S Brunelli

M Radescu

N Dubois

M Batisse

H E Vaughan

V Fischer

Pischedda

C Cavallari
email: chiara.cavallari@esrf.fr

M Brunelli

S Radescu

M Dubois

N Batisse

G B M Vaughan

H E Fischer

V Pischedda
email: vittoria.pischedda@univ-lyon1.fr

Structural and electronic changes in graphite fluorides as a function of fluorination rate: An XRS, PDF and DFT study

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Graphite fluorides CxF, are fluorine-graphite compounds presenting covalent (x≤2) or semicovalent (x>2) C-F bonds, depending on the fluorine content and the synthesis conditions. They exhibit excellent tribological and electrochemical properties and therefore are used in industry as solid lubricants or as cathode in primary lithium batteries [START_REF] Nakajima | Fluorine-Carbon and Fluoride-Carbon Materials: Chemistry, Physics, and Applications[END_REF][START_REF] Giraudet | Comparative performances for primary lithium batteries of some covalent and semi-covalent graphite fluorides[END_REF][START_REF] Hamwi | Chapter 17 -Fluorine-intercalated graphite for lithium batteries[END_REF]. The discharge potential and capacity in primary lithium battery can be controlled by fluorine concentration; for example it has been found that sub-fluorinated CF0.78 has a powder density 14 times higher than that of the typical Li/CF1 battery [START_REF] Hamwi | Chapter 17 -Fluorine-intercalated graphite for lithium batteries[END_REF][START_REF] Yazami | Fluorinated carbon nanofibres for high energy and high power densities primary lithium batteries[END_REF]. The presence of non-fluorinated graphitic carbons allows the electron flux to be ensured in the insulating CFx active material. Good performances of CxF as solid lubricants are also related to the presence of sp 2 carbons, in particular: i) low friction coefficients are observed for intermediate fluorine contents [START_REF] Thomas | Fluorinated Nanocarbons for Lubrication[END_REF] and ii) a defluorination process is observed during the tribofilm formation [START_REF] Nomède-Martyr | Tribological properties of fluorinated nanocarbons with different shape factors[END_REF]. Clearly, a deep investigation of the graphite phase distribution into the fluorocarbon matrix of CxF is of primary importance.

The fine tuning of graphite content, F concentration and C-F bonding allows adjusting the applicative properties such as chemical and thermal stability, tribological properties and the discharge potentials (the stronger the C-F bond, the lower the potential). For these reasons, there has been much interest in the last decades and many discussions in literature to clarify the structure of CxF compounds and the nature of C-F bonding as well as the repartition of remaining sp 2 carbon atoms. However, as it has not been possible until now to synthesize a homogenous and perfectly crystalline sample, it is difficult experimentally to clarify the crystal structure and a large variety of techniques have been applied to characterize these materials such as XRD, infra-red, optical Raman, XAS, NMR and many others [START_REF] Touhara | On the Structure of Graphite Fluoride[END_REF][START_REF] Giraudet | Solid state NMR studies of covalent graphite fluorides (CF)n and (C2F)n[END_REF][START_REF] Giraudet | Solid-State NMR ( 19 F and 13 C) Study of Graphite Monofluoride (CF)n: 19 F Spin-Lattice Magnetic Relaxation and 19 F/ 13 C Distance Determination by Hartmann-Hahn Cross Polarization[END_REF][START_REF] Sato | Short-range structures of poly(dicarbon monofluoride) (C2F)n and poly(carbon monofluoride) (CF)n[END_REF][START_REF] Dubois | EPR and Solid-State NMR Studies of Poly(dicarbon monofluoride) (C2F)n[END_REF][START_REF] Ahmad | NMR and NEXAFS Study of Various Graphite Fluorides[END_REF].

Theoretical studies suggest also a variety of possible structural models for each CxF compound [START_REF] Pischedda | Experimental and DFT high pressure study of fluorinated graphite (C2F)n[END_REF][START_REF] Pischedda | Fluorinegraphite intercalation compound (C4F)n at high pressure: Experimental and theoretical study[END_REF][START_REF] Han | Unraveling Structural Models of Graphite Fluorides by Density Functional Theory Calculations[END_REF].

