Seasonal correlation of sporadic schizophrenia to Ixodes ticks and Lyme borreliosis

Background  

Being born in winter and spring is considered one of the most robust epidemiological risk factors for schizophrenia. The aetiology and exact timing of this birth excess, however, has remained elusive so far. Since during phylogeny, Borrelia DNA has led to multiple germ-line mutations within the CB1 candidate gene for schizophrenia, a meta analysis has been performed of all papers on schizophrenic birth excesses with no less than 3000 cases each. All published numerical data were then plotted against the seasonal distributions of Ixodes ticks worldwide.     

Persistence of Borrelia burgdorferi sensu lato in patients with Lyme borreliosis

In 18 patients with Lyme borreliosis the authors proved the persistence of Borrelia burgdorferi sensu lato by detection of the causal agent by immune electron microscopy or of its DNA by PCR in plasma or cerebrospinal fluid after an interval of 4-68 months. Clinical manifestations common in Lyme borreliosis were present in only half the patients, in the remainder non-specific symptoms were found. In nine subjects with confirmed Borrelia burgdorferi sensu lato in the cerebrospinal fluid the cytological and biochemical finding was normal. Examination of antibodies by the ELISA method was negative in 7 of 18 patients during the first examination and in 12 of 18 during the second examination. In all negative examinations the specific antibodies were assessed by the Western blot or ELISA method after liberation from the immunocomplexes. In the authors' opinion it is advisable to examine repeatedly plasma and other biological material from potentially affected organs by PCR and subjects with persisting or relapsing complaints after the acute form of Lyme borreliosis as well as to examine cerebrospinal fluid in case on non-specific symptoms and concurrent pathic EEG or MR findings.     

Identification and characterization of Borrelia antigens as potential vaccine candidates against Lyme borreliosis

The three Borrelia species, Borrelia afzelii, Borrelia burgdorferi and Borrelia garinii are the main species causing the most common tick-borne zoonosis, Lyme borreliosis. By applying a genomic approach relying on human antibodies we have identified 122 antigenic Borrelia proteins associated with Lyme borreliosis, including already known and published protective antigens. The heterogeneity of the Borrelia species causing Lyme borreliosis makes the search for conserved antigens providing broad protection challenging. Using several in vitro assays we narrowed down the selection to 15 vaccine candidates. These antigens were further analyzed for antigenicity and cross-reactivity using sera from mice infected with the three pathogenic Borrelia species. All antigens analyzed showed a high degree of cross-reactivity between the three Borrelia species, essential for providing cross-protection. We also investigated whether mice infected with B. afzelii through tick exposure are primed to mount cytokine responses. For a selection of these antigens, we observed preferentially a pro-inflammatory response in C3H/HeN mice, while in contrast also a type 2 T cell response was seen in the Borrelia-resistant mouse strain BALB/c. Thus, antigens mounting a type 2 or mixed type 2/type 1 T cell response might be preferred vaccine candidates for evaluation in animal models of Lyme borreliosis.     

Diversity of Borrelia genospecies in Ixodes ricinus ticks in a Lyme borreliosis endemic area in Switzerland identified by using new probes for reverse line blotting

In Europe, 7 Borrelia species belonging to the Borrelia burgdorferi sensu lato complex have been reported in Ixodes ricinus ticks. In addition, another Borrelia, related to the relapsing fever spirochaetes, has also been described. In the present study, we designed probes for reverse line blotting allowing detection and identification of all these Borrelia species after amplification of the variable spacer region between the 23S and 5S ribosomal genes. These new probes allowed us investigate the diversity of Borrelia in 915 I. ricinus collected on the south-facing slope of Chaumont (Switzerland). Among the 159 infected ticks, 7 Borrelia species were identified, and B. spielmanii and relapsing fever-like (RFL) spirochaetes were identified in this area for the first time. B. valaisiana and B. spielmanii were significantly less present in male than in female or nymphal ticks. Mixed infection with RFL spirochaetes and Lyme borreliosis spirochaetes were detected in 4 ticks. In addition, the set of probes could identify the recently described species, B. bavariensis.     

