Ticks and Tick-borne Diseases 5 (2014) 607–619
Contents lists available at ScienceDirect
Ticks and Tick-borne Diseases
journal homepage: www.elsevier.com/locate/ttbdis
Review Article
Monitoring human tick-borne disease risk and tick bite exposure in
Europe: Available tools and promising future methods
Vinh Vu Hai a,b , Lionel Almeras a,b , Cristina Socolovschi a , Didier Raoult a ,
Philippe Parola a,∗∗ , Frédéric Pagès a,c,∗
a
Aix-Marseille Université, Unité de Recherche en Maladies Infectieuses et Tropicales Emergentes (URMITE), UM 63, CNRS 7278, IRD 198, Inserm 1095, WHO
Collaborative Center for Rickettsioses and Other Arthropod-Borne Bacterial Diseases, Faculté de Médecine, 27 Boulevard Jean Moulin, 13385 Marseille
Cedex 5, France
b
Institut de Recherche Biomédicale des Armées (IRBA), Antenne Marseille, Unité de Parasitologie, URMITE UMR 6236, GSBdD de Marseille Aubagne, 111
Avenue de la Corse BP 40026, 13568 Marseille Cedex 02, France
c
CIRE/ARS Océan Indien, 2 bis Avenue Georges Brassens CS 60050, 97408 Saint Denis Cedex 9, Reunion
a r t i c l e
i n f o
Article history:
Received 23 July 2013
Received in revised form 28 July 2014
Accepted 28 July 2014
Available online 12 August 2014
Keywords:
Tick-borne diseases
Salivary antigens
Exposure markers
Europe
Monitoring tools
a b s t r a c t
Ticks are the main vector for infectious disease pathogens in both humans and animals, and tick-borne
diseases are currently spreading throughout Europe. Various surveillance methods have been developed
to estimate the burden and risk of tick-borne diseases and host exposure to tick bites. The ultimate aims
of these approaches are to determine the risk level of a tick-borne disease in a given area, determine its
health priority, identify the at-risk population and propose specific countermeasures or complementary
studies as needed. The purpose of this review is to present the current methods for monitoring the
circulation of tick-borne diseases and to highlight the use of salivary antigens as original and recently
developed serological tools that could be useful for tick bite risk assessment and could improve the
current surveillance methods.
© 2014 Elsevier GmbH. All rights reserved.
Contents
Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Tick-borne diseases in Europe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Estimating the burden and risk of tick-borne diseases in Europe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
The human approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Epidemiological surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Reports and literature analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Specific surveys . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
The animal approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Animals as sentinels for pathogen circulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Animals as sentinels for tick distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Limitations of the animal approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
The entomological approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
The modeling/forecasting approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
“The host vector bite exposure approach” of using the antigenic properties of tick salivary proteins: estimation of host/vector contact
by serology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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∗ Corresponding author at: Aix-Marseille Université, Unité de Recherche en Maladies Infectieuses et Tropicales Emergentes (URMITE), UM 63, CNRS 7278, IRD 198, Inserm
1095, WHO Collaborative Center for Rickettsioses and Other Arthropod-Borne Bacterial Diseases, Faculté de Médecine, 27 Boulevard Jean Moulin, 13385 Marseille Cedex 5,
France. Tel.: +33 491 32 43 75; fax: +33 491 83 03 90.
∗∗ Corresponding author. Tel.: +33 491 32 43 75; fax: +33 491 83 03 90.
E-mail addresses: [email protected] (P. Parola), frederic [email protected] (F. Pagès).
http://dx.doi.org/10.1016/j.ttbdis.2014.07.022
1877-959X/© 2014 Elsevier GmbH. All rights reserved.
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V. Vu Hai et al. / Ticks and Tick-borne Diseases 5 (2014) 607–619
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Authors’ contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Background
Ticks are currently the second most important vectors for
pathogens that cause diseases in humans and animals after
mosquitoes (Beugnet and Marie, 2009; Raoult and Parola, 2007).
These obligate hematophagous arthropods parasitize every class of
vertebrate, with the exception of fishes, in almost every region of
the world and can transmit pathogens, including bacteria, viruses
and protozoa, to mammalian hosts during blood meals (Parola and
Raoult, 2001). The emergence of new tick-borne diseases (TBDs)
and the re-emergence of existing ones are public health concerns
for all continents (Hubalek and Rudolf, 2012; Oteo and Portillo,
2012; Socolovschi et al., 2009). Some TBDs, such as tick-borne
encephalitis (TBE), are considered public health priorities, and there
are benefits from specific prevention programs such as vaccination, education and public information (Beugnet and Marie, 2009;
Raoult and Parola, 2007). For the efficient transmission of tickborne pathogens in a geographic area, the following five elements
should be present and should interact: the pathogen, a natural
reservoir, a natural or accidental host, a vector and a suitable
biotope for vector development. Modifying even one element acting on the complex host-vector-pathogen equilibrium can change
the epidemiology of TBDs in an area. For example, the introduction of a new pathogen or the mutational adaptation of an old
pathogen to its vector or host (Simon et al., 2008); the introduction of a new vector; the proliferation of suitable hosts (e.g., deer
for Ixodes ricinus) (Medlock et al., 2013); human behavior modification (e.g., mushroom collection, forestry activities); changing
landscapes in wild areas; climatic changes; and tick control programs can all modify the epidemiology of TBDs in an area (Daniel
et al., 2009; Estrada-Pena et al., 2010, 2012a; Godfrey and Randolph,
2011; Halos et al., 2010; Laurenson et al., 2007; Stefanoff et al.,
2012). Thus, an alteration in the aforementioned factors can lead
to either the (re-)emergence or the reduction of TBDs in an area.
Additionally, weather and climatic changes have a direct impact
on the geographic distribution and behavior of tick species (Parola
et al., 2008). Recent studies have reported the colonization of new
areas by tick species such as Rhipicephalus sanguineus, Dermacentor
reticulatus, and I. ricinus, the main vectors for the causative agents
of Mediterranean spotted fever (MSF), scalp eschar and neck lymphadenopathy after a tick bite (SENLAT), and Lyme borreliosis (LB)
plus TBE, respectively (Allegue et al., 2009; Rizzoli et al., 2011;
Rovery and Raoult, 2008).