Several studies established that at low concentration of fluorine, correlated with a low treatment temperature, it is possible to preserve a graphitic structure, with mainly intercalated fluoride ions. This is the case of C4F in which the hybridization of the carbon atoms remains sp 2 as in the case of graphite. At lower value of x, that is higher fluorine content, as for C2F and CF, the structure corrugates; the C atoms become mainly hybridized sp 3 , as in the diamond structure, with the presence of out of plane C-F bonds [START_REF] Sato | Short-range structures of poly(dicarbon monofluoride) (C2F)n and poly(carbon monofluoride) (CF)n[END_REF][START_REF] Ahmad | NMR and NEXAFS Study of Various Graphite Fluorides[END_REF]. The nature of C-F bonds, covalent for intermediate and higher fluorine contents (C2F and C1F) and weakened covalence for low concentration (as C4F) was estimated by NMR, EPR and XAS techniques [START_REF] Giraudet | Solid state NMR studies of covalent graphite fluorides (CF)n and (C2F)n[END_REF][START_REF] Dubois | EPR and Solid-State NMR Studies of Poly(dicarbon monofluoride) (C2F)n[END_REF][START_REF] Ahmad | NMR and NEXAFS Study of Various Graphite Fluorides[END_REF][START_REF] Giraudet | Solid-state NMR study of the post-fluorination of (C2.5F)n fluorine-GIC[END_REF]. The origin of the weakened covalence (also called semi-covalence) is due to hyperconjugation, i.e. the electrons involved in the C-F covalent bonds are delocalized by the presence of out of plane pz orbitals from the graphitic planes due to the coexistence of conjugated C=C double bonds in non-fluorinated parts and covalent C-F bonds in fluorocarbon parts [START_REF] Sato | Short-range structures of poly(dicarbon monofluoride) (C2F)n and poly(carbon monofluoride) (CF)n[END_REF].

In previous works by in-situ high pressure Raman spectroscopy, XRD and ab-initio calculations we investigated the structural, vibrational and electronic behavior of C2F and C4F at ambient conditions and high pressure exploring the sp 2 -sp 3 carbon transition upon fluorination and physical compression [START_REF] Pischedda | Experimental and DFT high pressure study of fluorinated graphite (C2F)n[END_REF][START_REF] Pischedda | Fluorinegraphite intercalation compound (C4F)n at high pressure: Experimental and theoretical study[END_REF]. Density functional theory (DFT) calculations showed that the coverage of the graphene layer by fluorine is more stable in a single-sided fluorinated configuration (where all the F atoms bind on one side of the graphene layer), while the C2F structure has a complex mixed sp 2 -sp 3 character where graphene layers are intercalated among sp 3 carbon hybridized structural domains. However, the models do not take into account structural, chemical and core-surface inhomogeneity observed in the experimental data. Raman spectroscopy and XRD data clearly indicate the presence of disorder, meaning that conventional approach based on Bragg diffraction is not well adapted for structural studies of these compounds.

In this paper, we investigate the C-F bonding nature of graphite fluorides with different fluorine concentrations C4F, C2F and C1F using two techniques, which, to the best of our knowledge, have never been used before for characterizing these materials: X-ray Raman Scattering (XRS) and Pair Distribution Function (PDF) analysis. These are both bulk techniques very sensitive to the atomic local and electronic structure and C hybridization.

PDF is a well-established technique for studying disordered or semi-ordered materials. XRS is a non-resonant inelastic X-ray scattering technique that allows observing the core electron excitations in the sample, thus providing information about the C-F bonding character and the hybridization of the C states [START_REF] Suzuki | X-Ray Raman Scattering Experiment[END_REF][START_REF] Suzuki | X-Ray Raman Scattering. II. Experiment with Cr Kα Radiation[END_REF][START_REF] Huotari | A largesolid-angle X-ray Raman scattering spectrometer at ID20 of the European Synchrotron Radiation Facility[END_REF][START_REF] Huotari | X-ray-Raman-scattering-based EXAFS beyond the dipole limit[END_REF]. Compared to other techniques such as XPS and soft-XAS, that allow obtaining similar information, XRS has the great advantage that the penetration depth of the hard X-ray beam in the sample is of the order of hundreds of micrometers (compared to few nanometers or few hundreds nanometers for XPS and XAS, respectively). This bulk sensitivity is important for the study of graphite fluorides that often present core-surface heterogeneity, the fluorination process being limited by the diffusion of fluorine into the carbon lattice. DFT calculations allow data interpretation to be verified and validated.

Experimental

Sample preparation

Graphite fluorides at different levels of fluorination were measured: C4F, C2F and C1F.

Sample preparation proceeded via treatment in fluorine gas of graphite powder used as a precursor. More details about the synthesis and fluorination process of the samples are reported in [START_REF] Giraudet | Solid state NMR studies of covalent graphite fluorides (CF)n and (C2F)n[END_REF][START_REF] Giraudet | Solid-State NMR ( 19 F and 13 C) Study of Graphite Monofluoride (CF)n: 19 F Spin-Lattice Magnetic Relaxation and 19 F/ 13 C Distance Determination by Hartmann-Hahn Cross Polarization[END_REF][START_REF] Dubois | EPR and Solid-State NMR Studies of Poly(dicarbon monofluoride) (C2F)n[END_REF][START_REF] Giraudet | Solid-state NMR study of the post-fluorination of (C2.5F)n fluorine-GIC[END_REF]. Pristine graphite powder was natural sample from Madagascar (grain size 75 μm), supplied by Mersen. Graphite and diamond powders were measured as references.

