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Lyme disease in livestock

Lyme disease in livestock

Lyme disease in livestock

Previous authors: E HODZIC AND S W BARTHOLD

Current authors:
D M IMAI - Assistant, Clinical Health Sciences Professor, Comparative Pathology Laboratory, University of California, California, 95616, USA 
E HODZIC - Director of Core Facility, DVM, MSci, PhD, Davis School of Veterinary Medicine, University of California, One Shields Avenue, California, 95616, USA

GENERAL INTRODUCTION: SPIROCHAETES

Introduction

Lyme disease, or Lyme borreliosis, was first described in 1977 as a distinctive entity in a cluster of children from Lyme, Connecticut, USA. These children had symptoms resembling juvenile rheumatoid arthritis, a disease that does not cluster and is rare in children.107 Based upon similarities with recognized human clinical syndromes in Europe that were of unknown aetiology, but associated with the bite of Ixodes ricinus ticks, the causative agent was isolated from North American Ixodes scapularis ticks in 1981,20 and subsequently named Borrelia burgdorferi.53 Once the connection was made between vector, agent, and the human disease, Lyme disease has been diagnosed throughout the world, but its significance is greatest in North America and Europe.47, 89, 98, 100 Borrelia burgdorferi has become an important public health problem and the most prevalent tick-borne disease in the United States.1, 64 It emerges across much of the northern hemisphere, causing considerable morbidity and in some cases mortality in humans, domestic animals, and occasionally wildlife.

The wide geographic distribution and the broad host range of both the vector and the bacterium provide ample opportunity for livestock species to be infected with B. burgdorferi. Most of what is known about Lyme disease, however, is based upon clinical studies in humans, and experimental studies in laboratory rodents. The amount of well-documented information on Lyme disease in livestock is limited.

Aetiology

Borrelia burgdorferi is a Gram-negative spiral or corkscrew shaped diderm bacterium, measuring 10 to 30 µm in length and 0,2 to 0,3 µm in diameter, with a lipoprotein-rich outer cell membrane and periplasmic flagella.53, 88, 114 For culture in vitro, this micro-aerophilic slow-growing organism requires a complex liquid medium, and an optimal temperature of 33 to 35 °C. 3

The genome of B. burgdorferi is small (~1.5 Mb) but complex, composed of 1 large, highly conserved linear chromosome and many small, highly variable linear and circular plasmids.24

Based on 16S ribosomal DNA gene sequences, the genus Borrelia belongs to the order Spirochaetales, family Spirochetaceae, but genomically unique and not closely related to any other bacteria, including the other spirochaetes. Other related genera include Spirochaeta, Cristispira, Treponema and Brachyspira (formerly Serpulina). It was first believed that B. burgdorferi was the only bacterium that could cause Lyme disease, but differences in morphology among isolates from diverse geographic locations suggested that additional spirochaetes may be involved in the aetiology.41

A major effort has been undertaken to analyse the phenotypic and genotypic diversity of B. burgdorferi isolates from around the world, using polymerase chain reaction (PCR) techniques that target 16S and 23S ribosomal DNA, flagellin, OspA, bdr genes, and intergenic spacers, as well as complete genome sequencing. It is now apparent that B. burgdorferi is genetically diverse, and is represented by more than 20 different genospecies grouped within the B. burgdorferi sensu lato (s.l.) complex. Borrelia burgdorferi sensu stricto (s.s.) is present in the USA and Europe (but not in Eurasia and Asia); B. afzelii, B. garinii, B. valaisiana, B. spielmanii, and B. lusitaniae are present in Eurasia; B. japonica, B. turdae, and B. tanukii in Japan; and B. bissettii and B. andersoni in the USA.34, 51, 80, 89 The causative genospecies of Lyme disease in humans and livestock are B. burgdorferi s.s., B. afzelii, and B. garinii.  B. valaisiana has also been proposed as a causative agent of the human disease.59, 62, 116

Borrelia burgdorferi s.l. belongs to a guild of pathogens, including Ehrlichia and Babesia spp. and tick-borne encephalitis viruses, that are maintained within the same vector reservoir niches.112 Thus, co-infection with one or more of these agents can occur and may be responsible for ‘paraLyme disease’ syndromes. Since these other agents have a wide host range, they also infect livestock.

