Abstract
Background
Ticks are important medical arthropods that can transmit hundreds of pathogens, such as parasites, bacteria, and viruses, leading to serious public health burdens worldwide. Unexplained fever is the most common clinical manifestation of tick-borne diseases. Since the emergence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the surge of coronavirus disease 2019 (COVID-19) cases led to the hospital overload and fewer laboratory tests for tick-borne diseases. Therefore, it is essential to review the tick-borne pathogens and further understand tick-borne diseases.
Purpose
The geographic distribution and population of ticks in the Northern hemisphere have expanded while emerging tick-borne pathogens have been introduced to China continuously. This paper focused on the tick-borne pathogens that are threatening public health in the world. Their medical significant tick vectors, as well as the epidemiology, clinical manifestations, diagnosis, treatment, prevention, and control measures, are emphasized in this document.
Methods
In this study, all required data were collected from articles indexed in English databases, including Scopus, PubMed, Web of Science, Science Direct, and Google Scholar.
Results
Ticks presented a great threat to the economy and public health. Although both infections by tick-borne pathogens and SARS-CoV-2 have fever symptoms, the history of tick bite and its associated symptoms such as encephalitis or eschar could be helpful for the differential diagnosis. Additionally, as a carrier of vector ticks, migratory birds may play a potential role in the geographical expansion of ticks and tick-borne pathogens during seasonal migration.
Conclusion
China should assess the risk score of vector ticks and clarify the potential role of migratory birds in transmitting ticks. Additionally, the individual and collective protection, vector control, comprehensive surveillance, accurate diagnosis, and symptomatic treatment should be carried out, to meet the challenge.
Graphical Abstract
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Introduction
Ticks (Acarina Ixodoidea) are obligate hematophagous arthropod ectoparasites, which can be distinguished by their morphology and divided into 3 families: Ixodidae (hard ticks), Argasidae (soft ticks) and Nuttalliellidae. At present, a total of 9 genera, and 124 species of ticks have been identified in China [1]. They can not only bite their hosts and suck their blood but also spread pathogens via their saliva. Tick-borne infections are zoonoses. Humans are usually considered the occasional hosts for ticks and have no role in maintaining tick-borne pathogens in the natural cycles [2]. The pathogens, spread by ticks, are called tick-borne pathogens. The diseases, caused by tick-borne pathogens, are called tick-borne diseases.
Ticks and tick-borne pathogens are one of the biggest public health threats and veterinary problems in the world. First, tick-borne pathogens, such as Babesia, Theileria, and Anaplasma phagocytophilum, are threatening over 80% of the cattle population. The reproduction of meat, milk, and leather and the death of infected animals have brought significant economic loss. According to the statistics of the Food and Agriculture Organization of the United Nations (FAO), the gross economic loss in the world is annually USD 13.9–18.7 billion [3], with the average loss being USD 7.3 for each animal per year. Moreover, the cost of the prevention and the control of tick-borne diseases are high. For example, the reported cost for cattle alone, which are in areas at risk of being affected by ticks, has reached USD 380 million [4]. Second, tick-borne pathogens have also significantly threatened public health. On the one hand, the expense of medical treatment is high and has led to a considerable burden on society. According to the statistics of the National Institutes of Health (NIH), the expense for tick-borne diseases totaled USD 56 million in the United States in 2020 [5]. The reported cost for Lyme disease reached USD 40 million in Germany and 20 million in Holland in 2017, respectively [6]. On the other hand, a multitude of pathogens is usually harbored by one tick. Given this, it is unsurprising to observe the co-infection with genetically distinct pathogens in human beings. A plethora of studies reported seropositivity against multiple pathogen combinations [7,8,9]. However, our understanding of the interactions of these agents remains poor. Various pathogen combinations might behave synergistically, indifferently, or antagonistically within hosts, and thus modulate disease severity [10]. Challenges have been presented during diagnosis and treatment.
In recent years, reported tick-borne pathogens have shown a resurgence trend while emerging tick-borne pathogens have been continuously identified from the tick population, which have attracted extensive attention from medical and veterinary personnel. The purpose of this review is to summarize the research progress of tick-borne pathogens, including their epidemiology, species of vector ticks, clinical manifestations, diagnosis, treatment, prevention, and control dynamics. Additionally, tick load has been detected in a variety of migratory birds [11]. They can easily cross the mountains, glaciers, deserts, and oceans, and transport ticks and tick-borne pathogens from epidemic countries to China. Therefore, further understanding of ticks and tick-borne pathogens will help to detect, monitor, prevent, and control these public health threats and challenges in China comprehensively.