Vaccination with meningococcal outer membrane vesicles carrying Borrelia OspA protects against experimental Lyme borreliosis

Currently there is no human vaccine against Lyme borreliosis, and most research focuses on recombinant protein vaccines, as such a vaccine has been proven to be successful in the past. The expression of recombinant antigens in meningococcal Outer Membrane Vesicles (OMVs), with the OMV functioning both as adjuvant and delivery vehicle, greatly enhances their potential. Immunization studies in mice have shown that OMV-based vaccines can protect against various pathogens and an OMV-based meningococcal vaccine is approved and available for human use. Because of its surface localization in Borrelia and the detailed knowledge regarding its immunogenicity and structure, OspA was chosen as a suitable lipoprotein to be tested as an OMV-based vaccine against Lyme borreliosis. We have previously shown that the OMV-OspA vaccine was immunogenic in mice and here we assessed the efficacy of OMV-OspA.We generated a second-generation OMV-OspA vaccine and vaccinated C3H/HeN mice with (EDTA extracted) meningococcal OMVs expressing OspA from B. burgdorferi strain B31. The adjuvant effect of empty OMVs on recombinant OspA was tested as well. We subsequently challenged mice with a subcutaneous injection of B. burgdorferi.Average antibody end-point titers against the OspA-OMV construct were high, although lower compared to the antibodies raised against recombinant OspA. Interestingly, antibody titers between recombinant OspA adjuvanted with aluminum hydroxide and recombinant OspA with OMV as adjuvant were comparable. Finally, qPCR and culture data show that both the OspA-OMV and the vaccine based on recombinant OspA with OMV as adjuvant provided significant, yet partial protection, against Borrelia infection.OMV-based vaccines using Borrelia (lipo)proteins are an easy and feasible vaccination method protecting against B. burgdorferi infection and could be a promising strategy in humans.     

Ophthalmic manifestations in Lyme borreliosis

We reviewed ophthalmic manifestations in Lyme borreliosis, concentrating on clinical and laboratory diagnosis, differential diagnosis and treatment options. Ocular involvement may occur in every stage of the disease. Conjunctivitis and episcleritis are the most frequent manifestations of the early stage. Neuro-ophthalmic disorders and uveitis occur in the second stage whereas keratitis, chronic intraocular inflammation and orbital myositis have been reported in the third stage of borreliosis.     

Borrelia in Ethiopian ticks

Two regions (Jimma and Dire Dawa) in Ethiopia were investigated for the presence of soft ticks. Although no Ornithodoros spp. ticks were collected during this survey, published records of their existence in Ethiopia were found. An overwhelming infestation of Argas persicus was revealed in a village located adjacent to Dire Dawa. These ticks primarily were feeding on poultry, but were also biting humans. Furthermore, hard ticks were collected from livestock and companion animals in these regions.Collected ticks were assessed for Borrelia by real-time PCR followed by conventional PCR and sequencing to identify species present. A. persicus ticks were found to carry B. anserina in 3 of 40 (7.5%) A. persicus tick pools, whilst hard tick pools yielded 2 of 16 (12.5%) positive for B. theileri. Collectively, these borrelial species and their tick vectors are likely to have an important economic impact of particular relevance to subsistence farmers in Ethiopia.     

Infection of hard ticks in the Caspian Sea littoral of Iran with Lyme borreliosis and relapsing fever borreliae

The Caspian Sea littoral of Iran is home to various hard tick species, including Ixodes ricinus, the notorious vector of Lyme borreliosis (LB) in Eurasia. Here, in this area, we examined I. ricinus and other hard ticks, along with common rodents and small mammals for LB and relapsing fever (RF) borreliae infection. Ticks were collected from various mammalian hosts, including sheep, goats, cattle, camels, horses, dogs, donkeys, rodents, and hedgehogs. Rodents and small mammals were live-captured from different habitats. A real-time PCR for 16S rRNA sequence revealed borrelial DNA in 71 out of 501 (≈14 %) specimens belonging to I. ricinus and Rhipicephalus ticks. None of the rodents and small mammals showed borrelial infection in the viscera. PCR amplification and sequencing of a 600-bp sequence of the flaB identified Borrelia bavariensis, Borrelia garinii, Borrelia afzelii, and Borrelia valaisiana, and the RF Borrelia, B. miyamotoi in I. ricinus ticks. The RF-like Borrelia in Rhipicephalus ticks shared the highest identity (98.97 %) with an isolate infecting Haemaphysalis megaspinosa ticks in Japan. Our phylogeny and BLAST analysis suggest the range extension of the European I. ricinus-associated borreliae into the north of Iran.     

