Faculty; Immunity, Innate; Lyme Disease; Rheumatology; Tick-Borne Diseases; Lyme Neuroborreliosis
My laboratory studies the pathogenesis of Lyme disease, a tick-borne infection with the spirochete Borrelia burgdorferi. We use the murine model of Lyme borreliosis to investigate the host immune response to the spirochete and mechanisms by which the spirochete persists in the host. Using molecular genomic, proteomic and imaging approaches, we are studying 1) spirochete interactions with ticks and host tissues in vivo in real-time; 2) mechanisms of spirochete evasion of innate and adaptive immune defenses, including biophysical studies of the spirochete; and 3) protein profiles of spirochetes during acute and chronic infection for improving diagnostic tests.
Specialized Terms: Pathogenesis of Lyme disease; Tick-borne infections; Innate immunity; Multiphoton imaging; Faculty development in context of team science
Extensive Research Description
Lyme borreliosis is an infectious disease caused by the
tick-transmitted spirochete Borrelia burgdorferi. Since its recognition in the United States in the early
1970’s, it has emerged as the most common vector-borne disease in North America
and a significant health care concern, with nearly 30,000 confirmed new cases
in 2009. The infection can present
with a localized skin rash at the site of tick bite or with involvement of
other organ systems, especially the heart, joints and nervous system. Although the infection is highly
responsive to antibiotic therapy when detected early, the time to symptom
resolution may be protracted. A
delay in diagnosis can result in disease manifestations, such as arthritis,
that persist despite antibiotics effective at earlier stages of the illness.
My laboratory used the murine model of Lyme borreliosis to study the host immune response to B. burgdorferi in an effort to understand factors that influence clearance of the organism and disease expression. Our published work has demonstrated the importance of innate immunity, especially phagocytes and T cell independent antibody, in control of pathogen burden and the role of IgG subtypes and Fc receptors in severity of arthritis. Through imaging modalities, we have begun to dissect the role of spirochete motility and fluidity of its outer membrane in evasion of the innate and adaptive immune responses. In collaboration with Dr. Eric Dufresne (Yale Department of Engineering), we are using optical tweezers and speckle microscopy to measure the mobility of proteins in the spirochete outer membrane and the consequences of membrane fluidity on the ability of phagocytes to capture and ingest B. burgdorferi. In vivo, we are using multiphoton microscopy to measure in real time the speed and motility patterns of spirochetes as they move between the tick and the mammal, and the requirement for select B. burgdorferi proteins in this process. Using this system, we have also shown that the vast majority of spirochetes are eliminated within the first few days of antibiotic therapy for disseminated Lyme borreliosis, but antigenic debris can persist in tissue adjacent to cartilaginous structures. Our current studies are designed to investigate the duration of persistence of this debris and the potential for it to incite inflammation, which may contribute to persistent symptoms after treatment for Lyme disease.
In addition to pathogenesis studies, we are also working in conjunction with L2 Diagnostics, Inc., to improve the diagnosis of Lyme disease. We have identified panels of B. burgdorferi antigens expressed at early and late stages of infection that are underrepresented in lysates of cultured spirochetes, which are the substrates of current serologic tests for Lyme disease. These antigens are being evaluated for use as new antigens for diagnosing Lyme disease and for evaluating response to therapy. 1. Real-time intravital microscopy of Borrelia burgdorferi infection in mice
This project is using multiphoton microscopy to define in real-time spirochete interactions between the feeding tick and the mammalian host, including modes of spirochete dissemination from the skin and evolving host immune responses.
2. Biophysical properties of Borrelia burgdorferi outer surface membrane
This collaborative project with Dr. Eric Dufresne (Yale Dept. of Engineering) employs optical tweezer technology and speckle microscopy to measure Borrelia burgdorferi outer membrane protein mobility and the relationship to directional forces exerted by spirochetes when trapped at one end.
3. Cutaneous host immune response to Borrelia burgdorferi.
This project seeks to understand the skin immune response to tick feeding and tick-introduced pathogens.
