Tick-borne pathogens and the vector potential of ticks in China

Ticks, as obligate blood-sucking ectoparasites, attack a broad range of vertebrates and transmit a great diversity of pathogenic microorganisms. They are considered second only to mosquitoes as vectors of human disease, and the most important vector of pathogens of domestic and wild animals. Of the 117 described species in the Chinese tick fauna, 60 are known to transmit one or more diseases: 36 species isolated within China and 24 species isolated outside China. Moreover, 38 of these species carry multiple pathogens, indicating the potentially vast role of these vectors in transmitting pathogens. Spotted fever is the most common tick-borne disease, and is carried by at least 27 tick species, with Lyme disease and human granulocytic anaplasmosis ranked as the second and third most widespread tick-borne diseases, carried by 13 and 10 species, respectively. Such knowledge provides us with clues for the identification of tick-associated pathogens and suggests ideas for the control of tick-borne diseases in China. However, the numbers of tick-associated pathogens and tick-borne diseases in China are probably underestimated because of the complex distribution and great diversity of tick species in this country.

Ticks, as obligate blood-sucking ectoparasites, attack a broad range of vertebrates, including humans, and they are considered second only to mosquitoes as vectors of human disease, and the most important vector of pathogens of domestic and wild animals [1]. They transmit a variety of pathogens of medical and veterinary interest, including viruses, bacteria, rickettsiae, helminthes, and protozoans, all of which are able to cause damage to livestock production and human health. The global threat of tick-borne diseases is increasing, with new pathogens identified continuously [2]. There are an estimated 899 species of ticks belonging to three families: Argasidae, Ixodidae, and Nuttalliellidae (represented by a monotypic species restricted to South Africa) [3].
In China, 117 species of the following genera have been identified: Argas (seven species), Carios (four species), and Ornithodoros (two species) in the family Argasidae; and Amblyomma (eight species), Anomalohimalaya (two species), Dermacentor (twelve species), Haemaphysalis (forty four species), Hyalomma (six species), Ixodes (twenty four species), and Rhipicephalus (eight species) in the family Ixodidae [4]. Some of these species carry or transmit one or more infectious pathogens, resulting in severe zoonotic diseases. The most commonly observed human tick-borne diseases in China are reportedly Lyme disease, tick-borne encephalitis, Crimean-Congo hemorrhagic fever, Q fever, tularemia, and North-Asia tick-borne spotted fever [5]. Epidemiologically important tick-borne diseases, such as Human Granulocytic Anaplasmosis (HGA) and severe Fever with Thrombocytopenia Syndrome (FLTS), have also emerged in recent years. The characterization of a new bunyavirus (associated with fever, thrombocytopenia, and leukopenia syndrome) in 2010 has prompted greater attention to ticks and tick-borne diseases throughout China. However, tickassociated pathogens and diseases are still underestimated because of the complex distribution and the large diversity of tick species in China.
Although the rapid development of molecular techniques has greatly advanced the identification of emerging tick pathogens, continuous research is required to fully comprehend the diversity of tick-borne pathogens and to completely identify the vector roles of ticks in China. In this study, with regard to the Chinese tick fauna, we reviewed the tick-associated pathogenic microorganisms that have been identified world-wide, and evaluated the potential roles of the ticks as vectors throughout China. This will extend the identification of tick-associated pathogens and suggest better strategies for the control of tick-borne diseases in China.

Role of argasid ticks as vectors in China and their associated tick-borne pathogens
In China, there are 13 species of argasid ticks, belonging to three genera: Argas (seven species), Carios (four species), and Ornithodoros (two species) [4]. The majority of these are nidicolous, usually residing in the burrows, caves, or nests of their hosts. Among all the argasids found in China, four Argas species, two Carios species, and two Ornithodoros species are competent to transmit or cause human disease (Table 1) [6][7][8][9][10][11][12][13][14][15][16][17]. Among these eight tick species, four (A. japonicas, A. persicus, O. tartakovskyi, and O. tholozani) have been confirmed as causing host illnesses in China. A case of human dermatitis was recorded in 1986 after a bite by A. japonicas, but no pathogen has been identified from this tick species in China [6]. The tick A. persicus mainly infests poultry and carries the most diverse array of pathogens in the family Agarsidae, including Borrelia anserine, Kyasanur Forest disease virus, and Wolbachia persica n. sp. However, only B. anserine, known to cause avian spirochetosis, has been confirmed in China [7]. Lake Clarendon virus was isolated from A. robertsi; Quaranfil virus and Gissar virus were identified in A. vulgaris; and "Issyk-Kul" virus has been identified in C. vespertilionis. No virus has been detected in ticks collected in China. The symptoms or diseases caused by these viruses are still unclear [11][12][13]16], and the vector roles of these ticks in China remain unknown.
Carios capensis can be coinfected by pathogen DNA from Borrelia, Coxiella, and Rickettsia, as well as West Nile virus [14,15], although no pathogens have been reported in this tick species collected in China. Ornithodoros tartakovskyi and O. tholozani both cause tick-borne relapsing fever in China, but carry different pathogens, B. latyshevyi and B. persica, respectively [17].
Ixodid ticks in China, their roles as vectors, and associated tick-borne pathogens There are 104 species of ixodid ticks in China in seven genera: Amblyomma (eight species), Anomalohimalaya (two species), Dermacentor (twelve species), Haemaphysalis (forty four species), Hyalomma (six species), Ixodes (twenty four species), and Rhipicephalus (eight species) [4]. Of these, 52 species from six genera have been shown to carry or transmit pathogenic microorganisms: Ixodes (seven species), Amblyomma (three species), Dermacentor (nine species), Haemaphysalis (twenty one species), Hyalomma (five species), and Rhipicephalus (seven species) ( Table 2) . Of these 52 species, 32 occur in China (Table 2). Tick-borne spotted fever is the most commonly detected disease, carried by at least 27 tick species. Lyme disease and human granulocytic anaplasmosis are the second and third most widespread tick-borne diseases, transmitted by at least 13 and 10 tick species, respectively ( Table 2). Eight tick species are vectors for human granulocytic ehrlichiosis, seven tick species carry tick-borne encephalitis and babesiosis, and six species transmit hemorrhagic fever. The ixodid ticks that act as vectors of Babesia are usually coinfected with more than one Babesia species. These ticks include I. persulcatus, D. nuttalli, Rh. microplus, and Rh. haemaphysaloides, which are often infected by Babesia bigemina and Ba. bovis (Table 2).   [26], and B. afzelii has not been detected in I. nipponensis distributed in China [28]. Although their pathogens have not been confirmed in China, the vector roles of these ticks are widely recognized [26,28]. Tick-borne encephalitis virus has not been found in I. kazakstani in China [27], whereas Ehrlichia and R. japonica have only been found in the species I. ovatus, distributed outside China [29,31].