Tick-Borne Parasite
Piroplasma
Piroplasma (class: Apicomplexa, order: Piroplasmida) is the causative agent of piroplasmosis, which mainly consists of parasites in the family Babesiidae and Theileriidae. Ixodes ricinus is predominantly responsible for the transmission of Piroplasma in Europe, while Ixodes persulcatus is predominant in China. Through trans-ovarial and transstadial transmission, their larval, nymphal, and adult ticks can transmit the parasite to mammals (including human beings) during a blood meal. Additionally, other tick species have been proven to be vectors of Piroplasma: Rhipicephalus microplus, Rhipicephalus decoloratus, Rhipicephalus australis, Rhipicephalus sanguineus, Rhipicephalus annulatus, Dermacentor reticulatus, Haemaphysalis elliptica, and Haemaphysalis longicornis [12]. It should be noted that the distribution of tick vectors is far more extensive than that of the relevant piroplasmosis. The threat of this agent may be underestimated.
Babesiosis is a tick-borne parasitic disease endangering the world, which is caused by protozoan parasites of the genus Babesia. So far, more than 100 species of Babesia have been identified in domestic and wild animals, among which Babesia bigemina, Babesia Bovis, and Babesia divergens mainly infect livestock animals, while Babesia microti, B. divergens, Babesia Duncani, and Babesia venatorum are the causative agents of human babesiosis [13]. Bovine babesiosis could lead to severe economic loss, which is associated with apocleisis, low feed conversion efficiency, reduced production, abortion, and death of cattle. The clinical symptoms of human babesiosis are similar to malaria, including but not limited to fever, chills, and sleepiness. Additionally, the incidence of hemolytic anemia can be observed in severe cases. However, the severity of babesiosis depends on the species of Babesia and the immune status of the patients [14].
In China, the distribution of Babesia is shown in Fig. 1. It was previously thought that the responsible species of human infections were B. microti and B. venatorum in Eastern and Northeastern China. However, two emerging Babesia species, Babesia crassa, and Babesia sp. XXB/HangZhou, have been identified in Heilongjiang province and Zhejiang province respectively [15]. Additionally, an initial report of human infection with B. divergens in Gansu province has raised medical awareness [16]. It was the first report of Babesia infections in Gansu province. Interestingly, as the etiological agent of bovine babesiosis, B. divergens has not been identified in cattle in China. In the United States, the number of human infection cases has rapidly increased in the past 20 years. Therefore, the US government has included babesiosis as a nationally notifiable consideration [17]. This suggested that China should pay increased attention to this emerging threat and carry out systematic epidemiological surveys. In the prevalent regions, local physicians should be aware of the differential diagnoses for babesiosis and the risk for transfusion-transmitted babesiosis.
Theileria is an intracellular protozoan parasite, which could lead to bovine theileriosis and constrain cattle production in develo** countries, whereby ticks are their natural vectors. The cattle infected with Theileria exhibit fever, anemia, jaundice, and superficial lymphadenopathy. In China, Theileria infection is common (Fig. 1). The causative agents are Theileria orientalis, Theileria sinensis, and Theileria annulata. T. orientalis is a blood protozoan transmitted by Haemaphysalis ticks and clustered into the benign Theileria spp. group. This group has low pathogenicity to cattle and buffalo, leading to only inconspicuous clinical symptoms. However, the T. orientalis Ikeda genotype is a newly identified genotype with strong virulence. It can lead to erythrocyte lysis, causing cause anemia and hypoxia in cattle [18]. Additionally, even if the pregnant cows are cured, they are still at risk of abortion. T. sinensis, transmitted by H. qinghaiensis, was initially isolated from cattle in Gansu province in China. It showed solid host specificity and can only infect cattle, yaks, and buffalo. However, due to its low pathogenicity, farmers usually pay insufficient attention to this agent, leading to constant invisible losses to the cattle industry. T. annulata is the causative agent of tropical theileriosis and has brought a significant impact on the cattle industry. It is transmitted by Hyalomma ticks and is prevalent in the arid and semi-arid areas in Northern China. The diagnosis is based on clinical symptoms (such as jaundice, severe anemia, anterior shoulder, and posterior bone lymphadenopathy) and the results of blood and lymph node smear. However, in the case of chronic or subclinical infection, the parasitemia level is extremely low and the parasites might not be detected via these methods [19].