4. Development of improved diagnostic tests for Lyme disease
These projects, performed in collaboration with L2 Diagnostics, seek to develop improved diagnostic tests for Lyme disease based on in vivo expressed Borrelia burgdorferi proteins.
5. Innate immune pathways in elderly and immunosuppressed populations
This contract with Drs. Fikrig and Montgomery will analyze human innate immune cell function in aging and medication-induced immunosuppression and identify critical pathways and mechanisms that mediate impaired/dysregulated immune responses in the elderly and immunosuppressed populations.
Spirochete antigens persist by cartilage after murine Lyme borreliosis therapy.
L.K. Bockenstedt, D. Gonzalez, A. Haberman, and A.A. Belperron. Spirochete antigens persist by cartilage after murine Lyme borreliosis therapy. J. Clin. Invest. 2012, 122(7):2652-2662. PMCID:PMC3386809.
The heterogeneous motility of the Lyme disease spirochete in gelatin mimics dissemination through tissue.
Harman, M.W., S.M. Dunham-Ems, M.J. Caimano, A.A. Belperron, L.K. Bockenstedt, H.C. Fu, J.D. Radolf, and C.W. Wolgemuth. The heterogeneous motility of the Lyme disease spirochete in gelatin mimics dissemination through tissue. Proc. Natl. Acad. Sci. USA 2012, 109(8): 3059-64. PMCID: PMC3286914
Age –associated elevation in TLR5 leads to increased inflammatory responses in the elderly.
Qian, F., X. Wang, L. Zhang, S. Chen, M. Piecychna, H. Allore, L.K. Bockenstedt, S. Malawista, R Bucala, A.C. Shaw, E. Fikrig, and R.R. Montgomery. Age –associated elevation in TLR5 leads to increased inflammatory responses in the elderly. Aging Cell 2012, Feb 11(1):104-110. PMCID:PMC3257374.
The impact of nanoparticle ligand density on dendritic cell targeted vaccines.
Bandyopadhyay, A., R.L. Fine, S. Demento, L.K. Bockenstedt, and T. Fahmy. The impact of nanoparticle ligand density on dendritic cell targeted vaccines. Biomaterials. 2011, 32:3094-3105.
The caspase 1-inflammasome is not required for control of murine Lyme borreliosis.
Liu N, AA Belperron, CJ Booth, LK Bockenstedt. The caspase 1-inflammasome is not required for control of murine Lyme borreliosis. Infect Immun. 2009, 77:3320-3327. PMCID: PMC2715671
Langerhans cell deficiency impairs Ixodes scapularis suppression of Th1 responses in mice.
Vesely, D.L., D. Fish, M. Shlomchik, D.H. Kaplan, and L.K. Bockenstedt. (2009). Langerhans cell deficiency impairs Ixodes scapularis suppression of Th1 responses in mice. Infect. Immun. 77:1881-1887. PMCID: PMC2681756
Marginal zone B-cell depletion impairs murine host defense against Borrelia burgdorferi infection.
Belperron, AA, CM Dailey, CJ Booth, and LK Bockenstedt (2007) Marginal zone B-cell depletion impairs murine host defense against Borrelia burgdorferi infection. Infect. Immun. 75:3354. PMCID: PMC1932939
Infection-induced marginal zone B cell production of Borrelia hermsii-specific antibody is impaired in the absence of CD1d.
Belperron AA, CM Dailey, and LK Bockenstedt (2005) Infection-induced marginal zone B cell production of Borrelia hermsii-specific antibody is impaired in the absence of CD1d. J Immunol 174:5681.
Myeloid differentiation antigen 88 deficiency impairs pathogen clearance but does not alter inflammation in Borrelia burgdorferi-infected mice.
Liu N, RR Montgomery, SW Barthold, LK Bockenstedt (2004) Myeloid differentiation antigen 88 deficiency impairs pathogen clearance but does not alter inflammation in Borrelia burgdorferi-infected mice. Infect Immun 72:3195. PMCID: PMC415708
Detection of attenuated, noninfectious spirochetes in Borrelia burgdorferi-infected mice after antibiotic treatment.
