Abstract

Lyme disease is the leading vector-borne infection in temperate climates and presents with heterogeneous cutaneous, neurologic, cardiac, and rheumatologic manifestations that complicate diagnosis and follow-up. This narrative review integrates current evidence on Borrelia burgdorferi transmission dynamics, virulence strategies, organ-specific pathophysiology, host immune responses, and pharmacologic management. We summarize how phase-regulated outer surface proteins, complement evasion, antigenic variation and biofilm-like phenotypes enable persistent infection, while dysregulated Th1-skewed immunity, inadequate IL-10 signalling and genetic susceptibility contribute to antibiotic-refractory arthritis and post-treatment Lyme disease symptoms. Key diagnostic issues, including limitations of two-tier serology in early localized disease and the role of modified ELISA algorithms and CSF analysis in neuroborreliosis, are critically appraised. Finally, we outline evidence-based antimicrobial regimens for stagespecific disease and highlight the need for immunomodulatory strategies in refractory cases. A mechanistic understanding of pathogen–host interactions is essential to improving outcomes and long-term functional recovery in this increasingly prevalent multisystem disorder.

• 1.   Akhavan BJ, Karaman M, Paragas V. Amoxicillin. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023.
• 2.   Barthold SW, Hodzic E, Imai DM, Feng S, Yang X, Luft BJ. Antibiotic treatment of animals infected with Borrelia burgdorferi. Clin Microbiol Rev. 2009;22(3):552–574.
• 3.   Arvikar SL, Steere AC. Lyme arthritis. Curr Opin Rheumatol. 2022;34(3):289–295.
• 4.   Bankhead T. Role of the VlsE lipoprotein in immune avoidance by the Lyme disease spirochete. Microbes Infect. 2016;18(8):567–573.
• 5.   Bockenstedt LK, Gonzalez DG, Habluetzel A, et al. Immune response to Borrelia: Lessons from Lyme disease and Lyme borreliosis. Front Immunol. 2020;11:3396.
• 6.   Branda JA, Aguero-Rosenfeld ME, Ferraro MJ, et al. Evaluation of modified 2-tiered serodiagnostic testing algorithms for early Lyme disease. Clin Infect Dis. 2017;64(8):1074–1080.
• 7.   Bui T, Preuss CV, Sticco KL. Cephalosporins. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024.
• 8.   Caine JA, Coburn J. Multifunctional and redundant roles of Borrelia burgdorferi outer surface proteins in tissue adhesion, colonization, and vascular transmigration. Front Immunol. 2016;7:442.
• 9.   Dennis VA, Jefferson T. Interleukin-10 anti-inflammatory response to Borrelia burgdorferi, the agent of Lyme disease. J Clin Immunol. 2006;26(1):92–107.
• 10.   Feng J, Leone J, Schweitzer F, et al. Ceftriaxone pulse dosing fails to eradicate biofilm-like microcolonies of Borrelia burgdorferi. Front Microbiol. 2016;7:1744.
• 11.   Frontiers in Immunology. Borrelia burgdorferi keeps moving and carries on [Internet]. 2017 [cited 2026 Mar 12].
• 12.   Grab DJ, Nyarko E, Obando D, et al. Borrelia burgdorferi, host-derived proteases, and the blood–brain barrier. Infect Immun. 2005;73(2):1014–1022.
• 13.   Golovchenko M, Grubhoffer L, Rudenko N. Borrelia burgdorferi sensu lato complex: An updated overview of geographical distribution, epidemiology and epidemiological situation in Eurasia. Ticks Tick Borne Dis. 2023;14(5):102168.
• 14.   Hovis KM, Tran E, Sundy CM, et al. Selective binding of Borrelia burgdorferi OspE paralogs to factor H and serum proteins from different animals demonstrating the concept of a microbial mechanism for expanding the host range. J Immunol. 2006;177(11):7650–7659.
• 15.   Johns Hopkins Lyme Disease Research Center. Lyme disease treatment and prognosis [Internet]. 2023 [cited 2026 Mar 12].