Genus Haemaphysalis
The majority of ixodid ticks found in China belong to the genus Haemaphysalis.  (Table 2) . The most commonly detected diseases vectored by this genus of ticks are spotted fever and human granulocytic anaplasmosis, which are transmitted by 11 and six species, respectively. Borrelia is carried by at least five species of this genus, and Babesia by at least four species ( Table 2). The ticks H. longicornis, H. punctata, and H. concinna support the greatest diversity of pathogenic microorganisms, with H. longicornis the major vector of B. burgdorferi, Theileria spp., Coxiella burnetti, Babesia spp., Anaplasma phagocytophilum, Ehrlichia, Bartonella, spotted-fevergroup rickettsiae, Huaiyangshan virus, and the recently identified New bunyavirus (Table 2), which has caused many deaths in China, Japan, and Korea [40][41][42][43][44][45][46][47]. Haemaphysalis concinna is mainly distributed in northern China, where multiple outbreaks of H. concinna-borne disease have been reported since the early 20th century. These outbreaks have been attributed to a diverse array of pathogens, including B. garinii, human granulocytic Ehrlichia, spotted-fever-group Rickettsiae, and encephalitis viruses [23,[48][49][50]. Haemaphysalis punctata transmits B. burgdorferi sensu stricto, Ba. major, T. orientalis, Crimean-Congo hemorrhagic fever virus, Rickettsia, R. aeschlimannii, An. phagocytophilum, and Flavivirus, resulting in diseases such as Lyme disease, babesiosis, tick-borne encephalitis, and Crimean-Congo hemorrhagic fever [3,[51][52][53][54][55]. Haemaphysalis formosensis has been shown to carry pathogen DNA from a number of bacterial species, including R. asiatica sp. nov., Kyasanur Forest disease virus, R. japonica, and An. phagocytophilum, but these pathogens have not yet been detected in this tick species within China. Among the pathogenic microorganisms transmitted by Haemaphysalis species, most have been characterized with molecular techniques, and some species have been shown to transmit particular pathogens under controlled experimental conditions (Table 2).

Genus Dermacentor
Nine of the 12 species of Dermacentor found within China can transmit pathogens, and seven of these species (D. nuttali, D. silvarum, D. auratus, D. everestianus, D. marginatus, D. niveus, and D. sinicus) are of epidemiological importance in China (Table 2) [23,. The widely distributed D. nuttalli, D. reticulates, and D. silvarum carry the largest numbers of different pathogenic microorganisms, and Rickettsiae are the most commonly found bacteria in this genus ( Table 2). The causative agent of human granulocytic ehrlichia has been detected in D. silvarum and D. nuttalli within China [23], and Babesia is commonly found in D. nuttalli and D. reticulatus outside China [89]. Borrelia burgdorferi has been found in D. marginatus [51] and D. nuttalli within China [87]; An. ovis and Bacillus tularensis are most commonly found in D. everestianus [100] and D. niveus within China [104]; and An. phagocytophila is specifically detected in D. reticulatus outside China [92].

Conclusion
Of the estimated 117 species of ticks in China, 36 have been confirmed to carry or transmit one or more pathogens, and 24 additional species are known to be pathogenic vectors in other countries. Furthermore, 38 species have been shown to carry multiple pathogens, indicating the major roles they play in the spread and transmission of these pathogens. Therefore, the number of pathogens and the vector potential of ticks may still be underestimated, because of the complex distributions and the great diversity of tick species in diverse ecological habitats in China. However, such knowledge will provide clues to the further identification of tick-associated pathogens, especially in epidemic areas with multiple tick species. Much more work is required to better distinguish between ticks that carry potential pathogens and those that are competent to transmit pathogens to a host. Targeted prevention methods will then be more effective in controlling tick-borne diseases.

Competing interests
The authors declare that they have no competing interests.
Authors' contributions YZ-J and LJ-Z conceived and designed the study, drafted the manuscript, and critically revised the manuscript. W H, W T-H, S W-Y and YX-L participated in data collection and helped to revise the manuscript. All authors read and approved the final manuscript.