veterinary sciences Review Tick-Borne Relapsing Fever Spirochetes in the Americas Job E. Lopez 1,2,*, Aparna Krishnavahjala 1, Melissa N. Garcia 1 and Sergio Bermudez 3 1 Department of Pediatrics, National School of Tropical Medicine, Baylor College of Medicine, Houston, 77030 TX, USA; [email protected] (A.K.); [email protected] (M.N.G.) 2 Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, 77030 TX, USA 3 Departamento de Investigación en Entomología Médica, Instituto Conmemorativo Gorgas de Estudios de la Salud, P.O. Box 816-02593, City of Panama, Panama; [email protected] * Correspondence: [email protected]; Tel.: +1-832-824-0557 Academic Editor: Ulrike Munderloh Received: 8 June 2016; Accepted: 8 August 2016; Published: 15 August 2016 Abstract: Relapsing fever spirochetes are tick- and louse-borne pathogens that primarily afflict those in impoverished countries. Historically the pathogens have had a significant impact on public health, yet currently they are often overlooked because of the nonspecific display of disease. In this review, we discuss aspects of relapsing fever (RF) spirochete pathogenesis including the: (1) clinical manifestation of disease; (2) ability to diagnose pathogen exposure; (3) the pathogen’s life cycle in the tick and mammal; and (4) ecological factors contributing to the maintenance of RF spirochetes in nature. Keywords: relapsing fever spirochetes; Borrelia; Ornithodoros; argasid; ixodid 1. Introduction Relapsing fever (RF) spirochetes are a significant cause of disease on five of seven continents, and are transmitted by argasid and ixodid ticks, and the human body louse. The pathogens are categorized as endemic (tick-borne) or epidemic (louse-borne), and all but two species (Borrelia recurrentis and Borrelia duttonii) are maintained in enzootic cycles with humans as accidental hosts [1,2]. In regions of Africa, the ecology and epidemiology of RF spirochetes have been extensively studied and the pathogens are a significant cause of child morbidity and mortality [3–11]. Outside of the African continent less is known regarding how RF spirochetes are maintained in nature. This review primarily examines the ecology of tick-borne RF spirochetes in the Americas, with a focus on argasid-borne RF (ABRF). Moreover, since the epidemiology of ABRF in North America has been comprehensively reviewed [12–15] and little attention has been given to Latin America, in addition to the disease’s ecology our review also highlights epidemiological findings and case reports from Central and South America. We also review studies on Borrelia miyamotoi, an ixodid-borne RF (IBRF) species transmitted by Ixodes species, which was recently recognized to cause human disease [16]. While the last decade has resulted in a better understanding of how RF spirochetes are maintained in a tick-mammalian transmission cycle, there are deficiencies that remain and should be addressed. We conclude our review by addressing these critical questions and suggest actions suitable for progress in our understanding of ABRF and IBRF in the Americas. 2. Clinical Manifestation of Disease In humans, ABRF presents with an onset of fever (104–107 ◦F) within four to 18 days after tick bite [17]. Acute disease is complemented with myalgia, headache, chills, diaphoresis, anorexia, nausea, and vomiting [14]. Febrile episodes may last three to four days, and are followed by an afebrile period Vet. Sci. 2016, 3, 16; doi:10.3390/vetsci3030016 www.mdpi.com/journal/vetsci Vet. Sci. 2016, 3, 16 2 of 17 Vet. Sci. 2016, 3, 16 2 of 18 afebrile period of up to 10 days [14]. The cyclic nature of disease can continue for months if left untreated [17,18], and is due to antigenic variation [19]. An antibody response is generated against ofthe up predominant to 10 days [14 variable]. The cyclic membrane nature ofprotein disease (Vmp) can continue produced for on months the surface if left untreatedof members [17 ,within18], and the is duespirochete to antigenic population, variation resulting [19]. An in antibodypathogen responseclearance. is However, generated the against spirochetes the predominant switch to produce variable membranea Vmp variant protein that (Vmp) is not produced recognized on by the the surface host ofimmune members response, within theand spirochetea new population population, of resultingspirochetes in emerges pathogen in clearance. the blood However,[20,21]. the spirochetes switch to produce a Vmp variant that is not recognizedUncommon, by yet the severe, host immune clinical response, manifestations and a newof disease population are associated of spirochetes with emerges the systemic in the bloodnature [ 20of,21 the]. circulating ABRF spirochetes. Patients may develop acute respiratory distress, characterizedUncommon, by