Epidemiology

Borrelia burgdorferi s.l. is geographically distributed in temperate regions of the northern hemispheres. These areas have the environmental conditions and reservoir hosts conducive to ixodid ticks. The range of B. burgdorferi s.l. was previously limited to northern Africa at its most southern extreme.2 Nevertheless, migratory birds, particularly seabirds, likely contributed to the expansion of its geographic distribution, with documentation of B. burgdorferi s.l. DNA in ixodid ticks or seropositivity in livestock, as far south as the Falkland Islands, Crozet Islands, and off-shore islands of New Zealand,76 and now, in Chile, Brazil, and Uruguay.4

Borrela burgdorferi and its vector ticks tend to be nonselective in their host range, and B. burgdorferi has been isolated from a wide variety of birds and mammals.2 Most hosts harbour subclinical infections. For example, in hyperendemic areas such as New York and Connecticut states in the USA, a high percentage of dogs are seropositive (and probably infected), but only a small fraction manifest clinical signs.61 A hallmark of Lyme borreliosis is persistent infection (even without antimicrobial agents), which is the rule in its many hosts. This has been experimentally proven in Peromyscus mice,95 laboratory mice,9 rats,68 hamsters,40 gerbils,85 guinea pigs,102 dogs,108 and non-human primates,90 and in reported confirmed spontaneous cases in humans based on culture,3, 57, 63, 65, 101, 104, 109  and PCR.17, 70, 71, 117

Among a large number of hard tick species, B. burgdorferi has been primarily detected in Ixodes ricinus, which is prevalent in Europe, Ixodes persulcatus, which is prevalent in Eastern Europe and Asia, and Ixodes scapularis and Ixodes pacificus in Northern America.81, 103 Clinical cases of Lyme disease could therefore be expected in localities where these Ixodes ticks are common. During their life cycle, which could take from two to six years to complete, ticks feed as larvae on small rodent reservoir hosts, thereby acquiring infection. After the larvae moult and harden, infected nymphs attach and feed on a variety of birds, reptiles and mammals, including livestock. Finally, adult I. scapularis, I. ricinus, and I. persulcatus ticks seek and parasitize large mammals, including deer or livestock, and are considered to be the most common vectors of Lyme disease for large animals.60, 78, 94 Borrelia burgdorferi s.l. has been identified in other ixodid ticks that parasitize livestock, such as Haemaphysalis spp., Hyalomma spp., Amblyomma spp., and Rhipicephalus spp.13, 28, 32, 37, 119, 121

Serosurveys for B. burgdorferi antibody in horses have revealed that the endemic and seasonal distribution of exposure closely corresponds to the prevalence of B. burgdorferi infection in humans in the same regions. Seroprevalence of B. burgdorferi antibodies was demonstrated in 10 per cent of horses in the New Jersey-Pennsylvania area,29 and in 62 per cent of horses in Wisconsin.22 In Connecticut, where Lyme disease is endemic, 45,1 per cent of horses had detectable antibodies to B. burgdorferi.62 In the UK the percentage of seropositive horses was low, but increased in areas that had a high prevalence of human and canine borreliosis,23 while in the region of München, Germany, 48 per cent of all tested horses were found to be seropositive.38 A study conducted in Sweden demonstrated that 16,8 per cent of horses had seroreactivity to B. burgdorferi s.l.31 Thus, like dogs within endemic areas, horses frequently seroconvert, indicating exposure and probable infection, but most do not manifest clinical signs.