Characterization 2.2.1 Pair Distribution Function analysis

XRD data for real space analysis were collected at the ID15A beamline (ESRF, Grenoble, France), selecting an energy of E = 65.35 keV (λ = 0.18971 Å), of the incoming beam. Using a Pilatus CdTe detector, a 2D detector system and placing the samples to a sample-to-detector distance of 12.05 cm, a maximum momentum transfer Q = 4π sin θ/λ of Qmax ~ 35 Å -1 was reached. Power samples of C4F, C2F, CF and graphite were loaded into 1.5 mm diameter kapton tubes. 64 images of 10 s each were collected (for a total data collection time of about 10 minutes). Data on empty tube was also collected to obtain sufficient statistics for background subtraction. Sample spinning was used to increase powder averaging. Data collected on a CeO2 powder sample were used for geometrical calibration (7 images of 10 s).

Background was systematically subtracted on the raw images before azimuthal integration (using in-house software).

In this work, the PDF is described with the G(r) formalism [START_REF] Egami | Underneath the Bragg Peaks: Structural Analysis of Complex Materials[END_REF], which indicates the probability of finding a pair of atoms separated by a distance r. G(r) is experimentally determined via sine Fourier transform of the total scattering function F(Q):

where Q is the magnitude of the scattering vector, Q = 4π sin θ/λ, and r is the interatomic distance. S(Q) is the experimental coherent X-ray scattering intensity, after correcting the raw data for sample self-absorption, multiple and Compton scattering.

Data integration was performed using pyFAI [START_REF] Ashiotis | The fast azimuthal integration Python library: pyFAI[END_REF] and extraction of the G(r) functions was performed using PDFGetX3 software [START_REF] Juhás | PDFgetX3: a rapid and highly automatable program for processing powder diffraction data into total scattering pair distribution functions[END_REF], employing data for the Fourier Transformation to a Qmax = 35 Å -1 .

Neutron powder diffraction (NPD) data [START_REF] Cavallari | Neutron powder diffraction study of fluorinated graphites[END_REF] for real space analysis were collected at the D4C instrument (ILL, Grenoble, France) [START_REF] Fischer | D4c: A very high precision diffractometer for disordered materials[END_REF] at an incident neutron wavelength λ = 0.4964(5) Ǻ, covering a Q-range between 0.35 and 23.5 Ǻ -1 . Powder samples were placed inside a sealed 7 mm diameter Vanadium cylindrical cell and measured under ambient temperature and vacuum conditions.Vanadium rod, empty cans and boron powder patterns were also measured in order to properly subtract the background and normalize the data. Backgrounds were measured periodically during the experiment in order to assess their stability. PDFs from NPD data were obtained using the standard Placzek correction and Fourier transform, implemented into a software procedure developed at the D4C instrument [START_REF] Fischer | Neutron and x-ray diffraction studies of liquids and glasses[END_REF]. In particular, an appropriated background, taking into account a linear combination of the diffraction data for the empty bell jar and empty can and Placzek corrections, was subtracted from the raw data. In addition, multiple scattering and absorption corrections were made using the CORRECT program [START_REF]CORRECT: A correction program for neutron diffraction data[END_REF].

Resolution of the PDF (i.e. shorter distances which can be distinguished) in the real space covered by the X-ray and the neutron experiments was δr ~ 0.1 ÷ 0.16 Å, respectively.

X-ray Raman scattering

All XRS data were collected using the large solid angle spectrometer of the beamline ID20 at the ESRF (Grenoble, France) dedicated to XRS studies [START_REF] Huotari | A largesolid-angle X-ray Raman scattering spectrometer at ID20 of the European Synchrotron Radiation Facility[END_REF][START_REF] Huotari | X-ray-Raman-scattering-based EXAFS beyond the dipole limit[END_REF]. The pink beam from four U26 undulators was monochromatized by using a nitrogen cooled Si(111) monochromator and a Si (311) Channel Cut post-monochromator and then focused to a spot size of approximately 10 × 20 μm 2 (V × H) at the sample position with a mirror system in Kirkpatrick-Baez geometry. Measurements were performed by scanning the incident energy Ei so that the energy loss [Ef -Ei] matches the core-electron excitation of interest, in this case C and F K-edge. XRS data were collected in the vertical scattering plane using 36 spherically bent Si(660) analyzer crystals at the final energy Ef of 9.8 KeV and using 3 pixelated Maxipix detectors [START_REF] Ponchut | MAXIPIX, a fast readout photon-counting X-ray area detector for synchrotron applications[END_REF]. The overall energy resolution was 0.7 eV and the mean momentum transfer was 3.2 ± 0.3 Å -1 . All the samples were handled in air, ground into fine powder and pressed in an ad-hoc grooved flat Aluminium sample holder. The sample holder was placed on the goniometer stage at an incident beam angle of 10 degrees. All measurements were collected at room temperature and checked for consistency. The inelastic data were integrated over appropriated Region Of Interest (ROIs), averaged over the 36 crystals and treated with the XRS tools program package [START_REF] Sahle | Planning, performing and analyzing X-ray Raman scattering experiments[END_REF]. A background accounting for the valence Compton profile was subtracted following the procedure described in [START_REF] Sahle | Planning, performing and analyzing X-ray Raman scattering experiments[END_REF]. Finally normalization over the area across the edge was applied. XRS spectra are presented in energy loss scale.