Various surveillance methods have been developed to assess
TBD risk. The most current methods focus on the following:
(i) human health (i.e., the human approach: disease incidence
and human exposure in general or specific populations), (ii) animal health (i.e., the animal approach: disease, natural infection
and animal exposure), (iii) vector characteristics (i.e., the entomological approach: tick distribution and infection), and (iv)
modeling/forecasting (i.e., the determination of suitable areas for
tick-borne disease transmission, including climatic, geographic,
economic, human, animal and vector data). The final aim of all of
these approaches is to determine the level of TBD risk in an area,
determine its health priority, identify the risk for populations and
propose, if necessary, specific countermeasures or complementary
studies. The purpose of this review is to present the current methods used to monitor TBD risk and to highlight novel tools that are
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useful for assessing a host’s tick bite and could improve or complete
the current standard surveillance methods.
Tick-borne diseases in Europe
Despite improvements in prevention, TBD cases are still being
identified in new locations within endemic regions and in European countries where human cases of TBD had not been previously
identified (Beugnet and Marie, 2009; Dobler, 2010; Foley and Nieto,
2010; Hubalek and Rudolf, 2012; Raoult and Parola, 2007; Ruzek
et al., 2010; Socolovschi et al., 2009). Various tick genera have been
found in Europe, and the most prevalent ones with medical or
veterinary importance have been described, such as Ixodes spp.,
Rhipicephalus spp., Dermacentor spp., Hyalomma spp., and Haemaphysalis spp. (Heyman et al., 2010). These ticks are vectors for
several causative agents of TBD, among which the most frequently
encountered are LB, MSF, TBE, Crimean-Congo hemorrhagic fever
(CCHF), SENLAT and other rickettsioses (Bitam and Raoult, 2009).
The diversity and rapid evolution in the distribution and density of
tick species and their representative TBDs in Europe have caused
many difficulties for the optimal management of TBD risk. Thus,
monitoring TBD risk is essential throughout Europe.
LB is a multisystem inflammatory disorder caused by spirochetes of Borrelia burgdorferi sensu lato (s.l.). At least eight species
of the Borrelia burgdorferi sensu lato (s.l.) group (B. afzelii, B.
bavariensis, B. burgdorferi sensu stricto (s.s.), B. garinii, B. miyamotoi, B. recurrentis, B. spielmanii, and B. valaisiana), which are mainly
transmitted by I. ricinus, are currently known to occur in Europe
(Hulinska et al., 2009; Platonov et al., 2011; Rebaudet and Parola,
2006; Ryffel et al., 1999; Stanek and Reiter, 2011; Stanek et al.,
2012). Despite improvements in its prevention, diagnosis and
treatment, LB is still the most common ixodid tick-borne human
disease in the world (Rizzoli et al., 2011). Because LB cases have
been encountered in previously disease-free areas and because an
increasing number of severe forms have been reported in different
parts of Europe, an increase in the LB burden in Europe is expected
in the coming years (Bartosik et al., 2011; Hubalek, 2009; Palecek
et al., 2010).
MSF, also known as “boutonneuse fever”, is endemic to the
Mediterranean area, including southern Europe and northern Africa
(Parola et al., 2009b). The causative agent of this disease is Rickettsia
conorii conorii, which is transmitted by the brown dog tick R. sanguineus (Parola and Raoult, 2001). Recently, MSF cases have been
reported in new locations within the endemic region and in other
previously disease-free central and northern European countries.
Moreover, an increasing incidence within endemic regions has been
noted (Parola et al., 2013), and fatal and severe cases are most often
reported (Amaro et al., 2003; Papa et al., 2010).
TBE is caused by a Flavivirus (TBE virus) that was first isolated
in Russia in 1938 (Chumakov and Seitlenok, 1940). This virus is
transmitted by ticks of the Ixodes genus, primarily I. ricinus, in
western and central Europe (Hubalek and Rudolf, 2012). Every year,
several thousand cases of TBE are recorded in the Czech Republic,
Slovenia, Estonia, Lithuania and Latvia (Hubalek and Rudolf, 2012),
and the burden of the disease is increasing due to extension of
the affected areas and the circulation of TBE viruses (Briggs et al.,
2011; Fomsgaard et al., 2009; Kupca et al., 2010; Zimmermann,
2005). There has been much speculation that climate change is a
V. Vu Hai et al. / Ticks and Tick-borne Diseases 5 (2014) 607–619
major factor in the changing epidemiology of TBE, but Korenberg
(Korenberg, 2009) concluded that in Russia, human behavior and
the virus circulation rates in ticks are more important. In a series
of papers, a relatively minor role for climate in the change in TBE
epidemiology was also suggested for central and eastern Europe,
as summarized by Randolph (Randolph, 2010).
CCHF is caused by the CCHF virus, a Nairovirus that is transmitted by Hyalomma ticks, primarily H. marginatum in Europe.
The disease is transmitted mostly via infective tick bites but also
through the shearing of sheep with attached infectious ticks, the
slaughter of infected animals (livestock-to-human transmission)
and direct contact with human patients (nosocomial human-tohuman transmission) (Hoogstraal, 1979). Several recent outbreaks
have been recorded in southeastern Europe, including Bulgaria,
Kosovo, southern Russia, Albania and Turkey (Hubalek and Rudolf,
2012). The first case diagnosed in Greece was recorded in 2008
(Papa et al., 2008). The risk of a CCHF extension into western and
southern Europe and the emergent impact of this disease on public
health are serious concerns (Estrada-Pena et al., 2012b; Maltezou
and Papa, 2010; Mertens et al., 2013).
SENLAT syndrome, which is also known as Dermacentor-borne
necrotic erythema and lymphadenopathy (DEBONEL) or tick-borne
lymphadenopathy (TIBOLA), is defined as the association of a tick
bite with an inoculation eschar on the scalp together with cervical lymphadenopathies (Angelakis et al., 2010; Raoult et al., 2002).
The most important causative agents of SENLAT are R. slovaca and
R. raoultii, and they are transmitted by D. marginatus and D. reticulatus ticks (Ibarra et al., 2006; Mediannikov et al., 2008). Recently,
R. massiliae, Candidatus R. rioja, Bartonella henselae, and Francisella
tularensis have been detected in patients with the same clinical
symptoms (Angelakis et al., 2010; Oteo et al., 2004; Perez-Perez
et al., 2010). The first verified human case was described in France
in 1997 (Raoult et al., 1997). Since then, human cases have been
reported in other European countries (Parola et al., 2009a).
