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Tick borne relapsing fever (TBRF) is a zoonosis caused by various Borrelia species transmitted to humans by both soft-bodied and (more recently recognized) hard-bodied ticks. In recent years, molecular diagnostic techniques have allowed to extend our knowledge on the global epidemiological picture of this neglected disease. Nevertheless, due to the patchy occurrence of the disease and the lack of large clinical studies, the knowledge on several clinical aspects of the disease remains limited. In order to shed light on some of these aspects, we have systematically reviewed the literature on TBRF and summarized the existing data on epidemiology and clinical aspects of the disease. Publications were identified by using a predefined search strategy on electronic databases and a subsequent review of the reference lists of the obtained publications. All publications reporting patients with a confirmed diagnosis of TBRF published in English, French, Italian, German, and Hungarian were included. Maps showing the epidemiogeographic mosaic of the different TBRF Borrelia species were compiled and data on clinical aspects of TBRF were analysed. The epidemiogeographic mosaic of TBRF is complex and still continues to evolve. Ticks harbouring TBRF Borrelia have been reported worldwide, with the exception of Antarctica and Australia. Although only molecular diagnostic methods allow for species identification, microscopy remains the diagnostic gold standard in most clinical settings. The most suggestive symptom in TBRF is the eponymous relapsing fever (present in 100% of the cases). Thrombocytopenia is the most suggestive laboratory finding in TBRF. Neurological complications are frequent in TBRF. Treatment is with beta-lactams, tetracyclines or macrolids. The risk of Jarisch-Herxheimer reaction (JHR) appears to be lower in TBRF (19.3%) compared to louse-borne relapsing fever (LBRF) (55.8%). The overall case fatality rate of TBRF (6.5%) and LBRF (4–10.2%) appears to not differ. Unlike LBRF, where perinatal fatalities are primarily attributable to abortion, TBRF-related perinatal fatalities appear to primarily affect newborns.

Borrelia miyamotoi is a hard tick-borne spirochete genetically related to relapsing fever Borrelia and the etiological agent of an emerging infectious disease in humans. Like relapsing fever Borrelia , B. miyamotoi carries clusters of gene cassettes encoding variable major proteins (Vmps) on multiple linear plasmids and shows antigenic variation in mammalian hosts by switching the expression vmp gene cassette. However, it remains unknown how the switch occurs in B. miyamotoi . Here we determined the whole genome sequences of Japanese B. miyamotoi strains to identify the repertoire and arrangement of vmp gene cassettes on five linear plasmids, and based on this information, analyzed B. miyamotoi clones reisolated from experimentally infected mice. Our analyses revealed that the switch occurred by replacing the expression cassette and its downstream silent cassettes with the long segment from archival plasmid. As the result of this long segment conversion, the first cassette became the expression cassette. Notably, this phenomenon was not due to single gene conversion but the replacement of a long (up to 16 kb or more) plasmid segment. We also show that while bacterial elimination depended on the presence of specific antibodies, the segment conversion was detected at five days post-infection, earlier than antibody production in mice, and even in severe combined immunodeficient mice. These results provide novel insights into the mechanisms that Borrelia evolved to survive and persist in mammalian hosts.

Borreliae of the relapsing fever group (RFG) are heterogenous and can be divided mainly into three groups according to vectors, namely the soft-tick-borne relapsing fever (STBRF) Borreliae, the hard-tick-borne relapsing fever (HTBRF) Borreliae, the louse-borne relapsing fever (LBRF) Borreliae, and the avian relapsing fever ones. With respect to the geographical distribution, the STBRF Borreliae are further subdivided into Old World and New World strains. Except for the Avian relapsing fever group Borreliae, which cause avian spirochetosis, all the others share infectivity in humans. They are indeed the etiological agent of both endemic and epidemic forms of relapsing fever, causing high spirochaetemia and fever. Vectors are primarily soft ticks of Ornithodoros spp. in the STBRF group; hard ticks, notably Ixodes sp., Amblyomma sp., Dermacentor sp., and Rhipicephalus sp., in the HTBRF group; and the louse pediculus humanus humanus in the TBRF one. A recent hypothesis was supported for a common ancestor of RFG Borreliae, transmitted at the beginning by hard-body ticks. Accordingly, STBRF Borreliae switched to use soft-bodied ticks as a vector, which was followed by the use of lice by Borrelia recurrentis. There are also new candidate species of Borreliae, at present unclassified, which are also described in this review.