Computational details

All the calculations were performed within the ab-initio framework of the density functional theory using the pseudopotential and plane waves method, as implemented in the VASP code [START_REF] Kresse | Efficiency of ab-initio total energy calculations for metals and semiconductors using a plane-wave basis set[END_REF][START_REF] Kresse | Efficient iterative schemes for ab initio total-energy calculations using a plane-wave basis set[END_REF]. The parameters of the calculation are similar to those previously used in Ref [START_REF] Pischedda | Experimental and DFT high pressure study of fluorinated graphite (C2F)n[END_REF][START_REF] Pischedda | Fluorinegraphite intercalation compound (C4F)n at high pressure: Experimental and theoretical study[END_REF], with the van der Waals corrections to the total energy taken into account at the DFT level using the so-called Grimme's D2 method [START_REF] Perdew | Restoring the Density-Gradient Expansion for Exchange in Solids and Surfaces[END_REF]. The two 2s and two 2p outermost valence electrons of C and the two 2s and five 2p outermost valence electrons of F were dealt with explicitly in the calculations, while the rest of the electrons were considered frozen at the core. A projector augmented wave scheme was used [START_REF] Perdew | Generalized Gradient Approximation Made Simple[END_REF][START_REF] Grimme | A consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for the 94 elements H-Pu[END_REF] with a kinetic-energy cutoff in the plane waves expansions of 600 eV whereas for the integration over the Brillouin zone 15×15×5 Monkhorst-Pack grids were used. All these calculations correspond to hydrostatic pressures spanning the region of interest and zero temperature, with the small effect of the zero point energy neglected. The analysis of the electron localization function (ELF) was performed once electronic self-consistency was achieved and has provided very useful information on the bonding features for the studied materials. ELF was calculated from the valence electronic density obtained within the pseudopotential scheme implemented in VASP and the results were visualized using the VESTA 3.4.3 software and Jmol Visualization tool [START_REF] Momma | VESTA 3 for three-dimensional visualization of crystal, volumetric and morphology data[END_REF][START_REF]Jmol: an open-source Java viewer for chemical structures in 3D[END_REF]. The net atomic charges (NAC) were also calculated by means of the DDEC6 code [START_REF] Manz | Introducing DDEC6 atomic population analysis: part 1. Charge partitioning theory and methodology[END_REF][START_REF] Limas | Introducing DDEC6 atomic population analysis: part 2. Computed results for a wide range of periodic and nonperiodic materials[END_REF] (the frozen core electrons were included in the charge analysis). We have also carried out calculations of the core level binding energies for the C-1s and F-1s core state, including final-state core hole effects (core-level relaxation energy), which involve the recalculation of the Kohn-Sham eigenvalues for the core states for the chosen atom using a half core-hole [START_REF] Köhler | Density functional study of CO on Rh(111)[END_REF].

The C-1s and F-1s energy values are referred to the electrostatic potential at vacuum. The simulation periodic cell corresponds to a slab of material made up of a large enough number of layers (so as to recover bulk properties in the central layers of the slab) plus a large enough vacuum region between the periodic images.

Results and discussion

PDF analysis

A direct analysis of the Real Space data is carried out for the three C4F, C2F and C1F samples together with pristine powder graphite, for both X-ray and neutron diffraction data. The results are listed in Table 1. In Fig. 1 X-ray data in both reciprocal (left panel) and direct space (right panel) are plotted while the reference simulated models for the considered structures are sketched in Fig. 2 and described in Ref [START_REF] Pischedda | Experimental and DFT high pressure study of fluorinated graphite (C2F)n[END_REF][START_REF] Pischedda | Fluorinegraphite intercalation compound (C4F)n at high pressure: Experimental and theoretical study[END_REF]. Neutron data are reported in the SI file.

XRD data in reciprocal space clearly evidence the presence of the (002) pure graphite reflection at Q ∼1.9 Å -1 in all the samples, broader in C4F while sharp and well-defined in C2F and CF samples.

X-ray data in direct space show one single oscillation in the low r region of the G(r) of C4F, with the first shell distances centred at 1.44 Å (see Fig. 1 and Table 1 for esd). This value is in fair agreement with the DFT model a) in Fig. 2 and discussed in [START_REF] Pischedda | Fluorinegraphite intercalation compound (C4F)n at high pressure: Experimental and theoretical study[END_REF] that predicts three first (a) 25% -C4F [START_REF] Pischedda | Fluorinegraphite intercalation compound (C4F)n at high pressure: Experimental and theoretical study[END_REF]; (b1 and b2) 50% -C2F (sp 3 ) and C2F (sp 2 -sp 3 ), respectively [START_REF] Pischedda | Experimental and DFT high pressure study of fluorinated graphite (C2F)n[END_REF];

(c) 100% -CF [START_REF] Charlier | First-principles study of graphite monofluoride (CF)n[END_REF]. (model b1 in Fig. 2) and recently discussed in [START_REF] Pischedda | Experimental and DFT high pressure study of fluorinated graphite (C2F)n[END_REF]. In general, short distances at around 1.38 Å corresponding to C-F bonds may be enhanced by the presence of a larger number of dangling bonds at the edge of coherent (graphitic or not) domains. So, the smaller are the domains, e.g. in presence of a more disordered structure, the larger is the number of such C-F bonds. Therefore, this peak would appear stronger in the PDF. It should be noticed that the agreement with the model proposed by Han et al. [START_REF] Han | Unraveling Structural Models of Graphite Fluorides by Density Functional Theory Calculations[END_REF] and by Pischedda et al. [START_REF] Pischedda | Experimental and DFT high pressure study of fluorinated graphite (C2F)n[END_REF] (model b2 in Fig. 2) is poorer, i.e. with the distance at 3.2 Å not reproduced in the experimental data.

