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YALE JOURNAL OF BIOLOGY AND MEDICINE 84 (2011), pp.103-108. Copyright © 2011.

FOCUS: YALE SCHOOL OF MEDICINE BICENTENNIAL

close to home: A history of yale and

Shana Elbaum-Garfinkle

Department of Molecular Biophysics & Biochemistry, , New Haven,

Yale scientists played a pivotal role in the discovery of Lyme disease and are credited as the first to recognize, name, characterize, and treat the affliction. Today, Lyme disease is the most commonly reported vector-borne illness in the , affecting approximately 20,000 people each year, with the incidence having doubled in the past 10 years [1]. Lyme disease is the result of a bacterial infection transmitted to humans through the bite of an in - fected deer tick, which typically results in a skin rash at the site of attack. While most cases, when caught early, are easily treated by antibiotic therapy, delayed treatment can lead to se - rious systemic side effects involving the joints, heart, and central nervous system. Here we review Yale’s role in the discovery and initial characterization of Lyme disease and how those early discoveries are crucial to our current understanding of the disease.

Recognition — Lyme ARthRitis Yale School of Medicine, sparking an in - The Yale Team vestigation that would culminate in the characterization of what is now widely In the early fall of 1975, two mothers known as Lyme disease [2]. from Old Lyme, Connecticut, desperately The initial studies carried out in Lyme, sought medical help regarding the mysteri - Connecticut, and two surrounding towns on ous outbreak of arthritis and juvenile arthri - the eastern bank of the Connecticut River tis in their families and town. In the face of in New London County were led by Allan unexplainable symptoms and unsatisfying C. Steere, MD, and Stephen E. Malawista, diagnoses, they reached out to the Con - MD, from the Rheumatology section of the necticut State Department of Health and the Yale School of Medicine, in conjunction

To whom all correspondence should be addressed: Shana Elbaum-Garfinkle, 226 Whitney Bass 228, New Haven, CT; Tele: 203-432-5647; Fax: 203-432-5175; E-mail: [email protected].

†Abbreviations: ECM, erythema chronicum migrans ; EM, erythema migrans ; Osps, outer surface proteins; TROSPA, tick receptor protein.

Keywords: Lyme disease; Lyme arthritis 103 104 Elbaum-Garfinkle: Yale’s role in the discovery of Lyme disease

with David R. Snydman, MD, and Francis onset occurring from June through Septem - M. Steele, PhD, from the Connecticut State ber. Rheumatoid arthritis, a known autoim - Department of Health, among others. Dr. mune disease leading to inflammation of the Steere, the first author of the study, was a joints, had never before been, nor would it first-year fellow in rheumatology at the have been, expected to cluster geographi - time. Dr. Malawista, then Head of the cally or temporally in this way. Rheumatology Section at Yale, continues to The Skin Lesion-EM pioneer Lyme disease research at Yale. The term erythema migrans (EM) was The Investigation first mentioned in a presentation at the 1909 In December 1975, Steere and Malaw - meeting of the Swedish Dermatological So - ista led a surveillance study [3] to investigate ciety in Stockholm by Arvid Afzelius [2]. the cause of a sudden outbreak of rheuma - EM, also reported as erythema chronic mi - toid arthritis in and around Lyme. The study grans (ECM), was sometimes associated focused on the three contiguous towns of Old with a tick bite and was accompanied by Lyme, Lyme, and East Haddam, where 51 nerve pain, paralysis, or meningitis. In Eu - residents were diagnosed with juvenile rope, doctors believed that EM might be arthritis or arthritis of unknown cause (39 caused by a bacterium, and penicillin and children and 12 adults) out of a total popula - other antibiotics were moderately effective tion of 12,000. The investigation consisted at treating it. This connection between ticks of thorough physical examinations and blood and EM led Steere and Malawista to hypoth - work of each patient on site at Yale. Addi - esize that Lyme disease might be transmitted tionally, detailed patient histories were col - by the bite of an arthropod such as a tick. lected through interviews with each patient’s However, in the United States, there was local physician and family members. little experience with EM, and in the Euro - While the early physical examinations pean cases, EM never presented with arthritis. and laboratory tests revealed nothing out of Intrigued by the EM lesion described by pa - the ordinary, the interview aspect was sur - tients in their first study, Steere and Malaw - prisingly informative. Approximately 25 ista eagerly awaited the next “high season.” percent of the patients in the study reported Indeed, during the summer of 1976, 30 new a skin lesion with an expanding bull’s-eye patients were identified, a survey of which pattern four or more weeks preceding the strengthened the connection between the ini - onset of arthritic symptoms. The authors tial presentation of EM and the later devel - found this to be particularly intriguing, as opment of arthritis [5]. The Yale team thus the lesion matched the description of ery - officially declared EM as the initial mark of thema chronicum migrans (ECM), or ery - infection and as the diagnostic hallmark of thema migrans (EM), a lesion previously “Lyme arthritis,” the initial name given for reported in Europe that was thought to be a the disease by Yale investigators [6]. result of an infectious agent but had never The Tick before been associated with arthritis [4]. The mysterious arthritis also emerged While Steere and Malawista suggested in interesting patterns geographically and the tick as the vector of Lyme arthritis as temporally. Most of the patients lived in early as 1976 [3,5,6], in 1978 they showed close proximity within the towns ― several epidemiological evidence for a tick vector children lived on a particular road, and the by expanding their surveillance of the Lyme arthritis afflicted several members from the area across the Connecticut River [7]. They same family. The patients also exclusively found that the incidence of Lyme arthritis lived in the rural wooded areas of town, with was 30 times greater on the east side of the no cases present in the town centers. No - river, where Lyme is located, than it was on tably, there was also a unique temporal clus - the west side, similar to the difference in tering to the symptoms, with the majority of deer and deer tick distribution in the area [8]. Elbaum-Garfinkle: Yale’s role in the discovery of Lyme disease 105