Anaplasmosis, tularemia, and babesiosis pose additional threats
to both animal and human populations (Beugnet and Marie, 2009;
Edouard et al., 2012; Foley and Nieto, 2010). Anaplasmosis, caused
by Anaplasma phagocytophilum, is transmitted by I. ricinus, I. persulcatus, and possibly R. sanguineus and R. bursa ticks in Europe
(Berzina et al., 2013; Masala et al., 2012). Recent studies have
reported an increase in human anaplasmosis cases in Europe,
including fatal forms (de la Fuente et al., 2005; Edouard et al., 2012;
Mastrandrea et al., 2006; Pavelites and Prahlow, 2011; Sekeyova
et al., 2012). Tularemia, which is caused by Francisella tularensis, can be transmitted by ticks (i.e., I. ricinus, D. reticulatus, and
D. marginatum in Europe), biting flies, water exposure, food, and
aerosols (Foley and Nieto, 2010; Socolovschi et al., 2009). Babesiosis
is mainly caused by Babesia divergens in Europe (Hildebrandt et al.,
2013), which is transmitted by I. ricinus. Bartonellosis (which is
caused by Bartonella species, e.g., B. quintana and B. henselae, which
are transmitted by D. reticulatus and Ixodes spp.) and Q fever (which
is caused by Coxiella burnetii and has been detected in several tick
species) (Socolovschi et al., 2009) also occur in Europe. Although a
role for ticks in human infection is suspected for bartonellosis, the
transmission of Coxiella burnetti by ticks to humans is anecdotal
and has no significant epidemiologic impact.
Other emerging TBDs have recently been reported, such as
Israeli spotted fever, lymphangitis-associated rickettsiosis (LAR),
and other recently discovered rickettsial infections. Some of these
have been described as human pathogens (i.e., R. aeschlimannii detected in H. marginatum marginatum and H. marginatum
rufipes ticks in Europe and R. monacensis transmitted by I. ricinus)
(Fernandez-Soto et al., 2003; Hornok et al., 2013; Jado et al., 2007;
Madeddu et al., 2012; Rumer et al., 2011; Socolovschi et al., 2009),
and others are currently of unknown pathogenicity (Parola et al.,
2013). New pathogens such as Candidatus Neoehrlichia mikurensis
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are emerging in Europe (Jahfari et al., 2012; Khasnatinov et al.,
2009; Richter and Matuschka, 2012). The occurrence of TBD importation has also increased in parallel with increased international
travel (Socolovschi et al., 2009). It is difficult to determine whether
the (re-)emergence of these TBDs in Europe is attributable to an
increase in pathogen circulation, enhanced detection of clinical
cases either through the development of biological tests or physician education, or modifications in human behavior that favor
host/tick contacts. These changes are most likely the result of a mix
of these different factors. Hence, the surveillance of TBD evolution
in Europe is a high priority. Nevertheless, although many effective
entomological and epidemiological tools have been established, the
optimal management of TBDs remains difficult because of the lack
of a simple and effective approach for identifying the populations at
risk. The various approaches used at present are described below.
Estimating the burden and risk of tick-borne diseases in
Europe
The human approach
Epidemiological surveillance
One way to understand the dynamics of TBDs in Europe is to
systematically record human cases. This goal can be achieved by
implementing a specific surveillance system based on declarations
from general practitioners and/or infectious disease specialists. The
absence of mandatory surveillance for most TBDs at the European level is most likely related to the great heterogeneity of the
disease burden and to the large area of distribution in Europe.
Before 2012, only two TBDs were under mandatory surveillance
by the European Center for Disease Prevention and Control (ECDC),
namely tularemia and CCHF. Until October 2012, TBE was a notifiable disease in only fourteen European Union (EU) countries, and
because specific reporting does not exist in other endemic European countries, the results of specific focused studies and reports
from local surveillance systems were all that was available in many
areas (Kaiser, 2012; Kunze, 2012). The ECDC gathered the existing
information on TBE occurrence to obtain a better understanding of
the current magnitude of TBE in EU and European Free Trade Association (EFTA) countries (European Center for Disease Prevention
and Control, 2012), and subsequently, TBE was integrated into the
mandatory surveillance of TBDs in 2012 (Amato-Gauci and Zeller,
2012). Furthermore, most tick-borne diseases case definitions are
not standardized at the European level. This is due in part to heterogeneity in epidemiological conditions but also to the differential
availability of diagnostic tests among the countries and to different assessments of their relevance by national health authorities
according to disease prevalence. This situation contributes to the
lack of robust data for many tick-borne diseases at the European
level (Tables 1 and 2).
Reports and literature analysis
When the epidemiological surveillance of TBDs is not efficient
because of a low number of cases or a lack of routine tools in a country, TBD cases can be recorded retrospectively using bibliographic
analyses, hospital databases, and questionnaire surveys. However,
this approach cannot accurately estimate the burden of TBDs
because mild forms can be misdiagnosed and because these diseases are thought to be absent or very uncommon such that medical
practitioners may not be able to identify them. Without specific
surveillance data, an increase in the number of cases observed in the
literature could merely reflect an increase in medical practitioner
interest or an improvement in relevant laboratory facilities instead
of an increase in the burden of the disease (Bartosik et al., 2011;
Hubalek, 2009). Similarly, the apparent increase in severe forms of
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V. Vu Hai et al. / Ticks and Tick-borne Diseases 5 (2014) 607–619
Table 1
Emergence/re-emergence of tick-borne diseases in Europe.
Tick-borne disease
Pathogenic agent
Vector(s)
Reservoirs/hosts
Emergent/re-emergent
data
References
Lyme borreliosis
Borrelia burgdorferi sensu
lato
Ixodes ricinus
Small mammals: mice,
voles, and birds
- New endemic areas
throughout Europe
- Increase in severe and
fatal forms
- New possible
reservoirs: lizards,
badgers, and hedgehogs
Hubalek (2009), Palecek
et al. (2010), Rizzoli et al.
(2011), Skuballa et al.
(2012) and Stanek et al.
(2012)
Mediterranean
spotted fever
Rickettsia conorii conorii
Rhipicephalus sanguineus
Dogs and hedgehogs
- Newly identified
locations within endemic
regions
- Northward expansion
- Increase in MSF
incidence
- Increase in severe and
fatal forms
Ciceroni et al. (2006), De
et al. (2003), Papa et al.