PDF

Moreover, both the models (b1 and b2 in Fig. 2) fail to reproduce satisfactorily the data above 5.8 Å. Data suggests that we are in presence of fragmented nanostructured domains of the structural models.

Similarly, in the C1F sample, both X-ray and neutron data (see Table 1) show two distances in the low r region of the PDF, at 1.36 Å and 1.58 Å (see Fig. model a in Fig. 2 ) and 100%-F coverage (CF, model c in Fig. 2).

Figure 3: (top) ELF profiles in function of the distance between the two bonded atoms (left panel: C-C and C-CF. Right panel: C-F). A value of one indicates a high localization of electrons. For covalent bonds the valence electrons are localized between the two bonded atoms whereas for ionic bonds the valence electrons are localized near the anions. (bottom) Net atomic charges (NAC) at 25%-F coverage (left image) and 100%-F coverage (right image). A blue color is used to report the value of NAC on the C atoms whereas red indicates the NAC on the F atoms.

The ELF profiles depicted in Fig. 3 XRS spectra at the energy loss corresponding to the C K-edge and F K-edge for C4F, C2F and CF are shown in Fig. 4a and 4b respectively. The features at the C-K edge will be discussed first. Graphite and diamond powder have been measured as a reference and the experimental data are in good agreement with previous soft-XAS and EELS measurements [START_REF] Batson | Carbon 1s near-edge-absorption fine structure in graphite[END_REF][START_REF] Ma | Soft-x-ray resonant inelastic scattering at the C K edge of diamond[END_REF]. In graphite, the main features at the C 1s absorption edge are associated to the transitions of the C 1s electron of the empty π and σ states in the conduction band. These states, indicated as π* and σ*, come from the C π2pz orbitals oriented perpendicular to the carbon plane and the sp 2 hybridized C 2s,2px,y oriented in the carbon plane respectively. Therefore these are a clear indication of the C sp 2 hybridization that gives the trigonal C coordination within the graphene plane. In the graphite spectrum, the π* resonance is well defined at an energy of 285 eV, whereas the σ* band emerges at ~291 eV. The excitonic contribution expected at the edge onset [START_REF] Brühwiler | π * and σ * Excitons in C 1s Absorption of Graphite[END_REF] cannot be clearly distinguished from the σ* band itself because of the experimental resolution, both these features merging in one unique asymmetrical peak. The broader features extending above the threshold are attributed to core electron transitions to the empty σ electronic states in the conduction band associated to the interaction of carbon rings within the plane [START_REF] Batson | Carbon 1s near-edge-absorption fine structure in graphite[END_REF]. In the case of diamond, the σ* band is broader, with an onset energy of ~289 eV. In this case, the sharp excitonic contribution is distinguishable at the edge onset. In addition, the feature c emerges at ~ 305 eV. It originates from a large intensity dip at 302 eV due to a second absolute gap in the diamond band structure [START_REF] Gloter | Improving energy resolution of EELS spectra: an alternative to the monochromator solution[END_REF]. Globally, the shape of the σ* band (including the features indicated as σ*, σ*' and c in Fig. 4a) is a fingerprint of the C sp 3 hybridization in diamond. This confirms that the chemical bonding between carbon atoms in highly graphite fluorides is mainly due to covalent σ bonds. It is noteworthy noticing that the features are globally illdefined, most likely because of increased disorder and probable coexistence of several phases.

The XRS spectra at the F K-edge are reported in Fig. 4b. The features here are given by the F 1s electron transitions to the unoccupied electron states in the conduction band. The edge has an onset at around 685 eV and it is basically flat above 710 eV. We can distinguish three main bands: d from 686 to 688.5 eV, e at 693 eV and f from 695 to 700 eV. The edge onset shifts towards higher energy for the CxF compounds with higher degree of fluorination (x=1,2).

Moreover the relative intensity between d and f changes varying the stoichiometry: in C4F e is more intense than d, in C2F and CF this behavior is inverted, like for covalent C-F bonding in fluorobenzine [START_REF] Hitchcock | Antibonding .sigma.* valence MOs in the inner-shell and outer-shell spectra of the fluorobenzenes[END_REF]. This contrast is related to the number of free available electron states in the conduction band and gets modulated by the spatial orientation of the C-F bonds. Data of C4F do not correlate well with NEXAFS spectra of ionic C6F [START_REF] Seki | High-Energy Spectroscopic Studies of the Electronic Structures of Organic Systems Formed from Carbon and Fluorine by UPS, Vacuum-UV Optical Spectroscopy[END_REF], even though a precise comparison cannot be done as the samples were synthetized differently and XRS provides a powder averaged signal with high sensitivity to the core.