yetbilateral severe, infiltrates clinical manifestationsand rales on chest of disease X-rays are [22]. associated Central with nervous the systemic system natureinvolvement, of the including circulating nuchal ABRF spirochetes.rigidity, facial Patients paresis, may vertigo, develop positive acute respiratoryKernig’s sign, distress, and characterizedmyocarditis has by bilateralbeen noted infiltrates [14]. Hepatosplenomegaly and rales on chest X-rays is palpable [22]. Central on physical nervous examination, system involvement, with an includingelevation nuchalof liver rigidity, enzymes facial [14]. paresis, Cardiac vertigo, in positivevolvement Kernig’s has sign,been and rarely myocarditis reported, has beenwith notedelectrocardiographic [14]. Hepatosplenomegaly conduction delays is palpable and depres on physicalsion in examination, ejection fraction with on an echocardiography elevation of liver enzymesbeing observed [14]. Cardiac [23,24]. involvement In the event has beenof pregnanc rarely reported,y, transplacental with electrocardiographic transmission can conduction result in delaysmiscarriage and depression [25]. in ejection fraction on echocardiography being observed [23,24]. In the event of pregnancy,RF spirochetes transplacental are susceptible transmission to canbroad-spectrum result in miscarriage antibiotics [25 ].[14]. However, upon treatment 54% ofRF ABRF spirochetes patients are had susceptible a Jarisch-Herxheimer to broad-spectrum reaction antibiotics [12], which [14 is]. characterized However, upon by a treatmentprofound 54%deterioration of ABRF of patients symptoms had aincluding Jarisch-Herxheimer a sudden onset reaction of fever, [12], tachycardia which is characterized and tachypnea, by a and profound blood deteriorationpressure [26]. of This symptoms pathophysiology including aresults sudden from onset a ofmassive fever, tachycardia release of andtumor tachypnea, necrosis andfactor blood by pressuremacrophages [26]. and This is induced pathophysiology by spirochete results surface from lipoproteins a massive release[27]. of tumor necrosis factor by macrophagesAs a recently and isrecognized induced byhuman spirochete pathogen, surface the lipoproteins clinical presentation [27]. of B. miyamotoi is less severe than AsABRF. a recently The spirochetes recognized are human neurotropic pathogen, and the can clinical be detected presentation in the ofcerebrospinalB. miyamotoi fluidis less of severe those thandisplaying ABRF. symptoms The spirochetes of meningoencephalitis are neurotropic and [28]. can Patients be detected also present in the cerebrospinalwith headache, fluid fever, of chills, those displayingfatigue [29–31]. symptoms Although of meningoencephalitis B. miyamotoi possess [ 28homologues]. Patients alsofor Vmps present [32], with it is headache, unclear whether fever, chills, the fatiguepathogens [29 –undergo31]. Although antigenicB. miyamotoivariation,possess and the homologuesnumber of relapses for Vmps in the [32 ],host it is is unclear poorly whetherunderstood. the pathogens undergo antigenic variation, and the number of relapses in the host is poorly understood. 3. Diagnosis of Exposure to RF Spirochetes 3. Diagnosis of Exposure to RF Spirochetes Currently there are no commercial diagnostic tests available for RF spirochetes, with national referenceCurrently laboratories there are or no academic commercial laboratori diagnostices testsproviding available detection for RF spirochetes,capacities. Two with nationalprimary referencemethods of laboratories evaluating or mammalian academic laboratories exposure are providing microscopy detection and molecular capacities. assays. Two primary RF spirochetes methods ofattain evaluating high densities mammalian in mammalian exposure areblood, microscopy at which and point molecular the pathogens assays. can RF spirochetesbe visualized attain by dark high densitiesfield microscopy in mammalian or Giemsa blood, stained at which thin point smears thepathogens (Figure 1). can While be visualized high bacterial by dark loads field in microscopy the blood orare Giemsa associated stained with thin fever, smears accurate (Figure diagnosis1). While be hightween bacterial febrile loads episodes in the is blood challenging are associated because with the fever,pathogens accurate are diagnosisbelow the between limit of febrile detection episodes [33]. is During challenging the becausecourse of the infection pathogens as arean belowantibody the limitresponse of detection is generated [33]. against During RF the spirochetes, course of infection molecular as an diagnostic antibody assays response are is an generated alternative against method RF spirochetes,to confirm mammalian molecular diagnosticexposure. assays are an alternative