Toxoplasma gondii
T. gondii, in the family Apicomplexa, is an obligate intracellular parasite. The majority of warm-blooded animals (from birds to mammals, including human beings) can be infected as intermediate hosts, while only cats can be the definitive hosts. It is generally believed that T. gondii is acquired from the ingestion of water, soil, and/or food that is contaminated indirectly by feline feces. However, the oral infection route cannot explain the infection of herbivores, birds, and wild rodents. These animals would not actively eat raw meat nor come into contact with water and food contaminated from feline feces. Thus, some scholars have suggested that arthropods may be alternative vectors for the transmission of T. gondii. So far, T. gondii has been detected in Dermacentor variabilis, Dermacentor Andersoni, D. reticulatus, I. ricinus, H. Iongicornis, Amblyomma americanum, Amblyomma Cajennense, and Ornithodoros moubata [20]. It has been proved that T. gondii could survive and remain infective in H. Iongicornis for more than 15 days. Nevertheless, it could not be transmitted to hosts during a blood meal [21]. Overall, the presupposition needs more experimental data to confirm.
Toxoplasmosis, a neglected cousin of malaria, is a parasitic zoonosis with approximately a 30% infection rate in the world’s human population. However, the seroprevalence has obviously regional characteristics, which can nearly reach 90% in African populations, whereas 60% in Europe [22]. It is generally believed that acute infections of immunocompetent adults are asymptomatic or subclinical, manifesting as influenza-like symptoms. As for immunocompromised demographic groups, such as patients diagnosed with AIDS or cancer, their brains will be damaged [23]. Epilepsy, insanity, ataxia, schizophrenia, and cranial nerve palsy are some common symptoms. Pregnant women can transmit T. gondii to the fetus vertically, which leads to obstetric diseases for the fetus and newborns, including abortion and serious congenital anomalies such as hydrocephalus, microcephaly, and calcifications [24]. According to the latest sero-epidemiological investigations in China, the seropositivity of T. gondii antibodies in the general population is 5.1% [25]. The distribution of toxoplasmosis is nationwide (Fig. 1), whereby most of the infected people were in contact with cats. Therefore, eating well-cooked meat, drinking boiled water, and managing feline feces are key interventions for reducing the incidence of toxoplasmosis [26].
Tick-Borne Bacteria
Borrelia Burgdorferi Sensu Lato
B. burgdorferi sensu lato species complex, of order Spirochaetaceae and family Spirochaetales, is distributed throughout the Northern hemisphere. At present, a total of 21 species have been identified, of which 3 are associated with different clinical manifestations in afflicted human beings: B. burgdorferi sensu stricto, Borrelia garini, and Borrelia afzelii. Relying on the basic metabolic function of Ixodes ticks, B. burgdorferi could interact with the intestinal and salivary proteins of vector ticks to colonize, survive, and finally exit the ticks successfully [27]. This may be due to evolving stiffer peptidoglycan, as an adaptation to obligate parasitization of vector ticks [28]. Ixodes ticks are primarily responsible for the transmission of B. burgdorferi: I. scapularis mainly transmits the agent on the Eastern coast of the United States, while I. ricinus in Europe, and I. persuletus in Asia [17]. In Northern China, B. burgdorferi is transmitted by I. persuletus. As for Southern China, it is transmitted by Ixodes sinensis and Ixodes granulolatus. However, ticks can only transmit B. burgdorferi, B. garini, and B. afzelii transstadially as opposed to trans-ovarially [29].
Lyme disease is the most common zoonosis caused by B. burgdorferi, of which the incidence peak is in late spring and summer every year (because nymphal ticks are most abundant and active during that time). At present, more than 30 provinces in China have reported cases of Lyme disease (Fig. 2). Acute infection in dogs is characterized by fever, claudication, lymphadenopathy, and multiple arthritis. In addition to the above symptoms, weight loss and laminitis could also be observed in infected horses and cattle. Due to the high invasion capability of B. burgdorferi, the number of human cases is far more than that of any other tick-borne bacteria in Europe, North America, and Asia. Human infection is often characterized by a complicated multisystem illness, including erythema migrans (localized skin inflammation) [30], Bannwarth syndrome, and typical acrodermatitis chronica atrophicans. The skin, joints, heart, and nervous system are often damaged. The diagnosis is based on the standard two-tier testing (STTT) that consists of an enzyme immunoassay (EIA) or a chemiluminescence immunoassay (CIA) as an initial test, followed by Western blotting if the result is positive or equivocal. However, if a patient is in the early phase of Lyme disease, the EIA result may be negative or equivocal. Hence, an alternative test should be considered [31].