For both the edges, the agreement with previous soft X-ray NEXAFS characterization of the same CxF (x=4,2,1) compounds [START_REF] Ahmad | NMR and NEXAFS Study of Various Graphite Fluorides[END_REF] is very good: the global spectral shape, energy position and relative intensity of the peaks in the two datasets show an excellent match. However it should be noticed that, for all the stoichiometries and in particular at high F content, the fine structure of the XRS spectra is less clear and defined than the NEXAFS data. The first reason must be associated to the different energy resolution of the employed techniques: ~ 700meV (XRS) vs ~100 meV (NEXAFS). In addition, the sample depth probed by the two techniques is very different: few nm for the soft X-ray NEXAFS measurements [START_REF] Ahmad | NMR and NEXAFS Study of Various Graphite Fluorides[END_REF] vs hundreds of μm of XRS. XRS data suggests that in the bulk the F atoms do not show a homogenous local atomic environment and coordination as at the surface.

In order to interpret the binding energies of the core levels measured by XRS, these were calculated for the C1s and F1s core states in the final state approximation. We compared the binding energies of the C1s core levels for C4F and C2F to those of C bonded only to C or F atoms. The calculated values of the binding energies from graphite (0% fluorination) to C1F (100% fluorination) are given in Table 3. From these results we can see that in compounds in which the C atoms are bonded only to other C atoms, the C-1s values are similar to the ones obtained for graphite, however when the C atoms are attached to fluorine the energy value is higher.

Material

The presence of the electronegative F atoms in the nearest surroundings of the C atoms causes some electron transfer from C towards F; therefore the effective positive charge on C increases as well as the C-1s electron binding energy. This explains the progressive up-shift of the edge onset upon fluorination, particularly evident in highly graphite fluorides like CF. The results appear in good agreement with the reported binding energies measured by XRS and with the often reported values for the graphite core level [START_REF] Susi | X-ray photoelectron spectroscopy of graphitic carbon nanomaterials doped with heteroatoms[END_REF]. C2F compound is the one that shows the poorest agreement with the structural models proposed (models b1 and b2 in Fig. 2) Following the analysis procedure described in [START_REF] Ahmad | NMR and NEXAFS Study of Various Graphite Fluorides[END_REF], C-1s and F-1s spectra were aligned in energy by taking into account the energy separation between the F-1s and C-1s core levels. A value of ∆E ~399 eV was used for both C1F and C4F [START_REF] Sato | Short-range structures of poly(dicarbon monofluoride) (C2F)n and poly(carbon monofluoride) (CF)n[END_REF]. The result is shown in Figure 5a.

and
The fine structures of these two spectra are similar for features' number, shape and energy position, confirming that they are associated to the transition of C-1s and F-1s core electrons to the same set of final states, formed primarily by F-2p and C-2p states [START_REF] Ahmad | NMR and NEXAFS Study of Various Graphite Fluorides[END_REF]. We can see a clear correlation between the main peaks in both CF and C4F spectra. In particular, d becomes

  short distances C-Cshort = 1.40 Å, C-F = 1.46 Å and C-Clong = 1.50 Å, whose weighted average is about 1.46 Å. It is to note that these three distances cannot be resolved within the experimental resolution of the neutron and even synchrotron X-ray PDF data. The overestimation of the overall first short distances in the DFT model can be interpreted as an overestimation of the presence of the F atoms in the structure, with respect to the nominal fraction F/C = 0.25.

Figure 1 .Figure 2 :

 12 Figure 1. XRD patterns in the q-range [0.8-10] Å -1 (left panel) and corresponding PDFs of graphite (green), C4F (blue), C2F (red), and CF (black) samples plotted up to 3.5 Å (right panel) collected at the ID15A beamline of the ESRF, using λ=0.18971 Å.

For

  the C2F sample, experimental data show two distances in the low r region of the PDF at 1.37 Å and 1.56 Å (see Figure1, right panel), which agree very well with the distances C-F = 1.37 Å and C-C =1.56 Å predicted by the DFT model firstly proposed by Sato et al.[START_REF] Sato | Short-range structures of poly(dicarbon monofluoride) (C2F)n and poly(carbon monofluoride) (CF)n[END_REF]

  1, right panel), which are in good agreement with the distances predicted by the DFT calculated model [40] (model c in Fig. 2), i.e. C-F = 1.38 Å and C-C =1.57 Å. In this case, experimental data also seem to agree on second and third coordination shells. C1F being the compound with the highest F/C ratio (x= 1), the proposed theoretical model is close to the observation. To better understand the character of the C-C and C-F chemical bonds we report in Fig. 3 a theoretical study of the projected ELF along the C-F and C-C bonds at 25%-F coverage (C4F,

Table 2 :Figure 4 .