Scientists later confirmed that ticks in - ally only a small piece of a larger puzzle. deed are the transmission vector of the in - Now that the EM skin lesion was confirmed fectious agent in Lyme disease. In the United as the initial mark of infection, the Yale team States, Lyme disease is transmitted by the made a major effort to inform and educate deer tick, or Ixodes scapularis , member of the area near Lyme. The Yale team also the Ixodes family. Other related Ixodes ticks asked local healthcare providers to refer pa - have been found in Europe and Asia. The tients to them soon after infection, enabling Ixodes tick can become infected at any point them to further characterize the disease and of its 2-year lifespan, which consists of three onset. As the result of these further studies, distinct stages — larvae, nymph, and adult the team reports that Lyme disease can man - [9,10]. The tick’s survival depends on a feed - ifest in a variety of systemic ways, includ - ing or “blood meal” at each stage of its life. ing those involving the nervous system [13], The larvae hatched in late summer feed on the heart [14], and the joints [15-19]. small animals such as the white-footed In 1984, the Yale School of Medicine mouse that can be infected but remain brought together Lyme disease researchers asymptomatic, serving as a continuous re - from all over the world at the First Interna - source for infection. The larvae then molt tional Conference on Lyme Disease in New into nymphs who feed again the following Haven [10,20]. For the first time, profession - spring to early summer. Transmission to hu - als from a range of disciplines, including mans typically occurs by ticks in this stage, rheumatology, immunology, dermatology, as increases in outdoor activity coincides and neurology, as well as public health offi - with the nymph feeding cycle. The small size cials and practicing physicians were gathered of the nymph, about the size of a poppy seed, in recognition of this new complex and sys - allows them to go unnoticed. Furthermore, it temic disease. In 1985, Steere and Malawista has been shown that a tick must feed for 48 were awarded the Ciba-Geigy International or more hours to transmit infection. In the League Against Rheumatism Prize, an honor fall, nymphs molt into adult ticks, which then given once every 4 years, for the discovery feed on large animals, deer in particular. and elucidation of Lyme disease. A group of Adult ticks, which may actually mate on the Yale scientists continue to lead research ef - deer itself, are transmitted by deer to the sur - forts in various aspects of Lyme disease, in - roundings, usually leafy areas, where new cluding disease epidiomology (Durland Fish, larvae are hatched the following summer. PhD, and Eugene D. Shapiro, MD, from the Deer thus play an important role in the Yale School of Public Health); the life cycle tick life cycle by supplying a blood meal and of the bacterium (Erol Fikrig, MD, Infectious potentially serving as a mating ground for Diseases, Yale School of Medicine); and in - adult ticks. Accordingly, the recent explo - flammation and immunity (Linda Bockenst - sion of the United States deer population is edt, MD, and Stephen Malawista, MD, thought to be responsible for the dramatic Rheumatology, Yale School of Medicine). increase in the instances of Lyme disease, Clinical Features particularly in the Northeast [11]. Efforts to decrease the prevalence of Ixodes scapularis Today, Lyme disease is clinically de - ticks and Lyme disease through the control scribed as either “early” or “late.” Early of deer populations have proven successful Lyme disease initially presents itself with [12] and is thought to be one possible Lyme the characteristic bull’s-eye patterned lesion, disease prevention strategy. erythema migrans (EM). This lesion can last anywhere from several days to several weeks [21] and is most often accompanied Lyme DiseAse — moRe thAn by severe fatigue, myalgia, arthralgias, re - ARthRitis gional lymphodenopathies, and headaches To Steere and Malawista, it soon be - or fever. The initial EM lesion can some - came clear that “Lyme arthritis” was actu - times spread to produce smaller secondary 106 Elbaum-Garfinkle: Yale’s role in the discovery of Lyme disease