As for infected patients, antibiotics, such as penicillin, amoxicillin, ceftriaxone, doxycycline, and azithromycin, should be given as soon as possible. Otherwise, the lesion advanced to an early disseminated stage, and finally reaching the late stage with myocarditis, neuritis, or arthritis. Additionally, Hygromycin A, a compound produced by Streptomyces hygroscopicus, could be selectively taken up by B. burgdorferi and clear the infection in mice [32]. This compound holds the promise of providing a more selective antibiotic for Lyme disease. As for the vaccine, VLA15 is the only Lyme disease vaccine candidate that is reported to undergo phase-3 clinical trials [33]. It targets the outer surface protein A (OspA) of B. burgdorferi, which is one of the most important surface proteins, and induces the bacterium’s ability to leave the tick and infect human beings. Blocking OspA means that the transmission of B. burgdorferi is blocked. Additionally, OspA-based animal vaccines can effectively reduce nymphal infection in white-footed mice (Peromyscus leucopus), which are reservoirs of I. scapularis [33]. Interestingly, a new vaccine targeting the vector ticks instead of the pathogen has also been under development [34]. The vaccine contains 19 distinct mRNA snippets, which can order host cells to produce important tick salivary proteins. In turn, when faced with a tick bite, the immune system will rapidly react causing redness, inflammation, and itchiness around the bite for people to notice and pull the tick off. Within 36 h after the ticks attach, pulling the ticks off could effectively block the transmission of B. burgdorferi.
Spotted Fever Group Rickettsiae
Rickettsia (order: Rickettsiales, family: Rickettsiaceae) is an obligate intracellular Gram-negative bacterium, which is transmitted by arthropods such as ticks, mites, and fleas. At present, a total of 25 pathogenic species have been identified and can be phylogenetically divided into three groups: spotted fever, typhus, and transition groups. The spotted fever group Rickettsiae (SFGR) is one of the emerging tick-borne pathogens identified in mainland China. Through both trans-ovarial and transstadial transmission, Ixodidae ticks could reserve and transmit SFGR, which is distributed geographically, possibly expanding their distribution range through vector ticks [35].
Spotted fever is the general name for clinical diseases caused by SFGR. Different Rickettsia species will lead to various endemic diseases (Table 1). In the United States, reported Rocky Mountain spotted fever (RMSF) cases have dramatically increased tenfold over the past 20 years [36]. Emerging SFGR subspecies have also been discovered. Additionally, several Rickettsia species, which were previously considered non-pathogenic for decades, have been definitively reported to associate with human disease in Italy [37].
In recent years, an increasing number of emerging SFGRs have been reported in China, including Rickettsia parkeri [38], Rickettsia Japonica [39], Rickettsia sp. XY99 [40], Candidatus Rickettsia xinyangensis [77]. Following binding, DVD-121-801, a bispecific antibody, can provide therapeutic protection and become a strong candidate for therapeutic antibody cocktails [78].
In China, **-Ill virus paraphyletic taxa. Mol Phylogenet Evol 169:107411. https://doi.org/10.1016/j.ympev.2022.107411 " href="/article/10.1007/s11686-023-00658-1#ref-CR83" id="ref-link-section-d277691574e2061">83]. In recent years, two novel subtypes of TBEV have been isolated, named Himalayan (Him-TBEV) [84] and Baikalian (Bkl-TBEV) [85] respectively. At present, it has been reported that Eu-TBEV is mainly transmitted by I. ricinus, while Sib-TBEV and FE-TBEV are both transmitted by I. persulcatus. Additionally, D. reticulatus could also transmit the virus [86].
Most TBEV infections in human beings are asymptomatic. However, neurological symptoms, including encephalitis, meningitis, and meningoencephalitis can be observed in one-third of infection cases. The disease caused by TBEV is called tick-borne encephalitis (TBE), which is the most serious tick-borne neurological disease prevalent across the Eurasian continent from Japan to France, even in the United Kingdom [87]. The incidence and mortality rate are dependent on the subtype of the virus. The mortality of Eu-TBEV and Sib-TBEV is about 2%, associated with neurological sequelae and long-term infection. However, the mortality of FE-TBEV is up to 30% [88]. At present, there is no specific drug for TBEV. Therefore, active vaccination is a practical measure to prevent TBEV infection. Two safe and effective vaccines have been approved: FSME-IMMUN® (Pfizer, USA) and Encepur® (GlaxoSmithKline) [89]. The vaccines are generally safe with rare serious adverse events [90].
In China, a total of 3364 TBE cases have been reported from 2007 to 2018 [91]. It is mainly endemic in Northern and Western China (Fig. 3). Most cases involved people living or working in forests. Recently, evidence of TBEV in 2 areas of the United Kingdom attracted our attention [92]. According to the climatic forecasts, TBEV was thought to be incapable of establishing itself in the United Kingdom, as their vector ticks could not overcome the temperature limit. However, they challenged the climate, which was speculated to be carried by migratory birds [93]. This suggested that the contribution of migratory birds for TBE is substantial, particularly for medium- and long-distance dispersal. Hence, the threats might be potentially extensively underestimated.