 24 Figure 4. (a) XRS spectra at the Carbon K edge of graphite fluorides at different fluorination degree. From the bottom to the top: in green graphite, in blue C4F, in red C2F, in black CF, in pink diamond. (b) XRS spectra at the Fluorine K-edge of graphite fluorides at different fluorination degree. From the bottom to the top: in blue C4F, in red C2F, in black CF.

  Fig 4a, can be observed at higher degree of F (x=2,1), together with a progressive change in the global shape of the σ* band, that approaches the one of diamond. Upon fluorination, F atoms bond to the carbon plane through the C 2pz orbital and the carbon plane corrugates.

Figure 5 :

 5 Figure 5: a) Comparison between the XRS spectra at the C (top) and F (bottom) K-edge of CF (black curves) and C4F (blue curves). The spectra are aligned in energy using the energy separation ∆E (F 1s -C1s) equal to ~ 399 eV [10]. b) DOS and PDOS for both C4F and CF with a zoom of PDOS corresponding to C atoms from DFT calculations.

  up-shifts in energy as the feature b does, while increasing the fluorination content from C4F to CF, both being associated to the out of plane C-F bonds in the structure[START_REF] Ahmad | NMR and NEXAFS Study of Various Graphite Fluorides[END_REF][START_REF] Seki | High-Energy Spectroscopic Studies of the Electronic Structures of Organic Systems Formed from Carbon and Fluorine by UPS, Vacuum-UV Optical Spectroscopy[END_REF].In Figure5(b) we present the calculated total density of states (DOS) for the cases of 25% fluorination (C4F) and 100% fluorination (C1F), together with the projected density of states (PDOS) for each C and F species and projections onto s, px, py and pz orbitals of the C atoms. Therefore, the way the peaks in the PDOS overlap can shed light on the hybridization character in the compound, confirming the main covalent character of the C-F bonds (as discussed from the analysis of the ELF data). The comparison of the calculated PDOS at 25% and 100% fluorine coverage shows substantial differences at the top of the valence band and a bottom of the conduction bands, being the contribution of C-px+py and C-pz orbitals quite different. At 25% coverage a prominent peak of C-pz character is observed for non-fluorinated neighbouring C atoms at the edge of the valence (bonding states) and conduction band (antibonding states) edges indicating a π-type bond, whereas in the case of 100% coverage the loss of this peak is observed. A significant hybridization of C-pz states and C-px+py orbitals is observed. These results confirm the experimental data.

  In the present paper we show two new advanced methodologies to investigate graphite fluorides C4F, C2F and C1F as function of the fluorine and the residual sp 2 carbon atom contents, making use of XRS data and of PDF-analysed diffraction data, supported by DFT simulations. Information about the character of the C-F bonding were extracted, as well as about the first neighbour distances, the C-C and C-F bond lengths and finally the nature of the final states for 1s core-electron excitations probed by XRS. Our diffraction data, both in reciprocal and direct space, indicate the presence of a graphitic phase in the graphite fluorides compounds with stoichiometry C4F, C2F and CF. The analysis of XRS data confirms the presence of a graphitic phase, even at the highest fluorine content. With respect to the models proposed in literature, our study shows evidence for structural disorder and most likely coexistence of different phases, e.g. graphitic ones at the core of the particles where the diffusion of fluorine during the fluorination process is limited. Such data are crucial to deeply understand and therefore to optimize and control the synthesis with the view of practical applications. In the field of electrochemistry or tribology, the presence of a C-sp 2 phase in the fluorocarbon matrix is believed to trigger an improvement in the material performances.

Table 1 .

 1 First

		calculation / Å	Observed distances / Å from X-ray PDFs	Observed distances / Å from neutron PDFs
	graphite C4F	1.40, 1.46 and	1.425 ± 0.003 1.438 ± 0.006	1.417 ± 0.005 1.432 ± 0.005
		1.50 (model
		a)
	C2F	1.37 and 1.56 (model	1.375 ± 0.003	1.562 ± 0.003	1.50 ± 0.01
		b1)
	CF	1.38 and 1.57 (model	1.361 ± 0.002	1.574 ± 0.002	1.330 ± 0.005	1.570 ± 0.005
		c)

neighbours distances in the three fluorinated compounds, C4F, C2F and CF as observed in the experimental X-ray and neutron PDF data. The estimated standard deviations of the experimentally observed distances are derived from Gaussian fits of the G(r) curves.

Table 3 :

 3 Core Level Energies obtained from the DFT calculations.

		Core hole level site	DFT calculation
			(eV)
	C1F	C1s	285.9
		F1s	689.0
	C2F (sp 3 )	C1s (C)	284.6
		C1s (F)	285.8
		F1s	688.9
	C4F	C1s (C)	285.5
		C1s (F)	286.9
		F1s	687.0
	C-graphite	C1s	285.4

Acknowledgments

We thank the all the staff of the ID20 beamline of the ESRF for help and for support during the experiments. We acknowledge ESRF and ILL for beamtime allocation. We are grateful to to ESRF for funding, F. Ghelfi for participating to the XRS experiment and S. Huotari for providing the diamond powder sample. S.R. acknowledges the support from MINECO Project No. MAT2016-75586-C4-3-P. This work was supported by the LABEX iMUST (ANR-10-LABX-0064) of Université de Lyon, within the program "Investissements d'Avenir" (ANR-11-IDEX-0007) operated by the French National Research Agency (ANR).