Louse-borne relapsing fever (LBRF) is an epidemic disease with a fascinating history from Hippocrates' times, through the 6th century 'Yellow Plague', to epidemics in Ireland, Scotland and England in the 19th century and two large Afro-Middle Eastern pandemics in the 20th century. An endemic focus persists in Ethiopia and adjacent territories in the Horn of Africa. Since 2015, awareness of LBRF in Europe, as a re-emerging disease, has been increased dramatically by the discovery of this infection in dozens of refugees arriving from Africa. The causative spirochaete, Borrelia recurrentis, has a genome so similar to B. duttonii and B. crocidurae (causes of East and West African tick-borne relapsing fever), that they are now regarded as merely ecotypes of a single genomospecies. Transmission is confined to the human body louse Pediculus humanus corporis, and, perhaps, the head louse P. humanus capitis, although the latter has not been proved. Infection is by inoculation of louse coelomic fluid or faeces by scratching. Nosocomial infections are possible from contamination by infected blood. Between blood meals, body lice live in clothing until the host's body temperature rises or falls, when they seek a new abode. The most distinctive feature of LBRF, the relapse phenomenon, is attributable to antigenic variation of borrelial outer-membrane lipoprotein. High fever, rigors, headache, pain and prostration start abruptly, 2–18 days after infection. Petechial rash, epistaxis, jaundice, hepatosplenomegaly and liver dysfunction are common. Severe features include hyperpyrexia, shock, myocarditis causing acute pulmonary oedema, acute respiratory distress syndrome, cerebral or gastrointestinal bleeding, ruptured spleen, hepatic failure, Jarisch–Herxheimer reactions (J-HR) and opportunistic typhoid or other complicating bacterial infections. Pregnant women are at high risk of aborting and perinatal mortality is high. Rapid diagnosis is by microscopy of blood films, but polymerase chain reaction is used increasingly for species diagnosis. Severe falciparum malaria and leptospirosis are urgent differential diagnoses in residents and travellers from appropriate geographical regions. High untreated case-fatality, exceeding 40% in some historic epidemics, can be reduced to less than 5% by antibiotic treatment, but elimination of spirochaetaemia is often accompanied by a severe J-HR. Epidemics are controlled by sterilising clothing to eliminate lice, using pediculicides and by improving personal hygiene.

Relapsing fever group  Borrelia (RFGB) are motile spirochetes transmitted to mammalian or avian hosts through the bite of hematophagous arthropods, such as soft ticks (Argasidae), hard ticks (Ixodidae) and the human clothing lice. RFGB can infect pets such as dogs and cats, as well as birds, cattle and humans. Borrelia recurrentis , B. anserina and B. theileri are considered to have worldwide distribution, affecting humans, domestic birds and ruminants, respectively. Borrelia spp. associated with soft ticks are transmitted mainly by Ornithodoros ticks and thrive in endemic foci in tropical and subtropical latitudes. Nowadays, human cases of soft tick-borne relapsing fever remain neglected diseases in several countries, and the impact these spirochetes have on the health of wild and domestic animals is largely understudied. Human infection with RFGB is difficult to diagnose, given the lack of distinguishing clinical features (undifferentiated febrile illness). Clinically, soft tick or louse-borne relapsing fever is often confused with other etiologies, such as malaria, typhoid or dengue. In Latin America, during the first half of the twentieth century historical documents elaborated by enlightened physicians were seminal, and resulted in the identification of RFGB and their associated vectors in countries such as Mexico, Panama, Colombia, Venezuela, Peru and Argentina. Almost 80 years later, research on relapsing fever spirochetes is emerging once again in Latin America, with molecular characterizations and isolations of novel RFGB members in Panama, Bolivia, Brazil and Chile. In this review we summarize historical aspects of RFGB in Latin America and provide an update on the current scenario regarding these pathogens in the region. To accomplish this, we conducted an exhaustive search of all the published literature for the region, including old medical theses deposited in libraries of medical academies. RFGB were once common pathogens in Latin America, and although unnoticed for many years, they are currently the focus of interest among the scientific community. A One Health perspective should be adopted to tackle the diseases caused by RFGB, since these spirochetes have never disappeared and the maladies they cause may be confused with etiologies with similar symptoms that prevail in the region. Graphical Abstract

Relapsing fever is the most frequent bacterial disease in Africa. Four main vector / pathogen complexes are classically recognized, with the louse Pediculus humanus acting as vector for B. recurrentis and the soft ticks Ornithodoros sonrai, O. erraticus and O. moubata acting as vectors for Borrelia crocidurae, B. hispanica and B. duttonii, respectively. Our aim was to investigate the epidemiology of the disease in West, North and Central Africa. From 2002 to 2012, we conducted field surveys in 17 African countries and in Spain. We investigated the occurrence of Ornithodoros ticks in rodent burrows in 282 study sites. We collected 1,629 small mammals that may act as reservoir for Borrelia infections. Using molecular methods we studied genetic diversity among Ornithodoros ticks and Borrelia infections in ticks and small mammals. Of 9,870 burrows investigated, 1,196 (12.1%) were inhabited by Ornithodoros ticks. In West Africa, the southern and eastern limits of the vectors and Borrelia infections in ticks and small mammals were 13°N and 01°E, respectively. Molecular studies revealed the occurrence of nine different Ornithodoros species, including five species new for science, with six of them harboring Borrelia infections. Only B. crocidurae was found in West Africa and three Borrelia species were identified in North Africa: B. crocidurae, B. hispanica, and B. merionesi. Borrelia Spirochetes responsible for relapsing fever in humans are highly prevalent both in Ornithodoros ticks and small mammals in North and West Africa but Ornithodoros ticks seem absent south of 13°N and small mammals are not infected in these regions. The number of Ornithodoros species acting as vector of relapsing fever is much higher than previously known.

