72.5.2989-2994.2004
[44] Gwakisa, P., Yoshihara, K., Long To, T., Gotoh, H., Amano, F. and Momotani, E. (2001) Salivary Gland Extract of Rhipicephalus appendiculatus Ticks Inhibits in Vitro Transcription and Secretion of Cytokines and Production of Nitric Oxide by LPS-Stimulated JA-4 Cells. Veterinary Parasitology, 99, 53-61.
http://dx.doi.org/10.1016/S0304-4017(01)00445-9
[45] Hannier, S., Liversidge, J., Sternberg, J.M. and Bowman, A.S. (2004) Characterization of the B-Cell Inhibitory Protein Factor in Ixodes ricinus Tick Saliva: A Potential Role in Enhanced Borrelia burgdorferi Transmission. Immunology, 113, 401-408.
http://dx.doi.org/10.1111/j.1365-2567.2004.01975.x
[46] Kimsey, R.B. and Spielman, A. (1990) Motility of Lyme Disease Spirochetes in Fluids as Viscous as the Extracellular Matrix. Journal of Infectious Diseases, 162, 1205-1208.
http://dx.doi.org/10.1093/infdis/162.5.1205
[47] Sal, M.S., Li, C., Motalab, M.A., Shibata, S., Aizawa, S. and Charon, N.W. (2008) Borrelia burgdorferi Uniquely Regulates Its Motility Genes and Has an Intricate Flagellar Hook-Basal Body Structure. Journal of Bacteriology, 190, 1912-1921.
http://dx.doi.org/10.1128/JB.01421-07
[48] Charon, N.W., Goldstein, S.F., Marko, M., Hsieh, C., Gebhardt, L.L., Motaleb, M.A., et al. (2009) The Flat Ribbon Configuration of the Periplasmic Flagella of Borrelia burgdorferi and Its Relationship to Motility and Morphology. Journal of Bacteriology, 191, 600-607.
http://dx.doi.org/10.1128/JB.01288-08
[49] Dorward, D.W., Fischer, E.R. and Brooks, D.M. (1997) Invasion and Cytopathic Killing of Human Lymphocytes by Spirochetes Causing Lyme Disease. Clinical Infectious Diseases, 25, S2-S8.
http://dx.doi.org/10.1086/516169
[50] Nordstrand, A., Barbour, A.G. and Bergstrom, S. (2000) Borrelia Pathogenesis Research in the Post-Genomic and Post-Vaccine Era. Current Opinion in Microbiology, 3, 86-92.
http://dx.doi.org/10.1016/S1369-5274(99)00056-9
[51] Grab, D.J., Lanners, H., Martin, L.N., Chesney, J., Cai, C., Adkisson, H.D. and Bucala, R. (1999) Interaction of Borrelia burgdorferi with Peripheral Blood Fibrocytes, Antigen-Presenting Cells with the Potential for Connective Tissue Targeting. Molecular Medicine, 5, 46-54.
[52] Georgilis, K., Peacocke, M. and Klempner, M.S. (1992) Fibroblasts Protect the Lyme Disease Spirochete, Borrelia burgdorferi, from Ceftriaxone in Vitro. Journal of Infectious Diseases, 166, 440-444.
http://dx.doi.org/10.1093/infdis/166.2.440
[53] Girschick, H.J., Huppertz, H.I., Russmann, H., Krenn, V. and Karch, H. (1996) Intracellular Persistence of Borrelia burgdorferi in Human Synovial Cells. Rheumatology International, 16, 125-132.
http://dx.doi.org/10.1007/BF01409985
[54] Girschick, H.J., Meister, S., Karch, H. and Huppertz, H.I. (1999) Borrelia burgdorferi Downregulates ICAM-1 on Human Synovial Cells in Vitro. Cell Communication and Adhesion, 7, 73-83.
http://dx.doi.org/10.3109/15419069909034398
[55] Ma, Y., Sturrock, A. and Weis, J.J. (1991) Intracellular Localization of Borrelia burgdorferi within Human Endothelial Cell. Infection and Immunity, 59, 671-678.
[56] Montgomery, R.R., Nathanson, M.H. and Malawista, S.E. (1993) The Fate of Borreliaburgdorferi, the Agent for Lyme Disease, in Mouse Macrophages. Destruction, Survival, Recovery. Journal of Immunology, 150, 909-915.
[57] Steere, A.C. (2001) Lyme Disease. New England Journal of Medicine, 345, 115-125.
http://dx.doi.org/10.1056/NEJM200107123450207
[58] Livengood, J.A. and Gilmore, R.D. (2006) Invasion of Human Neuronal and Glial Cells by Infectious Strain of Borrelia burgdorferi. Microbes and Infection, 8, 2832-2840.
http://dx.doi.org/10.1016/j.micinf.2006.08.014
[59] Coburn, J., Fischer, J.R. and Leong, J.M. (2005) Solving a Sticky Problem: New Genetic Approaches to Host Cell Adhesion by the Lyme Disease Spirochete. Molecular Microbiology, 57, 1182-1195.
http://dx.doi.org/10.1111/j.1365-2958.2005.04759.x
[60] Brorson, O. and Brorson, S. (1998) In Vitro Conversion of Borrelia burgdorferi to Cystic Forms in Spinal Fluid, and Transformation to Mobile Spirochetes by Incubation in BSK-H Medium. Infection, 26, 144-150.
http://dx.doi.org/10.1007/BF02771839
[61] Aberer, E. and Duray, P.H. (1991) Morphology of Borrelia burgdorferi: Structural Patterns of Cultured Borreliae in Relation to Staining Methods. Journal of Clinical Microbiology, 29, 764-772.
