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Perspective ARTICLE

Front. Cell. Infect. Microbiol., 14 August 2013 | https://doi.org/10.3389/fcimb.2013.00040

Borrelia burgdorferi aggrecanase activity: more evidence for persistent infection in Lyme disease

Raphael B. Stricker* and Lorraine Johnson
  • International Lyme and Associated Diseases Society, Bethesda, MD, USA

Lyme disease is the most common tickborne illness in the world today. A recent study describes for the first time an enzyme produced by the spirochetal agent of Lyme disease, Borrelia burgdorferi, that cleaves aggrecan, a proteoglycan found in joints and connective tissue. Discovery of the spirochetal aggrecanase raises many questions about the pathogenesis of Lyme arthritis and lends support to the concept of persistent B. burgdorferi infection in patients with chronic Lyme disease symptoms.

Lyme disease is the most common tickborne illness in the world today (Stricker and Johnson, 2011). As of July 2013, the Medline database lists more than 25,000 published peer-reviewed articles about tickborne diseases. Despite this plethora of scientific information, however, the pathogenetic mechanisms of rheumatological, neurological and cardiac complications induced by the Lyme spirochete, Borrelia burgdorferi, have not been fully elucidated (Schmit et al., 2011; Lin et al., 2012). In particular, the mode of tissue invasion by the Lyme spirochete remains obscure.

In an elegant study of a potential mechanism of Lyme arthritis, Russell and Johnson describe for the first time an enzyme produced by B. burgdorferi that cleaves aggrecan, a proteoglycan found in joints and connective tissue (Russell and Johnson, 2013). The spirochetal aggrecanase, called BbHtrA, was identified in the three major species of B. burgdorferi, was expressed on the spirochete surface, and was shown to cleave aggrecan at a site that destroys the function of the proteoglycan. Furthermore, and perhaps of greatest importance, the proteoglycan degradation fragments produced by BbHtrA cleavage have been detected in the synovial fluid of patients with Lyme arthritis. These observations suggest that the spirochetal enzyme plays a role in the rheumatological pathology of Lyme disease (Russell and Johnson, 2013).

Although the discovery of BbHtrA suggests a novel spirochetal mechanism of Lyme arthritis, the involvement of aggrecanase in this process is not novel. A previous study by Behera et al. showed that B. burgdorferi may induce expression of ADAMTS-4, a host tissue aggrecanase that can cleave the proteoglycan in the joints of mice and humans (Behera et al., 2006). Thus, the Lyme spirochete may induce joint damage using both host tissue (ADAMTS-4) and spirochetal (BbHtrA) aggrecanases. Although Russell and Johnson touch briefly on this point in their report, the implications of the redundant enzyme activity merit further discussion.

Aggrecanase activity has been associated with various forms of arthritis and more recently with progression of degenerative disc disease and aortic aneurysm dissection (Huang and Wu, 2008; Mimata et al., 2012; Tian et al., 2013; Zhang et al., 2013). The principal tissue aggrecanases ADAMTS-4 and ADAMTS-5 appear to be regulated by inflammatory cytokines such as IL-6, TNF-α and IL-1β, and these enzymes appear to work in tandem to induce joint injury (Mimata et al., 2012; Tian et al., 2013). Based on their ability to damage proteoglycans, the tissue aggrecanases have been identified as potential therapeutic targets in the prevention and treatment of arthritis and connective tissue diseases (Huang and Wu, 2008; Mimata et al., 2012; Ren et al., 2013; Tian et al., 2013; Zhang et al., 2013). As pointed out by Russell and Johnson, secreted aggrecanases from several gram-negative bacteria also appear to be involved in tissue invasion and propagation of infection under varying stress conditions in the host (Wu et al., 2011; Hoy et al., 2013).