(2010), Parola et al. (2013),
Parola and Raoult (2001),
Parola et al. (2009b), Raoult
et al. (1983) and
Socolovschi et al. (2009)
SENLAT
R. slovaca, R. raoultii, R.
massiliae, Candidatus R.
rioja, Bartonella henselae,
Francisella tularensis,
Coxiella burnetii and B.
burgdorferi
Dermacentor marginatus, D.
reticulatus and I. ricinus
Small animals: sheep,
goats and bullfighting
cattle
-Cases reported in several
European countries,
including France,
Slovakia, Spain, Bulgaria,
Poland, Germany and
Italy
Chmielewski et al. (2011),
Ibarra et al. (2006),
Komitova et al. (2003),
Mediannikov et al. (2008),
Oteo et al. (2004), Raoult
et al. (1997), Rieg et al.
(2011), Sekeyova et al.
(2012) and Torina et al.
(2012)
Israeli spotted
fever
R. conorii israelensis
R. sanguineus
Dogs
- Emergent disease in
humans, with cases
reported in Portugal and
Italy
- Fatal cases recently
reported
Bechah et al. (2011), Boillat
et al. (2008), Chai et al.
(2008), Giammanco et al.
(2005) and Sousa et al.
(2008)
LAR
R. sibirica mongolitimonae
R. pusillus, R. bursa, and
Hyalomma asiaticum
excavatum
Migrant birds
Emergent disease in
humans, with cases
reported in France,
Greece, Portugal, Spain,
and Egypt
Aguirrebengoa et al.
(2008), De et al. (2006),
Edouard et al. (2013),
Psaroulaki et al. (2005) and
Ramos et al. (2013)
Tick-borne
encephalitis
Tick-borne encephalitis
virus
Ixodes ricinus
Small rodents
Increase in burden
caused by the extension
of affected areas and the
circulation of virulent
strains
Briggs et al. (2011),
Fomsgaard et al. (2009),
Hubalek and Rudolf (2012),
Kupca et al. (2010) and
Zimmermann (2005)
Crimean-Congo
hemorrhagic
fever
Crimean-Congo
hemorrhagic fever virus
Hyalomma marginatum
Small mammals: hares,
hedgehogs, and rats
- New extension in
western and southern
Europe
- Emergent impact on
public health
Chumakov (1974),
Estrada-Pena et al. (2012b),
Maltezou and Papa (2010),
Mertens et al. (2013), Papa
et al. (2008)
Anaplasmosis
Anaplasma
phagocytophilum
I. ricinus, I. persulcatus, R.
sanguineus, and R. bursa
Rodents, water voles,
hedgehogs, boars and
hares
- Increase in human cases
- Emergence of new
forms (e.g., congenital
infection) and fatal cases
de la Fuente et al. (2005),
Edouard et al. (2012),
Koebel et al. (2012),
Mastrandrea et al. (2006),
Pavelites and Prahlow
(2011) and Sekeyova et al.
(2012)
Babesiosis
Babesia divergens, B.
microti, B. venatorum
ricinus
Mammalian hosts,
mainly rodents, cattle,
terrestrial mammals,
and primates
- Confirmed cases
recently reported in
several European
countries, namely
Austria, Czech Republic,
Finland, Germany, Italy,
Montenegro, Portugal,
Poland and Switzerland
- Emergence of new
parasite strains (i.e., B.
venatorum EU1-3)
Haapasalo et al. (2010),
Hildebrandt et al. (2013),
Homer et al. (2000) and
Meer-Scherrer et al. (2004)
Undefined name
Candidatus Neoehrlichia
mikurensis
I. ricinus
Rodents, dogs, and
bank voles
New agent pathogen,
cases reported in Sweden,
Switzerland, and
Germany
Fertner et al. (2012),
Maurer et al. (2013), Parola
et al. (2013) and von
Loewenich et al. (2010)
V. Vu Hai et al. / Ticks and Tick-borne Diseases 5 (2014) 607–619
611
Table 2
Current tools for estimating the burden and risk of tick-borne diseases in Europe.
Monitoring tools
Details
Advantages
Disadvantages
Human approach
- Epidemiological surveillance:
Tularemia, Crimean-Congo
hemorrhagic fever, and tick-borne
encephalitis
- Reports and literature analysis:
retrospective case records in
bibliographic analyses and hospital
databases, questionnaire surveys
- Specific surveys: serological
investigation and molecular methods
Directly survey tick-borne diseases in
humans: incidence, trends
Homogeneity of the reports:
definitions of cases, specific data
collected
Easy to perform, low cost
Permitting the direct estimation of the
burden/infection rate of specific
populations at a specific moment
- Possible surveillance bias during the
first years of implementation
- Cannot clearly estimate the burden of
tick-borne diseases
- Bias in reporting that could over- or
underestimate the burden and trends
of a disease
- Expensive and difficult for routine use
- Results cannot be easily extended to
general populations
Animal approach
- Animals as sentinels for pathogen
circulation
- Animals as sentinels for tick distribution
Allows the risk of tick-borne diseases
in humans to be estimated by
monitoring them in animal hosts
Allows the tick distribution range to be
estimated
- The relation between animal host
abundance and the risk to humans is
not linear, is dependent on the animal
species, and varies over time
- Needs to be repeated several times
- Results only available for limited
areas
Entomological approach
Assessment of tick distribution in
relation to biotope, landscape, climate,
altitude and urbanization
Assessment of pathogen circulation
and measurement of their infection
rates in questing ticks
Describes the extension of the main
tick-borne disease vectors
Characterizes potential risk areas and
seasons
Allows the pathogen circulation in a
given area and emergent pathogens in
new areas to be evaluated
- Expensive
- Results available only for limited
areas
- Sensitivity questionable for some
tick-borne diseases such as tick-borne
encephalitis
Modeling/forecasting approach
Mathematical/forecasting models
using entomological data, climatic
data, human behavior, socio-economic
factors, animal abundance and
distribution, satellite data, geographic
information systems
Indirectly predicts the areas and
periods favorable for tick presence and
abundance and, thus, the risk of
tick-borne diseases in humans
Allows the modeling of risk or
distribution for large areas
Predicts the impact of environmental
modifications
- Difficult to realize because many
factors could influence the model
- Quality of results depend on the
quality of several data sources (e.g.,
environmental, socio-economic,
human behavior)
MSF, LB or TBE in some countries could be explained by the circulation of highly pathogenic strains leading to an increased occurrence
of severe cases rather than a general global increase in the number of cases (Khasnatinov et al., 2009; Kupca et al., 2010; Rovery
and Raoult, 2008). Therefore, conclusions regarding an apparent
increase or decrease in pathogenic diseases using case records must
be used with care.