lesions 3 to 5 weeks after the primary lesion. member of the family Spirochaetacaea , also Patients may further develop neurologic, known as spirochetes, which are Gram-neg - cardiac, and rheumatogical symptoms in the ative bacterium characterized by a wavelike early stage, the exact causes of which are body and flagella [21]. Burgdorfer and col - still not fully understood. leagues collected and dissected hundreds of One of the most common features of Ixodes ticks from Shelter Island, New York late Lyme disease is arthritis, particularly (another location with a high prevalence of asymmetric oligoarticular arthritis, involv - Lyme disease) and found that most of them ing large joints such as the knees. Arthritis contained spirochetes, specifically in the arises when an inflammatory response oc - mid gut region. They further characterized curs in the synovial tissue between the joints the spirochetes with dark field and electron and leads to painful swelling in the affected microscopy. Finally, indirect immunofluo - area. rescence revealed that antibodies extracted from serum of Lyme disease-infected pa - tients reacted positively with the spirochete, tReAtment while serum from control patients did not — In 1977, in the journal Science [5], thereby confirming the link between the Steere and Malawista reported the presence tick-derived spirochete and Lyme disease. In of common antibodies extracted from pa - the United States, Lyme disease is primarily tients experiencing an active EM lesion or caused by the spirochete Borrelia Burgdor - active arthritis, thereby suggesting a com - feri sensu stricto . Other related genospecies mon origin for these two clinical symptoms. of Borrelia such as B. garinii , and B. afzelii While it would be several years before the have been identified in Europe and Asia. infectious agent that causes Lyme disease Outer Surface Proteins would be isolated, the Yale team had grow - ing evidence for the role of a bacterial infec - B. burgdorferi ’s persistence inside the tion in the disease. In 1980, Steere and tick and transmission to its human host are Malawista determined that antibiotic treat - thought to be a product of altered expression ment “shortens the duration of ECM and of outer surface proteins (Osps). When in - may prevent or attenuate subsequent arthri - side the tick host, expression of OspA en - tis” [22]. The study consisted of 113 patients ables B. burgdorferi to persist in the gut. presenting the EM lesion. Half of the group More specifically, Erol Fikrig, MD, and col - did not receive treatment, while the other half leagues at Yale have found that a tick recep - were treated with antibiotics. In patients who tor protein (TROSPA) expressed in the tick did not receive antibiotics, the EM lesion and gut is responsible for tight binding to OspA associated symptoms resolved within a me - [25]. During a tick’s blood meal, expression dian of 10 days after the initial visit. Those of OspA is decreased, leading to dissocia - patients receiving antibiotic treatment expe - tion from the gut, and expression of OspC is rienced significantly faster resolution of EM, increased. OspC is thought to play a role in with a median of duration of 4 days. Fur - migration of the bacterium from the tick’s thermore, significantly fewer patients in the gut to its salivary glands [26]. Fikrig and antibiotic group went on to develop arthritis colleagues, along with Durland Fish, PhD, compared to patients in the control group. from the Yale School of Public Health, have Antibiotic therapy is still the major line of since shown that the interaction of OspC treatment for Lyme disease [23]. with the tick salivary protein Salp15 en - hances the infectivity of B. burgdorferi in its The Infectious Agent: B. burgdorferi new mammalian host [27]. Once inside the In 1982, Burgdorfer and colleagues iso - human host, B. burgdorferi induces immune lated the infectious agent that causes Lyme responses that lead to a variety of symptoms disease that now bears his name: Borrelia present in the disease. Vaccines incorporat - burgdorferi [24]. The genus Borrelia is a ing OspA, a strong antigen that induces an Elbaum-Garfinkle: Yale’s role in the discovery of Lyme disease 107