• 16.   Iliopoulou BP, Alroy J, Huber BT, Steere AC. HLA-DR alleles determine responsiveness to Borrelia antigens in Lyme arthritis. J Immunol. 2009;174(4):2048–2055.
• 17.   Jutras BL, Chenail AM, Stevenson B, et al. Borrelia burgdorferi peptidoglycan is a persistent antigen in patients with Lyme arthritis. PNAS. 2019;116(27):13498–13507.
• 18.   Klein JO. History of macrolide use in pediatrics. Pediatr Infect Dis J. 1997;16(4):427–431.
• 19.   Logan JJ, Ackerman LA, Hovis MF, et al. Ixodes scapularis density and Borrelia burgdorferi infection rates in naturally infected ticks across the northeastern United States. Sci Rep. 2024;14:14725.
• 20.   Miraflor AP, Reardon JM, Seoane BL, et al. The many masks of cutaneous Lyme disease. J Am Acad Dermatol. 2016;74(4):763–768.
• 21.   Moore SR, Belperron AA, Bockenstedt LK, et al. Hijacking factor H for complement immune evasion. Front Immunol. 2021;12:602277.
• 22.   MSD Manual Professional Version. Lyme disease [Internet]. 2025 [cited 2026 Mar 12].
• 23.   Murthy PK, Tran RV, Piesman J, Fikrig E. Interleukin-10 modulates proinflammatory cytokines in the brain of mice infected with Borrelia burgdorferi. J Infect Dis. 2000;182(1):420–425.
• 24.   Nature Communications. Targeted volume imaging reveals early vascular interactions and intravasation by Borrelia burgdorferi [Internet]. 2025 [cited 2026 Mar 12].
• 25.   Nau R, Sörgel F, Eiffert H. Penetration of drugs through the blood-cerebrospinal fluid barrier. Clin Pharmacokinet. 2010;49(3):159–188.
• 26.   Patel RS, Gifford RM, Eby GA. Doxycycline hyclate. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025.
• 27.   Pepin KM, Eisen RJ, Mead PS, Piesman J. Geographic variation in the relationship between human Lyme disease incidence and density of infected host-seeking Ixodes tick nymphs in the United States. Am J Trop Med Hyg. 2012;86(6):1005–1010.
• 28.   Radesich C, Montalbetti L, Manstretta E, et al. Lyme carditis: From pathophysiology to clinical management. Pathogens. 2022;11(5):556.
• 29.   Rupprecht TA, Elste C, Meilicke C, et al. The pathogenesis of Lyme neuroborreliosis: From infection to inflammation. J Neurovirol. 2007;13(2):128–137.
• 30.   Sadovsky R, Ochwansky SL, Scarpellino M. Antibacterial activity of azithromycin in children. Am Fam Physician. 1998;57(10):2503–2508.
• 31.   Schwan TG, Piesman J, Golde WT, et al. Vector interactions and molecular adaptations of Lyme disease spirochetes. Curr Opin Microbiol. 2002;5(3):318–324.
• 32.   Steere AC, Angelis SM, Duray PH, et al. Antibiotic-refractory Lyme arthritis is associated with HLA-DR molecules that bind a Bb outer-surface protein epitope. J Exp Med. 2006;203(4):961–971.
• 33.   Stupica D, Cerar T, Strle F, Ruzic-Sabljic E. Treatment of erythema migrans with doxycycline for 7 days versus 14 days. Emerg Infect Dis. 2023;29(3):497–503.
• 34.   Tan X, Jayasekera K, Yang XF. VlsE, the nexus for antigenic variation of the Lyme disease spirochete. Pathogens. 2022;11(5):565.
• 35.   Frontiers in Veterinary Science. Erythema migrans-like lesions associated with Borrelia [Internet]. 2025 [cited 2026 Mar 12
• 36.   Vrijmoeth HD, Schoen RT, Ratcliffe AH, et al. Determinants of persistent symptoms after treatment for Lyme borreliosis: A prospective, multi-site study. eBioMedicine. 2023;97:104809.
• 37.   Wilson TC, Fournier MR, Klimas NG. Erythema migrans: A spectrum of histopathologic changes. Int J Dermatol. 2012;52(8):1033–1039.
• 38.   Young S, Yeung A, Baranchuk A. Lyme carditis: A can’t-miss diagnosis. BC Med J. 2020;62(9):351–356.
• 39.   Zhao Y, Caradonna PB, Abdelnour E, et al. Systemic pharmacokinetics and cerebrospinal fluid uptake of ceftriaxone in rats with experimental Lyme disease. Antimicrob Agents Chemother. 2014;58(5):2675–2680.

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