Specific surveys
Exposure to tick bites can be estimated in a population via
self-administered questionnaires or by questioning general practitioners, occupational medicine practitioners or emergency services
personnel (Bursali et al., 2010; Jaenson et al., 2012b; Papa et al.,
2011). Studies have also been conducted to assess the risk of
subclinical (seroconversion) and clinical infections after a tick
bite (Fryland et al., 2011; Grzeszczuk et al., 2006; Richter and
Matuschka, 2012). Serological investigations of the general population or healthy groups such as blood donors can be conducted
to assess the circulation of tick-borne pathogens (Bazovska et al.,
2005; Lledo et al., 2004, 2006). Another method is to conduct specific limited prospective studies to determine the role of tick-borne
pathogens in unexplained cases of fever or encephalitis (Arnez et al.,
2003). Nevertheless, the distribution of TBDs is clearly linked to
tick ecology and to specific biotopes. Thus, the implementation
of a prospective study in a general population can be unsuccessful or very expensive because most subjects are not commonly
exposed to tick bites. Therefore, certain specific populations should
be used as sentinels to detect the emergence of new tick-borne
pathogens before their diffusion into the general population (Cetin
et al., 2006; Cisak et al., 2005; Kaya et al., 2008; Pancewicz et al.,
2011; Zwolinski et al., 2004). This strategy has primarily been used
to survey exposed populations and conduct serological investigations to assess contact with tick-borne pathogens. Nevertheless,
because the early and safe removal of ticks minimizes the risk
of pathogen transmission (Due et al., 2013), these data cannot be
extended to the general population because exposed populations
have a higher level of knowledge about TBDs and know how to
protect themselves against ticks by safely removing them. Hence,
knowledgeable populations have a lower risk of TBD transmission
(Bartosik et al., 2008). Similarly, general and occupational practitioners that serve exposed people are more wary of TBDs and may
have a convenient supply of antibiotics for minimizing the number
of clinical cases. However, physicians with easy access to serological testing could attribute the current symptoms of an acute fever
episode to a serological scar from a previous tick-borne infection.
These sentinel populations are predominantly composed of people working, living or engaging in recreational activities in rural
areas. Because ticks and infected ticks are also present in urban
and suburban areas, new at-risk populations must be identified,
and new sentinel populations should be proposed (Reis et al., 2011;
Schicht et al., 2011). In urban areas, the prevalence and incidence
of TBDs could be monitored in homeless people, and the serological testing of pets or wildlife in those areas has been proposed
as a means of assessing the circulation of tick-borne pathogens.
Ticks collected from patients or sentinel population members
could simultaneously be tested for multiple pathogens. By revealing whether ticks are mono- or multiple-pathogen vectors, this
approach could also help clarify whether multi-infections are
caused by high exposure to mono-infected ticks or by single bites
from multi-pathogen-infected ticks. This strategy could reveal the
co-occurrence of two TBDs in the same patient, as already described
(Kalinova et al., 2009). However, in endemic areas or in intensively
exposed populations, this approach is limited by the fact that ticks
collected on a patient may have been infected by that patient, so
the findings of such analyses will not reflect the current exposure
of people in an area but only the past exposure of the patients.
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The animal approach
Animals as sentinels for pathogen circulation
Because TBDs are zoonotic diseases, another way to evaluate
the human TBD risk is to monitor the circulation of pathogens in
wildlife, pets or cattle in the different landscapes affected by human
activities. Seroprevalence studies employing serological tools and
pathogen carriage assessment by molecular methods have been
conducted in most parts of Europe in rodents, pets, cattle, birds and
zoo animals (Achazi et al., 2011; Alexandre et al., 2011; Hapunik
et al., 2011; Ica et al., 2007; Kjelland et al., 2010; Knap et al., 2012;
Palomar et al., 2012; Smith et al., 2012; Stoebel et al., 2003). These
tools have contributed to knowledge about TBD circulation and
the emergence/re-emergence of TBD epidemics, thereby improving the estimates of human TBD risk (Beugnet and Marie, 2009).
Additionally, the level of TBD transmission risk was found to be positively correlated with the wild animal population density (Kuehn,
2013). Because tick host population manipulation could influence
tick density, control measures for host populations such as roe deer
and small rodents have helped decrease both tick density and the
human TBD risk in the UK (Gilbert et al., 2012; Hoen et al., 2009;
Rosa and Pugliese, 2007). Serological studies (e.g., TBE, LB) have
helped identify natural reservoir hosts and elucidated the role of
wildlife in the diffusion of pathogens across Europe and the role of
pathogenic strains (Dubska et al., 2009). High R. conorii seroprevalence in pets has been linked closely to a higher TBD risk in humans
(Mannelli et al., 2003).
Animals as sentinels for tick distribution
The use of sentinel animals has also been demonstrated as
a convincing method for describing the distribution and abundance of ticks (Pavlidou et al., 2008). These surveys have helped
assess the extension of tick species, determine their abundance
in selected areas, and determine suitable areas for TBD transmission. The identification of pathogens in feeding ticks that were
removed from animals has also helped assess the diffusion of
pathogens and therefore also the human TBD risk after a tick
bite (Silaghi et al., 2012; Trotta et al., 2012). Nevertheless, infection rates in adult ticks should be used with caution because
co-feeding or feeding on a viremic or bacteremic animal can infect
adult ticks. However, in some cases, these ticks cannot transmit pathogens into new hosts, particularly pathogens without
transovarial transmission. Thus, the transmission risk will be overestimated.
Limitations of the animal approach
The relationship between host abundance (natural variations,
creation of exclosures) and the risk to humans is not linear, and
multiple factors should be considered. In Sweden, it has been suggested that an increase in the I. ricinus population resulted from
an increase in the deer population and that subsequent reductions in deer numbers forced immature ticks to find alternative
hosts (such as rodents) that were infected with TBE viruses; these
two phenomena could thus be responsible for the extension of the
TBE range (Jaenson et al., 2012a). Several years of study in a specific biotope are necessary to understand these relationships, the
dynamics of host and tick abundance and their respective infections, and the situation in a geographical area can vary over the
years. For example, the introduction of an exotic species more
suitable as a pathogen reservoir than the endemic species (i.e.,
Siberian chipmunks as reservoirs of Lyme disease in France) can
modify the epidemiology of TBD in an area (Vourc’h et al., 2007).