Phenuiviridae: Severe Fever with Thrombocytopenia Syndrome Virus (Dabie bandavirus)
In 2009, researchers have detected a novel virus in Henan, Hubei, Shandong, Anhui, Jiangsu, and Liaoning provinces in China [52]. The virus could infect human beings and cause a febrile disease called severe fever with thrombocytopenia syndrome (SFTS). The clinical manifestations mainly include fever, thrombocytopenia, and leukopenia syndromes. Therefore, the virus was initially named severe fever with thrombocytopenia syndrome virus (SFTSV) and classified into the genus Phlebovirus and family Phenuiviridae. However, it was later renamed by the International Committee on Taxonomy of Viruses (ICTV) in 2019. This novel virus was finally denominated Dabie bandavirus and reclassified into the genus Bandavirus, family Phenuiviridae, and order Bunyavirales.
H. longicornis and I. sinensis have been proven to transovarially and transstadially transmit Dabie bandavirus [93]. While D. silvarum could transmit the virus transovarial rather than transstadial [94]. Additionally, Haemaphysalis flava, R. microplus, Amblyomma testudinarium, D. nuttalli, H. asiaticum kozlovi, H. concinna, I. persulcatus, and Ixodes nipponensis can harbor the virus [95]. Distributed in the Asia Pacific region, H. longicornis is the primary vector for Dabie bandavirus. However, recently, the United States reported the invasion of H. longicornis with increasing numbers infesting sheep [96], in addition to human beings bitten as well [97]. Migratory birds, as the natural hosts of H. longicornis have been suspected to indirectly expand the distribution of H. longicornis by carrying ticks during long-distance migration. There is evidence supporting the relationship between H. longicornis and the flyways of migratory birds [98]. However, according to the ecological niche modeling, H. longicornis have also been predicted to threaten more extensive regions, including Europe, South America, and Africa [1]. However, their vector competence has not been evaluated.
Due to the complexity of eco-social systems and the interconnectedness of pork industries around the world, interrupting the global spread of ASFV is quite difficult. The present strain in China was genotype I ASFV, which shared high similarity with NH/P68 and OURT88/3 [134], human beings, animals, and the environment are like the 3 arms of a triangle, whereby their relationship and interaction should be tackled. This highlighted the synergistic benefit of closer cooperation. Therefore, 3 vaccine frameworks need to be developed. Framework I vaccines are intended for the protection of economically valuable animals. Framework II vaccines are used to protect domestic animals and human beings. Finally, framework III vaccines are applicable for the protection of wild animals. This relies on further basic research of tick-borne pathogens' epitopes and therapeutic antibodies. With ready-made vaccines and abundant basic research, the prevention and control of emerging and re-emerging tick-borne pathogens will be rapid and accurate.
However, relying solely on vaccines is not enough. The comprehensive prevention and control of tick-borne pathogens are also dependent on individual and collective protection, vector control, comprehensive surveillance, accurate diagnosis, and symptomatic treatment. So far, 124 tick species and 103 tick-borne pathogens have been reported in China. A total of 29 tick-borne pathogens were associated with human infections, and the number is still increasing. This further highlighted the importance of assessing the transmission risk of vector ticks. Additionally, according to the assessment of vector ticks and tick-borne pathogens’ distributions [1], the suitable habitats were 14–476% larger than reported areas, indicating that the detection is seriously insufficient. At last, the possible role of migratory birds in China should also be identified to realize the comprehensive prevention and control of ticks and tick-borne pathogens.
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Funding
This work was supported by the Key Research and Development Project of Shaanxi Province (2020NY-017), the Animal Husbandry Special fund of Department of Agriculture and Rural Affairs of Shaanxi Province (XN14) and the State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences (SKLVEB2019KFKT007).
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YL: Conceptualization, Investigation, Visualization, Writing (original draft). JG: Data curation, Investigation, Resources. DZ: Writing (original draft). LM: Investigation. CY: Resources. MS: Writing (review & editing). GL: Writing (review & editing), Project administration, Funding acquisition. QL: Conceptualization, Resources, Writing (review & editing), Supervision, Project administration, Funding acquisition.
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Luan, Y., Gou, J., Zhong, D. et al. The Tick-Borne Pathogens: An Overview of China’s Situation. Acta Parasit. 68, 1–20 (2023). https://doi.org/10.1007/s11686-023-00658-1
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DOI: https://doi.org/10.1007/s11686-023-00658-1