Lyme disease in cattle often occurs as a herd problem with a geographic distribution similar to that among horses.22 In eastern Minnesota, a study revealed that higher prevalence rates of Lyme disease in lactating dairy cows were present during summer than in spring. This study also revealed a positive association between antibody titres and clinical lameness in the cows.120 Clinical Lyme disease has also been diagnosed in cows in Japan,50, 110 and in cows in Switzerland.32 A report from Norway  showed that 10 per cent of tested sheep were seropositive to B. burgdorferi, mainly in areas where ticks were prevalent.35 Seropositive sheep and goats were reported in Italy.27 In Bolivia, goats were reported seropositive, but not sheep.26 In Tunisia, borrelial DNA was most prevalently detected in goats (30.4 per cent), and less commonly in sheep (6.2 per cent), cattle (1.3 per cent), and camels (1.8 per cent).13 A report from Egypt identified PCR-positive blood samples from 16 per cent of cattle tested and was able to successfully culture spirochaetes from one cow.32 Furthermore, the prevalence of seroconversion was higher than the appearance of clinical signs in these species.

Pathogenesis

Transmission by the vector (nymphal or adult ticks) to the host is a complex three-way interaction between the tick, the host, and the pathogen. Hosts mount local inflammatory,  haemostatic and immune responses to the feeding tick, while tick saliva contains substances that counter the host response, thereby facilitating a successful blood meal and transmission of the pathogens.74 After tick attachment, B. burgdorferi spirochaetes undergo striking variations in the expression of antigens, and migrate from the tick midgut to its salivary glands.30, 96 After being transmitted, spirochaetes remain and multiply in the skin at the attachment site for several days, and then disseminate to many organs and tissues throughout the host.45, 97 Motility plays a major role in the spread of spirochaetes from the site of tick attachment, and allow contact with the host vasculature.69, 72 As a result of spirochaete multiplication at the tick attachment site, the host reacts with a localized skin rash (erythema migrans), which generally persists for weeks after detachment of the tick. The rash is observed in the majority of human cases, and has been reported occasionally in livestock. 19, 29, 59, 84

Clinical signs of illness are generally most apparent during the early stages of disseminated infection when spirochaetes are believed to elaborate pro-inflammatory lipoproteins that appear to facilitate the process of dissemination through host tissues. Despite the highly immunogenic nature of these lipoproteins, spirochaetes  effectively evade host immune clearance by yet-to-be understood mechanisms.11 It should be emphasized that Lyme borreliosis in untreated humans (and experimental animals) is ephemeral, with “spontaneous” resolution (without antimicrobial treatment) of erythema migrans, myocarditis, arthritis, and other signs.105, 106 Studies in animal models have shown that resolution of arthritis and myocarditis is mediated by the acquired humoral immune response of the host. Under these conditions, anatomically defined inflammation resolves, but infection persists.7, 8, 10

Whatever the mechanism, it is clear that spirochaetes undergo dramatic shifts in protein expression. For example, outer surface protein A (OspA) is a highly immunogenic lipoprotein that is expressed in the midgut of ticks, but is rapidly down-regulated upon onset of feeding, and is minimally expressed in the mammalian host. In contrast, OspC is up-regulated under similar circumstances.12, 66, 96 Up- and down-regulation have also been documented for several other lipoproteins, some of which are expressed exclusively in vivo, but their role is still unclear.11 Other possible explanations of immune evasion by B. burgdorferi spirochaetes have been proposed. These include sequestration in extracellular matrix,49 intracellular localization,67, 44 formation of cystic-like forms found in vivo 46 and in vitro,18 and the existence of complement-resistant strains that regulate and control complement activation.56 It has also been suggested that during the course of infection, B. burgdorferi proliferates and incidentally generates an increasingly heterogeneous population of replication-attenuated spirochaetes that emerge as a result of genetic alterations, including plasmid loss or formation of biofilm, and/or that suboptimal immune responses induced by the infection make persistence and resurgence possible.6, 16, 42, 43, 44, 92, 93, 115 Once spirochaetes have disseminated, some animals and humans develop clinical signs of Lyme disease, including fever, lethargy, weight loss, stiffness, swollen joints, laminitis, lameness, abortion, uveitis and, sometimes, encephalitis. In livestock clinical signs have been observed in cattle, horses, and sheep.21, 22, 27, 36, 48, 52, 54, 86, 120