Similarly, the introduction of different B. burgdorferi strains by
migrating birds can also modify the features of LB (Hasle et al.,
2011). Thus, to improve the value of animal approaches, studies
must be repeated at several time points to obtain reliable data. In
the same way, the interpretation of all serological test results is
complicated by the fact that the duration, magnitude and specificity of antibody responses vary according to the sentinel species
and to the pathogen.
The entomological approach
Entomological studies are conducted in most European
countries to assess tick distribution ranges in relation to biotopes,
landscapes, climates, altitudes and urbanization (Agoulon et al.,
2012; Barandika et al., 2010; Jameson and Medlock, 2011). The collection of questing ticks has provided descriptions of the spread
of primary TBD vectors and helped characterize their suitable
biotopes, thereby identifying potentially risky areas and seasons
(Nazzi et al., 2010). However, entomological studies of the main
TBD vectors (i.e., R. sanguineus, D. reticulatus, and I. ricinus) in
western and central Europe have highlighted changes in vector
distribution areas, which have new longitudinal and altitudinal
limits (Danielova et al., 2006; Jore et al., 2011; Szell et al., 2006;
Zygner et al., 2009). These ticks have been described not only in new
regions but also in new biotopes. Various explanations have been
proposed, including global warming, the impact of land occupation,
and a role for wild fauna in tick dispersion (Medlock et al., 2013).
In recent years, the Vbornet project from the ECDC has mapped
I. ricinus, I. persulcatus, H. marginatum and D. reticulatus tick distributions based on published historical data, and the work has
been confirmed by experts from the countries that participated
in this monitoring effort (Medlock et al., 2013). In addition, tick
abundance can vary from year to year according to climatic conditions; therefore, studies must be conducted at different periods
during successive years. Moreover, microclimatic conditions are
also important, and different biotopes in the same area must be
studied (Boyard et al., 2007).
The identification of pathogens in questing ticks and measurement of their infection rates has also been widely used to assess
the risk of infection after a tick bite for established and emerging
pathogens (Beytout et al., 2007; Bonnet et al., 2013; Cotté et al.,
2010; Franke et al., 2011; Jahfari et al., 2012; Reis et al., 2011; Rene
et al., 2012; Silaghi et al., 2011; Torina et al., 2010). This information
should provide an outline of pathogen circulation in a given zone
and allow for the detection of new pathogens in new areas (Reis
et al., 2011). However, the sensitivity of this strategy for assessing
the human TBD risk is questionable for some tick-borne diseases;
for TBE, the efficiency of this approach is not sufficient because
testing large numbers of collected ticks cannot consistently ensure
virus detection in known endemic foci (Stefanoff et al., 2013).
Although entomological studies provide important information on
potential vectors and their density and infectivity, these field methods are laborious and expensive, and the results are limited to the
monitored areas (Capelli et al., 2012).
The modeling/forecasting approach
The epidemiology of a TBD primarily depends on the distribution of its vector. The Vbornet network has already produced maps
of the major TBDs in Europe based on the literature and advice from
local experts. Vbornet experts have also used current entomological
data and current knowledge of climatic, human and other factors
affecting the distribution of I. ricinus in Europe to forecast its possible expansion (Medlock et al., 2013). Nevertheless, data are missing
from many countries, and there is thus a need to fill these gaps to
assess the risk of spreading tick-transmitted infections. The suitability of an area for ticks depends on climatic factors, landscape
use and the abundance of potential hosts (Hubalek et al., 2006; Rosa
et al., 2007). Because most of these factors can be monitored using
remote sensing or geographic information systems, it is possible to
V. Vu Hai et al. / Ticks and Tick-borne Diseases 5 (2014) 607–619
construct models that predict regions and periods favorable to the
presence or abundance of ticks (Estrada-Pena et al., 2007; Schwarz
et al., 2009a). Therefore, the use of mathematical models has been
proposed to characterize the impacts of climatic factors on tick
distribution for European vectors such as R. sanguineus (Beugnet
et al., 2011). Satellite data have been used to predict the risk of
TBDs in Europe, and a strong correspondence was found between
the predicted TBE cases and field reports (Randolph, 2002). A climatic approach has also been used to predict the possible extension
of tick territory and, thus, of TBDs in Europe as a consequence of
global warming (Estrada-Pena and Venzal, 2007). Studies have been
conducted with Geographic Information Systems (GIS) to identify
landscapes linked to a higher risk of TBDs (James et al., 2013). However, many factors influence the distribution of ticks and TBDs,
including changes in human activities, biotopes, animal abundance
and animal distribution (Lambin et al., 2010). Therefore, to identify
populations, regions or periods at risk for TBDs, forecasting models must account for many parameters. In Sweden, climate, wildlife
and human TBE victim databases were used to model the relations
between the TBE burden and climatic and wildlife factors. The final
model predicted an increase in TBE and was proposed as an early
warning system for the disease (Haemig et al., 2011). Conversely,
human behaviors and socio-economic factors have been shown to
have an impact on the resurgence of TBDs in a given area and on the
level of risk for human communities (Godfrey and Randolph, 2011;
Vanwambeke et al., 2010). In Belgium, the distribution determinants for LB that is transmitted by I. ricinus was studied using a
mathematical model that included factors linked to vectors, host
populations, landscape attributes and human behaviors. The study
showed that different populations were at risk for this disease
based on environmental and socioeconomic factors (Linard et al.,
2007). Furthermore, the development of ticks, pathogens and reservoir hosts is highly influenced by local conditions, and thus, the risk
areas are discontinuous. An effective model should include a variety of data from surveys, field reports and laboratory experiments.