[62] Mursic, V.P., Wanner, G., Reinhardt, S., Wilske, B., Busch, U. and Marget, W. (1996) Formation and Cultivation of Borrelia burgdorferi Spheroplast-L-Form Variants. Infection, 24, 218-226.
http://dx.doi.org/10.1007/BF01781096
[63] Leishman, W.B. (1920) The Horace Dobell Lecture on an Experimental Investigation of Spirochaetaduttoni, the Parasite of Tick Fever. Lancet, 2, 1237-1244.
[64] Hardy, P.H. and Nell, E.E. (1961) Influence of Osmotic Pressure on the Morphology of the Reiter Treponeme. Journal of Bacteriology, 82, 967-978.
[65] Miklossy, J., Kasas, S., Zurn, A.D., Mccall, S., Yu, S. and Mcgeer, P. (2008) Persisting Atypical and Cystic Forms of Borrelia burgdorferi and Local Inflammation in Lyme Neuroborreliosis. Journal of Neuroinflammation, 5, 40.
[66] Brorson, O. and Brorson, S.H. (1997) Transformation of Cystic Forms of Borrelia burgdorferi to Normal Mobile Spirochetes. Infection, 25, 240-246.
http://dx.doi.org/10.1007/BF01713153
[67] Miklossy, J. (2008) Biology and Neuropathology of Dementia in Syphilis and Lyme Disease. In: Duyckaerts, C., Litvan, I. and Aminoff, Eds., Handbook of Clinical Neurology, Volume 89, Elsevier, Edinburgh, London, New York, Oxford, Philadelphia, St-Louis, Toronto, Sydney, 825-844.
[68] Russell, T.M. and Johnson, B.J. (2013) Lyme Disease Spirochetes Possess an Aggrecan-Binding Protease with Aggrecanase Activity. Molecular Microbiology, 90, 228-240.
[69] Behera, A.K., Hildebrand, E., Szafranski, J., Hung, H.H., Grodzinsky, A.J., Lafyatis, R., et al. (2006) Role of Aggrecanase in Lyme Arthritis. Arthritis & Rheumatism, 54, 3319-3329.
http://dx.doi.org/10.1002/art.22128
[70] Mimata, Y., Kamataki, A., Oikawa, S., Murakami, K., Uzuki, M., Shimamura, T., et al. (2012) Interleukin-6 Upregulates Expression of ADAMTS-4 in Fibroblast-Like Synoviocytes from Patients with Rheumatoid Arthritis. International Journal of Rheumatic Diseases, 15, 36-44.
http://dx.doi.org/10.1111/j.1756-185X.2011.01656.x
[71] Huang, K. and Wu, L.D. (2008) Aggrecanase and Aggrecan Degradation in Osteoarthritis: A Review. Journal of International Medical Research, 36, 1149-1160.
http://dx.doi.org/10.1177/147323000803600601
[72] Ren, P., Zhang, L., Xu, G., Palmero, L.C., Albini, P.T., Coselli, J.S., et al. (2013) ADAMTS-1 and ADAMTS-4 Levels Are Elevated in Thoracic Aortic Aneurysms and Dissections. Annals of Thoracic Surgery, 95, 570-577.
http://dx.doi.org/10.1016/j.athoracsur.2012.10.084
[73] Zhang, E., Yan, X., Zhang, M., Chang, X., Bai, Z., He, Y., et al. (2013) Aggrecanases in the Human Synovial Fluid at Different Stages of Osteoarthritis. Clinical Rheumatology, 32, 797-803.
http://dx.doi.org/10.1007/s10067-013-2171-0
[74] Finlay, B.B. and Falkow, S. (1997) Common Themes in Microbial Pathogenicity Revisited. Microbiology and Molecular Biology Reviews, 61, 136-169.
[75] Hoyle, B.D. and Costerton, J.W. (1991) Bacterial Resistance to Antibiotics: The Role of Biofilms. Progress in Drug Research, 37, 91-105.
[76] Stewart, P. and Costerton, J.W. (2001) Antibiotic Resistance of Bacteria in Biofilms. Lancet, 358, 135-138.
http://dx.doi.org/10.1016/S0140-6736(01)05321-1
[77] Costerton, J.W., Stewart, P.S. and Greenburg, E.P. (1999) Bacterial Biofilms: A Common Cause of Persistent Infections. Science, 284, 1318-1322.
http://dx.doi.org/10.1126/science.284.5418.1318
[78] Sapi, E., Bastian, S.L., Mpoy, C.M., Scott, S., Rattelle, A., Pabbati, N., et al. (2012) Characterization of Biofilm Formation by Borrelia burgdorferi in Vitro. PLoS ONE, 7.
[79] Donlan, R.M. and Costerton, W.J. (2002) Biofilms: Survival Mechanisms of Clinically Relevant Microorganisms. Clinical Microbiology Reviews, 15, 167-193.
http://dx.doi.org/10.1128/CMR.15.2.167-193.2002
[80] Singh, R., Stine, O.C., Smith, D.L., Spitznagel Jr., J.K., Labib, M.E., et al. (2003) Microbial Diversity of Biofilms in Dental Unit Water Systems. Applied and Environmental Microbiology, 69, 3412-3420.
http://dx.doi.org/10.1128/AEM.69.6.3412-3420.2003
[81] Tibbles, C.D. and Edlow, J.A. (2007) Does This Patient Have Erythema Migrans? JAMA, 297, 2617-2627.
http://dx.doi.org/10.1001/jama.297.23.2617
[82] Aucott, J., Morrison, C., Munoz, B., Rowe, P.C., Schwarzwalder, A. and West, S.K. (2009) Diagnostic Challenges of Early Lyme Disease: Lessons from a Community Case Series. BMC Infectious Diseases, 9, 79.
http://dx.doi.org/10.1186/1471-2334-9-79

  
comments powered by Disqus

Copyright © 2018 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.