Louse-borne relapsing fever (LBRF) is known to have killed millions of people over the course of European history and remains a major cause of mortality in parts of the world. Its pathogen, Borrelia recurrentis, shares a common vector with global killers such as typhus and plague and is known for its involvement in devastating historical epidemics such as the Irish potato famine. Here, we describe a European and historical genome of B. recurrentis, recovered from a 15th century skeleton from Oslo. Our distinct European lineage has a discrete genomic makeup, displaying an ancestral oppA-1 gene and gene loss in antigenic variation sites. Our results illustrate the potential of ancient DNA research to elucidate dynamics of reductive evolution in a specialized human pathogen and to uncover aspects of human health usually invisible to the archaeological record.

The genus Borrelia comprises arthropod-borne bacteria, which are infectious agents in vertebrates. They are mainly transmitted by ixodid or argasid ticks. In Hokkaido, Japan, Borrelia spp. were found in deer and Haemaphysalis ticks between 2011 and 2013; however, the study was limited to a particular area. Therefore, in the present study, we conducted large-scale surveillance of ticks and wild animals in the western part of the main island of Japan. We collected 6,407 host-seeking ticks from two regions and 1,598 larvae obtained from 32 engorged female ticks and examined them to elucidate transovarial transmission. In addition, we examined whole blood samples from 190 wild boars and 276 sika deer, as well as sera from 120 wild raccoons. We detected Borrelia spp. in Haemaphysalis flava, Haemaphysalis megaspinosa, Haemaphysalis kitaokai, Haemaphysalis longicornis, and Haemaphysalis formosensis. In addition, we isolated a strain from H. megaspinosa using Barbour-Stoenner-Kelly medium. The minimum infection rate of ticks was less than 5%. Transovarial transmission was observed in H. kitaokai. Phylogenetic analysis of the isolated strain and DNA fragments amplified from ticks identified at least four bacterial genotypes, which corresponded to the tick species detected. Bacteria were detected in 8.4%, 15%, and 0.8% of wild boars, sika deer, and raccoons, respectively. In this study, we found seasonal differences in the prevalence of bacterial genotypes in sika deer during the winter and summer. The tick activity season corresponds to the season with a high prevalence of animals. The present study suggests that a particular bacterial genotype detected in this study are defined by a particular tick species in which they are present.

Lyme disease (LD) is caused by a group of tick-borne bacteria of the genus Borrelia termed Lyme disease Borreliae (LDB). The detection of serum antibodies to specific LDB antigens is widely used to support diagnosis of LD. Recent findings highlight a need for serological tests that can differentiate LD from tick-borne relapsing fever (TBRF) caused by a separate group of Borrelia species termed relapsing fever Borreliae. This is because LD and TBRF share some clinical symptoms and can occur in overlapping locations. The development of serological tests for TBRF is at an early stage compared with LD. This article reviews the application of line immunoblots (IBs), where recombinant proteins applied as lines on nitrocellulose membrane strips are used to detect antibodies in patient sera, for the diagnosis and differentiation of LD and TBRF.

In 1915, a British medical officer on the Western Front reported on a soldier with relapsing fever, headache, dizziness, lumbago, and shin pain. Within months, additional cases were described, mostly in frontline troops, and the new disease was called trench fever. More than 1 million troops were infected with trench fever during World War 1, with each affected soldier unfit for duty for more than 60 days. Diagnosis was challenging, because there were no pathognomonic signs and symptoms and the causative organism could not be cultured. For 3 years, the transmission and cause of trench fever were hotly debated. In 1918, two commissions identified that the disease was louse-borne. The bacterium Rickettsia quintana was consistently found in the gut and faeces of lice that had fed on patients with trench fever and its causative role was accepted in the 1920s. The organism was cultured in the 1960s and reclassified as Bartonella quintana; it was also found to cause endocarditis, peliosis hepatis, and bacillary angiomatosis. Subsequently, B quintana infection has been identified in new populations in the Andes, in homeless people in urban areas, and in individuals with HIV. The story of trench fever shows how war can lead to the recrudescence of an infectious disease and how medicine approached an emerging infection a century ago.