Although some data can be estimated by remote sensing (rainfall,
humidity, normalized difference vegetation index (NVDI), altitude,
and land use), most of the remaining data can only be obtained
from specific field studies and cannot always be incorporated into
every model. This situation limits the use of these models for determining risk levels at a local scale. Furthermore, standard statistical
techniques assume independence among the observations. If data
are biologically correlated, as hygrometry and temperature are
(collinearity), or spatially correlated because it has been collected
from proximal locations (spatial autocorrelation), the models used
can have unstable parameter estimates and yield unreliable significance tests. Therefore, different datasets must be used to select
the most accurate model according to the tick species and address
the autocorrelation and collinearity of covariates (Estrada-Peña
et al., 2013a). In recent years, the basic reproduction number of
a pathogen R0 , which determines whether a pathogen will spread
or fade when introduced to a fully susceptible population, has been
used to determine the potential extension of TBDs and to identify
them using their impact on R0 , which is one of the most important factors to include in models (Dunn et al., 2013). In Europe,
R0 models were used to investigate the persistence of 3 tick-borne
pathogens, B. microti, A. phagocytophilum and B. burgdorferi s.l., in an
Apodemus sylvaticus-I. ricinus system. Theoretical predictions were
compared with empirical data from the field. The results showed
high concordance between the model predictions and the field data.
Furthermore, the analysis permitted the identification of the most
important factors responsible for the establishment and persistence of tick-borne pathogens in a given tick-host system (Harrison
et al., 2011). If models and forecasting tools are to be relevant, they
must improve field studies and contribute to a reliable database
(Estrada-Peña et al., 2013b).
613
“The host vector bite exposure approach” of using the antigenic
properties of tick salivary proteins: estimation of host/vector
contact by serology
The saliva of a vector is composed of numerous active pharmacological molecules, including anti-hemostatic and immunomodulatory components, which facilitate blood feeding (Ferreira et al.,
2003; Francischetti et al., 2009; Frauenschuh et al., 2007; Juncadella
et al., 2007; Oliveira et al., 2010; Ribeiro et al., 1985; Steen et al.,
2006; Vancova et al., 2010). The injection of tick salivary proteins
into the host has been shown to elicit an antibody response directed
against arthropod salivary proteins (Francischetti et al., 2009).
Although the exact role of this host antibody response directed
against a limited number of vector salivary proteins remains to
be clarified, this anti-Ixodidae saliva antibody response has been
proposed for use as a surrogate biomarker of host exposure to tick
bites. The first demonstration was performed in the early 1990s
by Schwartz et al., who reported a correlation between the levels of antibodies against I. scapularis salivary protein extracts in
forestry workers in New Jersey and their exposure to I. scapularis
bites (Schwartz et al., 1990). Moreover, a correlation between host
antibody response level against tick salivary proteins and Lyme disease seropositivity has been demonstrated (Schwartz et al., 1990).
Collectively, these studies highlight the potential for the host’s
immune response directed against salivary vector proteins to be
used as a biomarker of tick bite exposure. Additionally, a significant decrease in the anti-tick saliva response was observed in
the absence of tick exposure for several months (from October to
January) (Schwartz et al., 1991). This study shows that this host
immune response is transitory and is thus useful for following seasonal exposure according to tick density.
Since that proof-of-concept study by Schwartz and collaborators, similar strategies for assessing human and animal exposure
to other blood-sucking vectors have been developed. The antibody
responses of humans and animals against whole salivary extract
have been successfully analyzed for several hematophagous vectors, including Culicidae (Doucoure et al., 2012a,b; Fontaine et al.,
2011b; Orlandi-Pradines et al., 2007; Palosuo et al., 1997; Remoue
et al., 2006), Phlebotominae (Barral et al., 2000; Martin-Martin et al.,
2012), Triatominae (Schwarz et al., 2009b) and Ixodidae (Inokuma
et al., 1999, 2000).
Despite the interest devoted to this approach, the use of
whole salivary protein extracts from vectors as a source of antigens presents numerous limitations. Saliva collection and salivary
gland dissection are tedious and time-consuming, and the protein extract yields are low, constituting major obstacles to the
widespread use of these salivary components (Almeras et al., 2010,
2009; Fontaine et al., 2011a). Moreover, salivary component heterogeneity according to sex, age and diet is another factor that
restricts the standardization of such protein extracts (Choumet
et al., 2007; Diaz-Martin et al., 2013; Prates et al., 2008; Volf et al.,
2000). The recent elucidation of sialotranscriptomes from several
hematophagous arthropods revealed that orthologous salivary proteins from different arthropod species share varying degrees of
sequence similarity (Alarcon-Chaidez et al., 2006; Ribeiro et al.,
2010), which could explain the occurrence of serological crossvector species/genus salivary protein recognition (Trevejo et al.,
2005; Wheeler et al., 1991). Conversely, a BLAST analysis of tick
salivary protein repertoires highlighted that some salivary proteins are unique at the species or genus level (Francischetti et al.,
2009). Thus, the judicious selection of a salivary protein specific to a vector species or conserved in a group of vectors (e.g.,
the protein sequence is shared between vectors from the same
complex, sub-genus or genus) could improve the sensitivity and
specificity of serological tests. However, the genus- or speciesspecific determination of salivary proteins could be hampered
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V. Vu Hai et al. / Ticks and Tick-borne Diseases 5 (2014) 607–619
Table 3
Properties of tick salivary proteins in the evaluation of host/tick contact.
Biomarker candidate
Additional information
Tick species
Rs24p
Rhipicephalus sanguineus 24 kDa protein
R. sanguineus
24
rTC
Recombinant tick calreticulin
47.5
Hsp70
PDI
Rs cement protein
THAP
EF-1␣
MSI
VDAC
Heat shock 70-kDa protein
Protein disulfide isomerase-2
R. sanguineus cement protein
Heme-binding aspartic proteinase
Translation elongation factor EF-1 alpha
RNA-binding protein musashi
Mitochondrial voltage-dependent
anion-selective channel
I. ricinus calreticulin
Valosin-containing protein
Tumor rejection antigen protein
Heme lipoprotein precursor
Amblyomma americanum,
Dermacentor variabilis, Ixodes
scapularis
R. sanguineus
R. sanguineus
R. sanguineus
R. sanguineus
D. reticulatus
D. reticulatus
R. sanguineus, D. reticulatus
Ir calreticulin
VCP
Trap
Hlp
I. ricinus
I. ricinus
I. ricinus
I. ricinus
by a lack of corresponding genomic or post-genomic knowledge.
Therefore, two main strategies have been developed to define salivary biomarkers: the “candidate” approach and the “antigenic”
approach.