Dermatological aspects of Lyme borreliosis

Lyme borreliosis is a tick-borne zoonosis due to bacterial infection by Borrelia (B.) burgdorferi sensu lato The disease presents differently in Europe or North America and may be called European borreliosis when acquired in Europe. Lyme borreliosis evolves in 3 stages. The main manifestations include cutaneous, neurological, and joint involvement. Erythema migrans (EM) is the most specific and most frequent finding in patients with Lyme borreliosis. It is the hallmark of early-localized borreliosis. EM is a slowly expanding red macula that occurs in about 60-80% of patients contracting Lyme borreliosis. Central clearing of the red patch can occur. It appears at the site of the tick bite, 7 to 20 days after the bite. Borrelial lymphocytoma (BL) occur rarely in patients with the early-disseminated stage of the disease. BL is a red or brown nodule or plaque located on the nipple, the earlobe, the scrotum, or the face. It should not be confused with cutaneous B-cell lymphoma. Acrodermatitis chronica atrophicans (ACA) is the cutaneous manifestation of late borreliosis. It starts as a violaceous patch, usually located on the extensor surface of a limb. Periarticular nodules and cords can also be present. Without treatment, it will evolve over weeks or months to the typical atrophic stage with extensive dermo-epidermal atrophy and visibility of superficial veins. Only these 3 manifestations are clearly related to an infection with B. burgdorferi. The relationship between infection with B. burgdorferi and other dermatoses, especially morphea, lichen sclerosus, and interstitial granulomatous dermatitis is still debated.     

Diversity of tick species biting humans in an emerging area for Lyme disease.

BACKGROUND. Although most tick bites in humans in areas of the northeastern United States in which Lyme disease is highly endemic are due to Ixodes dammini, no study documents the frequency of I. dammini bites in low-prevalence or emerging areas for Lyme disease. Data on the proportion of tick bites in humans that are due to I. dammini in a region may have implications for public health policy and clinical management. METHODS. A statewide survey of the tick species that parasitized humans in Maine was conducted during 1989 and 1990. Tick submissions from throughout the state were elicited through media announcements. All ticks that had been removed from humans were identified, and data were collected that included bite seasonality and geography and demographics of tick bite victims. RESULTS. Of 709 ticks submitted, only 17% were I. dammini. Ixodes cookei, a vector for Powassan encephalitis, accounted for 34% of bites, and Dermacentor variabilis accounted for 45%. Other tick species were occasionally implicated. CONCLUSIONS. The likelihood that a tick bite was due to I. dammini was lower in Maine than in areas in the northeastern United States in which Lyme disease is highly endemic. Other tick vectors, associated with diseases other than Lyme disease, were more frequently implicated. Regional tick bite surveys may prove useful in assessing the risk of Lyme disease following a tick bite.     

Cardiac manifestations of Lyme borreliosis

Lyme borreliosis is increasing in Poland in both incidence and recognition with 655 cases reported in 1997 and 3574 in 2003. Approximately 4% of patients will develop cardiac manifestations--the least well documented complication of Lyme disease. Cardiac involvement usually occurs within weeks to months of the infecting tick bite and includes varying degrees of atrioventricular block as the commonest manifestation and tachyarrhythmias, myopericarditis, mild cardiac muscle dysfunction. There has been evidence that long standing dilated cardiomyopathy may be associated with chronic Borrelia burgdorferi infection. Patients with atrioventricular block have good prognosis. Most cases resolve within 1 to 2 weeks. Temporary, but almost never permanent, cardiac pacing may be required for some patients. Cardiac manifestations of Lyme disease are treatable with antibiotics. Lyme carditis should be taken into consideration in patients with acute as well as chronic heart diseases.     

Biologic diagnosis of Lyme borreliosis

Lyme borreliosis (LB) is a multisystemic infection transmitted by ticks. Its diagnosis is based on clinical and biological criteria. These criteria could be different in Europe than in the USA, because of the existence of multiples strains of borrelia in Europe. In primary stage of LB, the diagnosis is often clinical. In the secondary stage, LB diagnosis is established with an Elisa serology confirmed by a Western blot. The interpretation criteria of these laboratory tests should follow European recommendations (EUCALB). LB with neurological involvement should be confirmed by screening for intrathecal synthesis of borrelia antibodies in CSF. LB with rheumatologic expression could be confirmed by screening for borrelia in joint fluid by PCR. There is no strong marker of activity of the disease. Follow-up for LB is difficult, because antibodies may persist for years and LB does not confer immunization.     