Lyme arthritis: an epidemic of oligoarticular antibody response, have been developed but arthritis in children and adults in three con - are currently off the market due to compli - necticut communities. Arthritis Rheum. cations [28,29]. 1977;20(1):7-17. 4. Hellerstrom S. Erythema chronicum migrans Diagnosis Afzelius with meningitis. Acta Derm Venereol. 1951;31(2):227-34. Clear diagnosis of Lyme disease has 5. Steere AC, Hardin JA, Malawista SE. Ery - been challenging. If the EM rash is present, thema chronicum migrans and Lyme arthri - then diagnosis is ameliorated, but since not tis: cryoimmunoglobulins and clinical activity of skin and joints. Science. all patients present with a purely character - 1977;196(4294):1121-2. istic rash and sometimes do not notice it in 6. Steere AC, Malawista SE, Hardin JA, Ruddy time, diagnosis remains difficult. Serologi - S, Askenase W, Andiman WA. Erythema cal tests that indirectly test for antibodies chronicum migrans and Lyme arthritis. The enlarging clinical spectrum. Ann Intern Med. produced against B. burgdorferi are often 1977;86(6):685-98. used, along with somewhat less accurate 7. Steere AC, Broderick TF, Malawista SE. Ery - PCR assays. There is some controversy over thema Chronicum Migrans and Lyme Arthri - tis ― Epidemiologic Evidence for a Tick misdiagnosis of Lyme disease and even the Vector. Am J Epidemiol. 1978;108(4):312- existence of long-term chronic Lyme disease 21. [9,21,30] that is beyond the scope of this ar - 8. Wallis RC, Brown SE, Kloter KO, Main AJ, ticle. However, a regimen of antibiotic ther - Jr. Erythema chronicum migrans and lyme arthritis: field study of ticks. Am J Epidemiol. apy is typically sufficient in treating the 1978;108(4):322-7. disease at any stage, with greatest efficacy 9. Murray TS, Shapiro ED. Lyme disease. Clin seen for patients receiving treatment soon Lab Med. 2010;30(1):311-28. after the tick bite and associated EM lesion. 10. Steere AC. 1st International-Symposium on Lyme-Disease ― Conference Summary. Yale J Biol Med. 1984;57(4):711-3. 11. Barbour AG, Fish D. The biological and so - concLusion cial phenomenon of Lyme disease. Science. 1993;260(5114):1610-6. The massive efforts taken by Steere and 12. Rand PW, Lubelczyk C, Holman MS, La - Malawista toward the investigation of the combe EH, Smith RP, Jr. Abundance of clustering of arthritis in Lyme in the late Ixodes scapularis (Acari: Ixodidae) after the 1970s and early 1980s have led to the dis - complete removal of deer from an isolated offshore island, endemic for Lyme Disease. J covery of a complex, multifaceted disease. Med Entomol. 2004;41(4):779-84. The results of their studies have laid the 13. Reik L, Steere AC, Bartenhagen NH, Shope foundation for our current understanding of RE, Malawista SE. Neurologic Abnormalities the role of the infectious agent, the tick as of Lyme Disease. Medicine. 1979;58(4):281- 94. vector for infection, the EM skin lesion, and 14. Steere AC, Batsford WP, Weinberg M, the systemic clinical symptoms of late onset. Alexander J, Berger HJ, Wolfson S, et al. Yale investigators continue to lead the field Lyme carditis: cardiac abnormalities of Lyme disease. Ann Intern Med. 1980;93(1):8-16. of Lyme disease research today. 15. Hardin JA, Walker LC, Steere AC, Trumble TC, Tung KS, Williams RC, Jr., et al. Circu - Acknowledgment: The author would like to lating immune complexes in Lyme arthritis. thank Stephen Malawista, MD, for thought - Detection by the 125I-C1q binding, C1q solid ful discussions. phase, and Raji cell assays. J Clin Invest. 1979;63(3):468-77. RefeRences 16. Malawista SE, Steere AC, Hardin JA. Lyme Disease ― a Unique Human-Model for an 1. Bacon RM, Kugeler KJ, Mead PS. Surveil - Infectious Etiology of Rheumatic Disease. lance for Lyme Disease ― United States, Yale J Biol Med. 1984;57(4):473-7. 1992-2006. MMWR. [Surveillance Sum - 17. Steere AC, Hardin JA, Ruddy S, Mummaw mary]. 2008;57(SS10):1-9. JG, Malawista SE. Lyme arthritis: correlation 2. Edlow JA. Bull’s Eye: Unraveling the Med - of serum and cryoglobulin IgM with activity, ical Mystery of Lyme Disease. New Haven: and serum IgG with remission. Arthritis Yale University Press; 2003. Rheum. 1979;22(5):471-83. 3. Steere AC, Malawista SE, Snydman DR, 18. Hardin JA, Steere AC, Malawista SE. Im - Shope RE, Andiman WA, Ross MR, et al. mune complexes and the evolution of Lyme 108 Elbaum-Garfinkle: Yale’s role in the discovery of Lyme disease