The “candidate” strategy consists of selecting proteins by comparing secreted salivary protein repertoires from the species or
groups of vector species of interest. A comparison of interesting candidates can be performed using BLAST tools (Poinsignon
et al., 2008) or by using more sophisticated in silico approaches
(Fontaine et al., 2012). Additional selection criteria can also be
considered, such as involvement in hemostasis, immunomodulatory properties and relative abundance. Sanders et al. selected and
produced a recombinant A. americanum calreticulin protein (rTC)
and observed an antibody response to this tick salivary protein in
rabbits that were exposed to A. americanum, D. variabilis (Sanders
et al., 1998) or I. scapularis (Sanders et al., 1999) and in humans
exposed to tick bites (Sanders et al., 1998). The anti-rTC levels correlated significantly with the duration of exposure and the level
of tick engorgement (Sanders et al., 1999). Interestingly, individuals exposed to Ae. aegypti did not develop anti-rTC antibodies,
emphasizing that rTC could be specific to tick bites. Hence, antirTC responses could be used as biomarkers for estimating host/tick
contact (Sanders et al., 1998). Since that study, the anti-rTC antibody has been used in a longitudinal study to assess the impact of
educational interventions on tick exposure (Malouin et al., 2003).
More recently, rTC salivary protein assessment has been successfully used to detect Ixodes tick exposure in mice and individuals
exposed to tick bites (Alarcon-Chaidez et al., 2006) (Table 3).
The second strategy, which is the “antigenic” approach, is
based on using the antigenic properties of vector salivary proteins. In this case, vector salivary proteins are chosen according to
their immunological recognition by serum from a host that was
exposed to the corresponding vector species. This strategy was
recently used to assess kinetic IgG responses in a tick-exposed
rabbit model against salivary gland protein extracts from two
major European TBD vector species, R. sanguineus and D. reticulatus. Salivary antigenic proteins shared between R. sanguineus
and D. reticulatus were identified. Among these, the mitochondrial
voltage-dependent anion-selective channel (VDCA), which is recognized by both tick species, could be a potential candidate for
evaluating exposure to R. sanguineus and D. reticulatus bites. Furthermore, among the tick salivary antigenic proteins identified,
some were specifically associated with either R. sanguineus (e.g.,
cement protein) or D. reticulatus (e.g., the RNA-binding protein
musashi) exposure and have been proposed as candidate antigenic
biomarkers for distinguishing between bites from these two European tick species (Table 3). A similar strategy was used to identify
MW (kDa)
72.5
57.3
20.6
38.8
43.5
37.4
29.7
48
90.7
90.2
153.3
References
Inokuma et al. (1999) and Inokuma
et al. (2000)
Alarcon-Chaidez et al. (2006), Malouin
et al. (2003), Sanders et al. (1999) and
Sanders et al. (1998)
Vu Hai et al. (2013a)
Vu Hai et al. (2013b)
antigenic salivary proteins from the Lyme disease vector I. ricinus
(Vu Hai et al., 2013b). I. ricinus calreticulin was unambiguously
identified among the antigenic salivary proteins. Cross-recognition
experiments using salivary extracts of R. sanguineus and D. reticulatus or sera from rabbits exposed to these two tick species helped
predict the potential of I. ricinus calreticulin for use as an antigen
biomarker. Taken together, salivary tools are a promising method
that could improve other previously developed tools for estimating
exposure to tick bites, information that is valuable for measuring
the TBD vector exposure risk of individuals and populations and
evaluating the efficiency of anti-tick intervention strategies.
Newly developed serological salivary tools could be used in
both epidemiological and entomological surveys to characterize
the endemic areas, seasonal variations, and potential extension
areas of TBD vectors. Salivary tools for monitoring host exposure to mosquito vectors have been extensively developed recently
(Doucoure et al., 2012b; Fontaine et al., 2011b; Rizzo et al., 2011).
Salivary tools have been compared with entomological studies and
clinical data (malaria incidence) to monitor malarial exposure and
assess the impact of vector control interventions (Drame et al.,
2010, 2012; Londono-Renteria et al., 2010). These tools are currently used in pre- and post-vector control interventions (Brosseau
et al., 2012) and to help monitor the vector exposure risk not only
at the population level but also at the individual level (Ali et al.,
2012). It is now time to develop serological tools to monitor the risk
of exposure to TBD vectors. Although the use of salivary antigens
as serological tools could be helpful in epidemiological studies, as
demonstrated by Schwartz (Schwartz et al., 1991), these tools are
powerless to predict the risk of host exposure to pathogens at the
individual level because of spatial and temporal variations in the
prevalence of tick infections. Nevertheless, the antigenic properties
of salivary proteins have been demonstrated, and their ability to
monitor host exposure to TBD vectors could be helpful in the diagnosis of diseases transmitted by these vectors and in the assessment
of vector control tools and strategies.
Conclusions
The distribution of TBDs is changing throughout Europe because
of tick proliferation, climatic changes and the modification of
human behaviors. Thus, monitoring TBD risk is a high priority for
the optimal management of TBDs. Several tools have been developed for TBD risk monitoring, ranging from human, animal, and
entomological approaches to modeling/forecasting. However, the
rapid evolution of tick distribution and density caused by multiple
factors has created a demand for novel models and new monitoring strategies. The antigenic properties of salivary proteins could
V. Vu Hai et al. / Ticks and Tick-borne Diseases 5 (2014) 607–619
make them a useful epidemiological tool for TBD vector surveys
in Europe and other endemic areas worldwide. Additionally, these
proteins could be helpful serological tools for estimating the risk
of TBDs in clinical diagnostics. These exposure biomarker candidates could be helpful in diagnosing diseases transmitted by these
vectors and in the assessment of vector control tools and strategies.
Conflicts of interest
The authors have no conflicts of interest to declare.
Authors’ contributions
PF, AL, PP and VHV conceived of the intellectual content of
this article. VHV, PF and AL collected the results presented in the
article and wrote the first draft of the manuscript. VHV, AL, PF,
SC, PP and RD participated in the production of the final version
of this manuscript. All authors have read and approved the final
manuscript.
Acknowledgments
We are grateful to Jean-Michel Berenger and Sarah Bonnet
for their thoughtful comments and input and to the anonymous
reviewers for their helpful comments, which have enriched the
quality of this manuscript. This study was supported by the French
Armed Forces Medical Service and the Délégation Générale pour
l’Armement (DGA, ARTHROSER project, grant 10CO401). The doctoral work of VHV was supported by the Méditerranée Infection
Foundation.
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