The mechanisms by which B. burgdorferi spirochaetes cause disease in infected hosts are being studied in animal models. Borrelia burgdorferi spirochaetes produce no known toxins yet are capable of invading virtually any mammalian tissue and causing infection and disease manifestations for months to years. It is suspected that the approximately 150 lipoproteins that are encoded by the B. burgdorferi genome play an important role in not only disease pathogenesis, but also host immunity, and are considered to be virulence determinants.73 An important first step in the establishment of infection is adhesion of spirochaetes to host cells and extracellular matrix components.33

Differential expression of pro-inflammatory lipoproteins, of which the majority are outer surface proteins, in various tissues and at different times during persistent infection appear to be critical determinants of disease.83 The genome has 12 linear and nine circular plasmids, and loss of plasmids has been correlated with decreased infectivity and pathogenicity.58, 87, 113

Clinical signs

The incubation period for Lyme disease in livestock has not been determined. Observed clinical signs in naturally infected horses and cows correlated within a month of the seasonal emergence of adult ticks, indicating a long incubation period.22, 38 No significant clinical signs were observed in experimentally infected cattle with cultured B. burgdorferi,116 nor in ponies that were exposed to ticks.25 Experimental infection of a pony with pulverized B. burgdorferi-infected ticks resulted in seroconversion on day nine, which continued for a three-week period, then waned. Re-challenge with cultured B. burgdorferi six months later led to seroconversion within four days.29 Infection efficiency has been found to depend upon the infectious dose, the strain of Borrelia, and the age of the host. Experimental infection of cattle with different doses and different strains of cultured organisms demonstrated that the mean infectious dose was 106 to 107 organisms, with some variations in infectivity among different strains.116

Clinical signs in horses and cattle, when present, are varied and often vague and non-specific. A skin rash resembling erythema migrans in humans is not a prominent feature of Lyme borreliosis in livestock though there are rare reports of erythema rashes in cattle and horses at the site of tick attachment, which can be under the lower jaw, on the abdomen and ventral chest, on the legs, in the region of the mane of horses, on the udder of cows, and on the tail.59, 78 In horses, clinical signs may include depression, low-grade fever (38,2 to 38,8 °C), swollen joints, shifting lameness, muscle tenderness, hyperaesthesia, ataxia, behavioural changes and uveitis.19, 21, 22, 38, 48, 52, 54, 78, 80, 86

Animals with disseminated disease can develop single or multiple swollen joints (arthritis), laminitis, stiffness, hyperaesthesia, and sporadic lameness, which are the most common clinical signs. Untreated cases can persist for years with chronic weight loss, neurologic dysfunction and polyarthritis.48 In pregnant mares, there is a suggested association with borreliosis and reproductive failure due to foetal resorption or abortion.25 In cattle, stiffness, swollen joints, and/or lameness are the most commonly reported clinical signs although reproductive failure, reduced milk production, fever and chronic weight loss are also observed.22, 50, 59, 78, 120  Arthritis has been most notable in the carpal-metacarpal, tibiotarsal and/or stifle joints. Other clinical signs in cattle include abortion and decreased milk production.  

In small ruminants, clinical signs are not often observed or reported. Lameness, poor condition and poor appetite have been reported in seropositive lambs,36 but other studies have found that all seropositive sheep were healthy at the time of serum sampling.27, 35 Sheep experimentally exposed by tick bite did not develop systemic infection.75 In the few reports involving goats, a high prevalence of B. burgdorferi antibodies have been found,26, 35 but clinical signs were not evaluated. It has been suggested that goats might develop clinical signs similar to those in cattle.84

Pathology

It appears that Lyme disease in livestock is not fatal, signs are often ephemeral, and disease is mild, if present at all, so the pathology of disease in these animals is not well characterized.