Bockenstedt LK, J Mao, E Hodzic, SW Barthold, D Fish (2002) Detection of attenuated, non-infectious spirochetes after antibiotic treatment of Borrelia burgdorferi infected mice. J Infect Dis 186:1430-7
Full List of PubMed Publications
- Harman MW, Hamby AE, Boltyanskiy R, Belperron AA, Bockenstedt LK, Kress H, Dufresne ER, Wolgemuth CW: Vancomycin Reduces Cell Wall Stiffness and Slows Swim Speed of the Lyme Disease Bacterium. Biophys J. 2017 Feb 28. PMID: 28256234
- Lawres LA, Garg A, Kumar V, Bruzual I, Forquer IP, Renard I, Virji AZ, Boulard P, Rodriguez EX, Allen AJ, Pou S, Wegmann KW, Winter RW, Nilsen A, Mao J, Preston DA, Belperron AA, Bockenstedt LK, Hinrichs DJ, Riscoe MK, Doggett JS, Ben Mamoun C: Radical cure of experimental babesiosis in immunodeficient mice using a combination of an endochin-like quinolone and atovaquone. J Exp Med. 2016 Jun 27; 2016 Jun 6. PMID: 27270894
- Wagemakers A, Koetsveld J, Narasimhan S, Wickel M, Deponte K, Bleijlevens B, Jahfari S, Sprong H, Karan LS, Sarksyan DS, van der Poll T, Bockenstedt LK, Bins AD, Platonov AE, Fikrig E, Hovius JW: Variable Major Proteins as Targets for Specific Antibodies against Borrelia miyamotoi. J Immunol. 2016 May 15; 2016 Apr 13. PMID: 27076681
- Dunn JM, Krause PJ, Davis S, Vannier EG, Fitzpatrick MC, Rollend L, Belperron AA, States SL, Stacey A, Bockenstedt LK, Fish D, Diuk-Wasser MA: Borrelia burgdorferi promotes the establishment of Babesia microti in the northeastern United States. PLoS One. 2014 Dec 29; 2014 Dec 29. PMID: 25545393
- Bockenstedt LK, Wormser GP: Review: unraveling Lyme disease. Arthritis Rheumatol. 2014 Sep. PMID: 24965960
- Belperron AA, Liu N, Booth CJ, Bockenstedt LK: Dual role for Fcγ receptors in host defense and disease in Borrelia burgdorferi-infected mice. Front Cell Infect Microbiol. 2014 Jun 11; 2014 Jun 11. PMID: 24967215
- Bockenstedt LK, Radolf JD: Xenodiagnosis for posttreatment Lyme disease syndrome: resolving the conundrum or adding to it? Clin Infect Dis. 2014 Apr; 2014 Feb 11. PMID: 24523213
- Bockenstedt LK, Gonzalez D, Mao J, Li M, Belperron AA, Haberman A: What ticks do under your skin: two-photon intravital imaging of Ixodes scapularis feeding in the presence of the lyme disease spirochete. Yale J Biol Med. 2014 Mar 5; 2014 Mar 5. PMID: 24600332
- Qian F, Guo X, Wang X, Yuan X, Chen S, Malawista SE, Bockenstedt LK, Allore HG, Montgomery RR: Reduced bioenergetics and toll-like receptor 1 function in human polymorphonuclear leukocytes in aging. Aging (Albany NY). 2014 Feb. PMID: 24595889
- Silver AC, Dunne DW, Zeiss CJ, Bockenstedt LK, Radolf JD, Salazar JC, Fikrig E: MyD88 deficiency markedly worsens tissue inflammation and bacterial clearance in mice infected with Treponema pallidum, the agent of syphilis. PLoS One. 2013; 2013 Aug 5. PMID: 23940747
- Krause PJ, Bockenstedt LK: Cardiology patient pages. Lyme disease and the heart. Circulation. 2013 Feb 19. PMID: 23429899