arthritis. Dissemination and localization of an Ixodes scapularis receptor for Borrelia abnormal C1q binding activity. N Engl J burgdorferi. Cell. 2004;119(4):457-68. Med. 1979;301(25):1358-63. 26. Schwan TG, Piesman J, Golde WT, Dolan 19. Pachner AR, Steere AC. Neurological Find - MC, Rosa PA. Induction of an outer surface ings of Lyme-Disease. Yale J Biol Med. protein on Borrelia burgdorferi during tick 1984;57(4):481-3. feeding. Proc Natl Acad Sci USA. 20. Steere AC. 1st International Symposium on 1995;92(7):2909-13. Lyme Disease ― Preface. Yale J Biol Med. 27. Ramamoorthi N, Narasimhan S, Pal U, Bao F, 1984;57(4):445. Yang XF, Fish D, et al. The Lyme disease 21. Marques AR. Lyme disease: a review. Curr agent exploits a tick protein to infect the mam - Allergy Asthma Rep. 2010;10(1):13-20. malian host. Nature. 2005;436(7050):573-7. 22. Steere AC, Malawista SE, Newman JH, 28. Sigal LH, Zahradnik JM, Lavin P, Patella SJ, Spieler PN, Bartenhagen NH. Antibiotic Bryant G, Haselby R, et al. A vaccine con - Therapy in Lyme Disease. Ann Intern Med. sisting of recombinant Borrelia burgdorferi 1980;93(1):1-8. 23. Wormser GP, Dattwyler RJ, Shapiro ED, outer-surface protein A to prevent Lyme dis - Halperin JJ, Steere AC, Klempner MS, et al. ease. Recombinant Outer-Surface Protein A The clinical assessment, treatment, and pre - Lyme Disease Vaccine Study Consortium. N vention of lyme disease, human granulocytic Engl J Med. 1998;339(4):216-22. anaplasmosis, and babesiosis: clinical prac - 29. Steere AC, Sikand VK, Meurice F, Parenti tice guidelines by the Infectious Diseases So - DL, Fikrig E, Schoen RT, et al. Vaccination ciety of America. Clin Infect Dis. against Lyme disease with recombinant Bor - 2006;43(9):1089-134. relia burgdorferi outer-surface lipoprotein A 24. Burgdorfer W, Barbour AG, Hayes SF, Be - with adjuvant. Lyme Disease Vaccine Study nach JL, Grunwaldt E, Davis JP. Lyme Dis - Group. N Engl J Med. 1998;339(4):209-15. ease ― a Tick-Borne Spirochetosis. Science. 30. Feder HM, Jr., Johnson BJ, O’Connell S, 1982;216(4552):1317-9. Shapiro ED, Steere AC, Wormser GP, et al. A 25. Pal U, Li X, Wang T, Montgomery RR, Ra - critical appraisal of “chronic Lyme disease.” mamoorthi N, Desilva AM, et al. TROSPA, N Engl J Med. 2007;357(14):1422-30.