Post-mortem examination and histopathologic finding associated with Lyme borreliosis in livestock in general include arthritis, synovitis, and myocarditis.48, 50, 59, 80 In spontaneous infections in horses, suppurative uveitis, necrotizing to non-suppurative meningitis and radiculoneuritis and non-suppurative myocarditis with intralesional argyrophilic spirochaetes have been documented.21, 48, 52, 54, 86 In cases of uveitis, spirochetaes have been visualized within the intravitreal suppurative exudate using silver stain.54, 86 The neurologic manifestation of Lyme borreliosis in the horse recapitulates the human disease and the equid is the only non-human host to develop neurologic disease after natural infection or after a biologically relevant route of experimental infection is used.48 A cow diagnosed with Lyme disease showed distention of the tibiotarsal joints. The synovial fluid collected from the joints was copious, watery, clear and amber. Endometritis and a few abnormalities in the abdomen were also found.59 In experimentally infected equids, lymphohistiocytic dermatitis at the tick attachment site with reactive regional lymphadenopathy were the only lessions identified.25

Although descriptions of abortion and metritis have been included in some reports, reproductive tract and foetal lesions have not been characterized and the direct role of B. burgdorferi is as yet undetermined but transplacental transmission of spirochetes has been documented.22

Diagnosis and differential diagnosis

The clinical signs of Lyme disease in domestic animals are very diverse, making an accurate clinical diagnosis difficult. An awareness of the tick vectors of the disease in the region and the opportunity for exposure to such ticks are important for diagnosis. For seroepidemiological studies, assays such as immunofluorescence assay, enzyme-linked immunosorbent assay and immunoblot are commonly used.14, 23, 35, 62, 118 The ‘gold standard’ for the diagnosis of Lyme disease, however, is the isolation of the organism from blood, skin biopsy, milk, vitreous humour, and synovial or cerebrospinal fluid. Culture requirements are stringent as this microaerophilic, slow-growing organism requires a complex liquid medium and incubation at 33 to 35ºC.5 A valuable ancillary procedure is PCR, especially real-time quantitative PCR (qPCR), which detects spirochaetal DNA, whether or not the organisms are alive. This is especially valuable when joint fluid, which tends not to contain viable organisms, is analysed.15, 25, 39, 101 Direct cytologic examination with identification of spirochaetes in vitreous humor has been successful in cases of uveitis.86

The differential diagnosis of Lyme disease must include, among numerous other possibilities, traumatically induced carpal hygromas and chronic carpal and hock swellings, interdigital dermatitis, white line disease, rabies, spinal compression, brucellosis, leptospirosis, equine protozoal myeloencephalitis, and vitamin E/selenium deficiency.21, 23, 60, 84, 120  In horses, negative serology and normal CSF or joint fluid analysis does not exclude the diagnosis.48, 54 For equine neuroborreliosis, histopathology is considered the most reliable diagnostic test.48, 54

Control

Chemotherapy of Lyme disease in animals is based upon that used for the treatment of the disease in humans. Antimicrobials such as doxycycline, amoxicillin, penicillin, ceftriaxone and cefotaxime have been shown to be effective against B. burgdorferi. Early treatment is desirable, as treatment is most effective when given during the early stages of infection. Chronic cases require prolonged treatment, which is often less successful.60, 78, 82 A bacterin and a recombinant vaccine based on OspA are available for veterinary use, but there is no evidence of their efficacy in livestock. The best way of controlling Lyme borreliosis in livestock is tick control. This can be achieved by biological control of ticks, by application of organophosphates or pyrethroids in the ticks’ habitat, or by the use of ectoparasiticides applied directly on animals.79, 91, 111

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