- Bockenstedt LK, Gonzalez DG, Haberman AM, Belperron AA: Spirochete antigens persist near cartilage after murine Lyme borreliosis therapy. J Clin Invest. 2012 Jul; 2012 Jun 25. PMID: 22728937
- Bandyopadhyay A, Fine RL, Demento S, Bockenstedt LK, Fahmy TM: The impact of nanoparticle ligand density on dendritic-cell targeted vaccines. Biomaterials. 2011 Apr; 2011 Jan 22. PMID: 21262534
- Dunne DW, Shaw A, Bockenstedt LK, Allore HG, Chen S, Malawista SE, Leng L, Mizue Y, Piecychna M, Zhang L, Towle V, Bucala R, Montgomery RR, Fikrig E: Increased TLR4 expression and downstream cytokine production in immunosuppressed adults compared to non-immunosuppressed adults. PLoS One. 2010 Jun 28; 2010 Jun 28. PMID: 20596538
- Liu N, Belperron AA, Booth CJ, Bockenstedt LK: The caspase 1 inflammasome is not required for control of murine Lyme borreliosis. Infect Immun. 2009 Aug; 2009 Jun 1. PMID: 19487481
- Vesely DL, Fish D, Shlomchik MJ, Kaplan DH, Bockenstedt LK: Langerhans cell deficiency impairs Ixodes scapularis suppression of Th1 responses in mice. Infect Immun. 2009 May; 2009 Mar 9. PMID: 19273564
- Pedra JH, Tao J, Sutterwala FS, Sukumaran B, Berliner N, Bockenstedt LK, Flavell RA, Yin Z, Fikrig E: IL-12/23p40-dependent clearance of Anaplasma phagocytophilum in the murine model of human anaplasmosis. FEMS Immunol Med Microbiol. 2007 Aug; 2007 May 23. PMID: 17521390
- Belperron AA, Dailey CM, Booth CJ, Bockenstedt LK: Marginal zone B-cell depletion impairs murine host defense against Borrelia burgdorferi infection. Infect Immun. 2007 Jul; 2007 Apr 30. PMID: 17470546
- Bockenstedt LK, Liu N, Schwartz I, Fish D: MyD88 deficiency enhances acquisition and transmission of Borrelia burgdorferi by Ixodes scapularis ticks. Infect Immun. 2006 Apr. PMID: 16552045
- Belperron AA, Dailey CM, Bockenstedt LK: Infection-induced marginal zone B cell production of Borrelia hermsii-specific antibody is impaired in the absence of CD1d. J Immunol. 2005 May 1. PMID: 15843569
- Liu N, Montgomery RR, Barthold SW, Bockenstedt LK: Myeloid differentiation antigen 88 deficiency impairs pathogen clearance but does not alter inflammation in Borrelia burgdorferi-infected mice. Infect Immun. 2004 Jun. PMID: 15155621
- Quan TE, Cowper S, Wu SP, Bockenstedt LK, Bucala R: Circulating fibrocytes: collagen-secreting cells of the peripheral blood. Int J Biochem Cell Biol. 2004 Apr. PMID: 15010326
- Pal U, Yang X, Chen M, Bockenstedt LK, Anderson JF, Flavell RA, Norgard MV, Fikrig E: OspC facilitates Borrelia burgdorferi invasion of Ixodes scapularis salivary glands. J Clin Invest. 2004 Jan. PMID: 14722614
- Bockenstedt LK, Shanafelt MC, Belperron A, Mao J, Barthold SW: Humoral immunity reflects altered T helper cell bias in Borrelia burgdorferi-infected gamma delta T-cell-deficient mice. Infect Immun. 2003 May. PMID: 12704174
- Bockenstedt LK, Mao J, Hodzic E, Barthold SW, Fish D: Detection of attenuated, noninfectious spirochetes in Borrelia burgdorferi-infected mice after antibiotic treatment. J Infect Dis. 2002 Nov 15; 2002 Oct 23. PMID: 12404158