The discovery of a spirochetal aggrecanase raises significant questions about the mechanisms of joint and connective tissue injury as well as tissue invasion by B. burgdorferi. How does this pathogen-associated enzyme work in conjunction with the tissue aggrecanases, and which one is dominant? How is the spirochetal enzyme regulated, and specifically do inflammatory cytokines influence expression of the spirochetal aggrecanase in the same manner as the tissue enzymes? Are the aggrecan cleavage sites the same for the tissue and spirochetal enzymes? Do tickborne coinfections influence expression of the spirochetal aggrecanase, as suggested by previous studies of tissue enzyme activity (Grab et al., 2007)? And as with other bacteria that secrete a similar aggrecanase, do these enzymes play a more general role in connective tissue invasion by B. burgdorferi, including induction of disease in other organ systems? The answers to these and related questions will help to elucidate both the mechanisms of acute Lyme arthritis and the evolution of persistent infection with the Lyme spirochete (Berndtson, 2013; Stricker and Johnson, 2013).

Controversy persists over the existence of chronic Lyme disease due to persistent infection with B. burgdorferi in patients who are untreated or undertreated for the spirochetal illness (Berndtson, 2013; Stricker and Johnson, 2013). While some researchers continue to insist that there is no “credible scientific evidence” for chronic Lyme disease, a growing body of clinical and research evidence supports persistent symptomatic infection with the Lyme spirochete (Miklossy, 2012; Berndtson, 2013; Ljøstad and Mygland, 2013; Stricker and Johnson, 2013). The discovery of a spirochetal aggrecanase that damages tissues and enhances tissue invasion by B. burgdorferi adds support to the concept of persistent symptomatic infection in Lyme disease. The extent to which this spirochetal enzyme helps B. burgdorferi to penetrate tissue sites, evade the immune response and survive antibiotic therapy remains to be determined.

The study by Russell and Johnson is yet another reminder of the complexity of B. burgdorferi pathogenesis (Salman-Dilgimen et al., 2011; Chaconas, 2012; Chaconas and Norris, 2013). The fact that the Lyme spirochete can apparently utilize its own enzyme as well as hijacking a host enzyme to facilitate tissue invasion underscores the regulatory and molecular complexity of the spirochete, which contains one of the “most unusual genomes on the planet” (Chaconas, 2012). From a microbiological perspective, the study of B. burgdorferi gene function is yielding fascinating clues about the interaction of this organism with its host and the coordinated interplay within its own genetic elements (Salman-Dilgimen et al., 2011; Schmit et al., 2011; Chaconas, 2012; Chaconas and Norris, 2013). Clearly we still have lots to learn about the science of Lyme disease (Pearson and Huyshe-Shires, 2013).

Conflict of interest statement

Raphael B. Stricker serves without compensation on the medical advisory panel of QMedRx Inc. He has no financial ties to the company. Lorraine Johnson has no conflicts to declare. The work is original, and both authors had a role in writing the manuscript.

References

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 Rheum. 54, 3319–3329. doi: 10.1002/art.22128

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Berndtson, K. (2013). Review of evidence for immune evasion and persistent infection in Lyme disease. Int. J. Gen. Med. 6, 291–306. doi: 10.2147/IJGM.S44114

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Chaconas, G. (2012). CSM Murray award lecture—functional studies of the lyme disease spirochete—from molecules to mice. Can. J. Microbiol. 58, 236–248. doi: 10.1139/w11-143

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Chaconas, G., and Norris, S. J. (2013). Peaceful coexistence amongst Borrelia plasmids: getting by with a little help from their friends? Plasmid 70, 161–167. doi: 10.1016/j.plasmid.2013.05.002

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Grab, D. J., Nyarko, E., Barat, N. C., Nikolskaia, O. V., and Dumler, J. S. (2007). Anaplasma phagocytophilum-Borrelia burgdorferi coinfection enhances chemokine, cytokine, and matrix metalloprotease expression by human brain microvascular endothelial cells. Clin. Vaccine Immunol. 14, 1420–1424.