Imbalanced presence of Borrelia burgdorferi s.l. multilocus sequence types in clinical manifestations of Lyme borreliosis

In this study we used typing based on the eight multilocus sequence typing scheme housekeeping genes (MLST) and 5S-23S rDNA intergenic spacer (IGS) to explore the population structure of Borrelia burgdorferi sensu lato isolates from patients with Lyme borreliosis (LB) and to test the association between the B. burgdorferi s.l. sequence types (ST) and the clinical manifestations they cause in humans. Isolates of B. burgdorferi from 183 LB cases across Europe, with distinct clinical manifestations, and 257 Ixodes ricinus lysates from The Netherlands, were analyzed for this study alone. For completeness, we incorporated in our analysis also 335 European B. burgdorferi s.l. MLST profiles retrieved from literature. Borrelia afzelii and Borrelia bavariensis were associated with human cases of LB while Borrelia garinii, Borrelia lusitaniae and Borrelia valaisiana were associated with questing I. ricinus ticks. B. afzelii was associated with acrodermatitis chronica atrophicans, while B. garinii and B. bavariensis were associated with neuroborreliosis. The samples in our study belonged to 251 different STs, of which 94 are newly described, adding to the overall picture of the genetic diversity of Borrelia genospecies. The fraction of STs that were isolated from human samples was significantly higher for the genospecies that are known to be maintained in enzootic cycles by mammals (B. afzelii, B. bavariensis, and Borrelia spielmanii) than for genospecies that are maintained by birds (B. garinii and B. valaisiana) or lizards (B. lusitaniae). We found six multilocus sequence types that were significantly associated to clinical manifestations in humans and five IGS haplotypes that were associated with the human LB cases. While IGS could perform just as well as the housekeeping genes in the MLST scheme for predicting the infectivity of B. burgdorferi s.l., the advantage of MLST is that it can also capture the differential invasiveness of the various STs.     

Non antibiotic treatments of Lyme borreliosis

Non-antibiotic treatment of Lyme borreliosis is only indicated in a few specific clinical situations. In chronic Lyme arthritis, intra-articular steroids are useful to immediately relieve symptomatic joint effusion. Nevertheless, 4 studies with weak methodological evidence were convergent enough to recommend not proposing intra-articular injection before or even immediately after antibiotic treatment. The injection can only be recommended in the treatment of patients whose joint effusion persists despite 2 courses of oral antibiotherapy or one course of IV antibiotherapy. For some experts, the injection can only be made after negative PCR assessment of the joint fluid for spirochetes. This recommendation, although logical, has never been evaluated. Radiation synovectomy may be indicated in persistent synovitis after antibiotherapy and before surgical synovectomy. Further studies are mandatory to confirm the role of radiation synovectomy in the local therapy. Arthroscopic synovectomy can reduce the period of joint inflammation when persistent synovitis is associated with significant pain or limited function. Several experts recommend using the procedure only if synovitis persists after 2 months of antibiotherapy and a negative PCR joint fluid assessment. Non-steroidal anti-inflammatory drugs are often prescribed for their symptomatic effects. Experimental data is consensual on the deleterious consequences of systemic corticosteroid therapy. Corticosteroids are not indicated in Lyme's disease. In post Lyme's disease syndrome, patient complaints may lead to a multidisciplinary therapeutic management and the use of neuro-psychiatric drugs.     

Potential foci of Lyme borreliosis in towns

In 1997 the presence of ticks Ixodes ricinus infected with the agent of Lyme borreliosis was detected on the vegetation of Kosice urban agglomeration. The density of ticks on the vegetation of pericentral area islands of forest stands and neglected gardens was 2.4 times lower than that observed in a peripheral park forest. Only sporadical findings of ticks were reported from the industrial central part of town with remnants of uncultivated vegetation. Central parks and housing estates were actually tick-free. Borrelia-infected ticks, from 12.8 to 15% were found in the park forest and pericentral areas. The results indicate potential risks for humans and domestic animals coming in contact with borrelia-infected ticks, also in the territory of large towns.     

Prevalence of Lyme borreliosis in The Netherlands]

In the autumn of 1989 a seroepidemiological study was carried out among 440 owners of hunting dogs and 1052 blood donors from different regions in the Netherlands. To detect IgG antibodies to Borrelia burgdorferi an enzyme-linked immunosorbent assay was performed. The prevalence of antibodies to B. burgdorferi in owners of hunting dogs was 15%, which was significantly higher than in blood donors (9%). In both groups the prevalence of seropositivity increased with age. There was no difference between men and women. The prevalence of antibodies to B. burgdorferi in blood donors from different regions varied significantly, ranging from 2% to 17%. Only 3% of the owners of hunting dogs could recall having had symptoms most likely to be due to Lyme borreliosis. Of the 68 seropositive hunters 64 (94%) were asymptomatic. The results of this study indicate that in the Netherlands asymptomatic infections with B. burgdorferi are common in individuals highly exposed to ticks and that there is considerable variation in the prevalence of seropositivity in the general population. Hence caution is called for in the clinical interpretation of IgG test results.