Pubmed Abstract | Pubmed Full Text

Hoy, B., Brandstetter, H., and Wessler, S. (2013). The stability and activity of recombinant Helicobacter pylori HtrA under stress conditions. J. Basic Microbiol. 53, 402–409. doi: 10.1002/jobm.201200074

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Huang, K., and Wu, L. D. (2008). Aggrecanase and aggrecan degradation in osteoarthritis: a review. J. Int. Med. Res. 36, 1149–1160. doi: 10.1177/147323000803600601

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Lin, T., Gao, L., Zhang, C., Odeh, E., Jacobs, M. B., Coutte, L., et al. (2012). Analysis of an ordered, comprehensive STM mutant library in infectious Borrelia burgdorferi: insights into the genes required for mouse infectivity. PLoS ONE 7:e47532. doi: 10.1371/journal.pone.0047532

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Ljøstad, U., and Mygland, Å. (2013). Chronic Lyme; diagnostic and therapeutic challenges. Acta Neurol. Scand. Suppl. 196, 38–47. doi: 10.1111/ane.12048

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Miklossy, J. (2012). Chronic or late Lyme neuroborreliosis: analysis of evidence compared to chronic or late neurosyphilis. Open Neurol. J. 6, 146–157. doi: 10.2174/1874205X01206010146

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

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. Int. J. Rheum. Dis. 15, 36–44. doi: 10.1111/j.1756-185X.2011.01656.x

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Pearson, S., and Huyshe-Shires, S. (2013). Lyme borreliosis: the need for more research. Q. J. Med. 106, 203. doi: 10.1093/qjmed/hct001

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

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. Ann. Thorac. Surg. 95, 570–577. doi: 10.1016/j.athoracsur.2012.10.084

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Russell, T. M., and Johnson, B. J. (2013). Lyme disease spirochetes possess an aggrecan-binding protease with aggrecanase activity. Mol. Microbiol. doi: 10.1111/mmi.12276. [Epub ahead of print].

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Salman-Dilgimen, A., Hardy, P. O., Dresser, A. R., and Chaconas, G. (2011). HrpA, a DEAH-box RNA helicase, is involved in global gene regulation in the Lyme disease spirochete. PLoS ONE 6:e22168. doi: 10.1371/journal.pone.0022168

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Schmit, V. L., Patton, T. G., and Gilmore, R. D. Jr. (2011). Analysis of Borrelia burgdorferi surface proteins as determinants in establishing host cell interactions. Front. Microbiol. 2:141. doi: 10.3389/fmicb.2011.00141

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Stricker, R. B., and Johnson, L. (2011). Lyme disease: the next decade. Infect. Drug Resist. 4, 1–9. doi: 10.2147/IDR.S15653

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Stricker, R. B., and Johnson, L. (2013). Persistent infection in chronic Lyme disease: does form matter? Res. J. Infect. Dis. 1, 2.

Tian, Y., Yuan, W., Fujita, N., Wang, J., Wang, H., Shapiro, I. M., et al. (2013). Inflammatory cytokines associated with degenerative disc disease control aggrecanase-1 (ADAMTS-4) expression in nucleus pulposus cells through MAPK and NF-κ B. Am. J. Pathol. 182, 2310–2321. doi: 10.1016/j.ajpath.2013.02.037

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Wu, X., Lei, L., Gong, S., Chen, D., Flores, R., and Zhong, G. (2011). The chlamydial periplasmic stress response serine protease cHtrA is secreted into host cell cytosol. BMC Microbiol. 11:87. doi: 10.1186/1471-2180-11-87

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

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. Clin. Rheumatol 32, 797–803. doi: 10.1007/s10067-013-2171-0

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Keywords: Lyme disease, Borrelia burgdorferi, aggrecanase, arthritis, BbHtrA

Citation: Stricker RB and Johnson L (2013) Borrelia burgdorferi aggrecanase activity: more evidence for persistent infection in Lyme disease. Front. Cell. Infect. Microbiol. 3:40. doi: 10.3389/fcimb.2013.00040

Received: 13 July 2013; Accepted: 25 July 2013;
Published online: 14 August 2013.

Edited by:

Catherine Ayn Brissette, University of North Dakota School of Medicine and Health Sciences, USA

Reviewed by:

Catherine Ayn Brissette, University of North Dakota School of Medicine and Health Sciences, USA
David Volkman, State University of New York at Stony Brook, USA

Copyright © 2013 Stricker and Johnson. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Raphael B. Stricker, 450 Sutter Street, Suite 1504, San Francisco, CA 94108, USA e-mail: rstricker@usmamed.com