Nathalie Boulanger
email: nboulanger@unistra.fr

Pierre Boyer

Emilie Talagrand-Reboul

Yves Hansmann

Ticks and tick-borne diseases

Keywords: tiques, Ixodes, maladies à tiques, Lyme, anthropisation ticks, Ixodes, tick-borne diseases, Lyme, anthropization

à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Ticks

Ticks are present worldwide and, depending on species, they may be observed in highly varied habitats, from the driest to the most humid. Ticks are acarines that may be distinguished from insects by the absence of segmented body and by their spherical form. A total of 900 species of ticks have been identified. They are mainly divided into two families: hard ticks or Ixodidae and soft ticks or Argasidae. A third family has been identified, i.e. Nuttalliellidae, but it is only made of one species:

Nuttalliella namaqua [START_REF] Guglielmone | The Argasidae, Ixodidae and Nuttalliellidae (Acari: Ixodida) of the world: a list of valid species names[END_REF]. This species is rarely observed and will thus not be referred to in the present article. A total of 193 species are part of the Argasidae family, mainly as two major genera: Argas and Ornithodoros. Almost 700 species are part of the Ixodidae family, and they are divided into seven genera. The main genera are: Amblyomma, Dermacentor, Haemaphysalis, Hyalomma, Ixodes, and Rhipicephalus. In France the most frequent genera are Ixodes (widely prevalent), Dermacentor, and Rhipicephalus for hard ticks, and the Argas genus for soft ticks (Figure 1).

Tick morphology

Ticks are large acarines (several millimeters long) with a non-segmented body or idiosome (merged prosoma [or thorax] and opisthosoma [or abdomen]), four pairs of legs in nymphs and adults, and three pairs of legs in larvae. Hard ticks have a hard dorsal scutum covering one third of their body, except for males as their entire body is covered by the scutum. This is why male hard ticks ingest small quantities of blood or no blood at all. Soft ticks do not have any scutellum. Their tegument looks like crumpled leather. The feeding structure of hard ticks is located in front of the head; it is quite large for Ixodes ticks and smaller for other hard ticks. Soft ticks have a very small and barely visible feeding structure located on the underside of the body or sub-terminal part of their body.

The various stages of development

Ticks go through four development stages: eggs, larvae, nymphs, and male/female adults. Blood must be ingested in-between each stage to induce molting. Ticks are thus hematophagous at all stages.

Female hard ticks drop off their vertebrate host after the blood meal, to lay thousands of eggs in the vegetation and die. Ixodes male ticks (Prostriata) do not feed, but they can be found on a host when they need to breed. Males of other hard ticks (Metastriata) can feed, but only very small quantities of blood (twice their weight). Most of these ticks feed on three different hosts and drop off on the ground between each stage to molt (three-host cycle, most ticks). For two-host cycles, larvae and nymphs stay on the same host and for one-host cycles, the whole life cycle of the tick occurs on one animal [START_REF] Apanaskevich | Life cycles and natural history of ticks[END_REF].

Soft ticks have several nymphal stages (between two and eight); ticks feed on blood inbetween each nymphal stage. Both males and females feed, and females lay a few hundred eggs after each blood meal. A blood meal lasts approximately 15 to 30 minutes, except for larvae as they can feed for up to several days [START_REF] Apanaskevich | Life cycles and natural history of ticks[END_REF]. This is why soft ticks are very rarely observed on patients, but rather in their habitats.

The blood meal

Ticks are all strictly hematophagous. Looking for hosts to feed on is therefore essential for their survival. They have developed a highly complex detection system (sensory bristles, pedipalps, Haller's organ on front legs) to detect hosts, mainly wild animals. Humans are accidental hosts. Ticks end up biting humans when they visit the tick's habitat. Conversely, mosquitoes come into the human habitat. These differences are associated with highly different prevention and vector control measures, which will be addressed later on. The blood meal is long in hard ticks, i.e. between 3 and 10 hours depending on the development stage, and tick bites rather occur during the day. Female adults may ingest blood amounts equivalent to up to 100 times their weight. However, later-stage soft ticks (nymphs and adults) only feed for a few minutes and bites rather occur at night.

Tick bite and saliva

The tick bite mechanism is particularly sophisticated. After finding a warm and humid spot on the skin, ticks pierce the epidermis with their sharp blades (chelicerates) and settle with their denticulated harpoon (hypostome). Ticks then secretes a cement-like substance that keeps them firmly attached to the skin and prevents premature dropping off. An inoculation compartment is formed around the feeding structures, followed by an hemorrhage. The role of tick saliva has extensively been studied and most involved molecules have been identified, mainly in hard ticks because of the long duration of their blood meals. Saliva has a pharmacological action on the host (coagulation and pain inhibition, etc.) but it also inhibits the host's local immune responses through immunosuppressive properties targeting various skin cells [START_REF] Bonnet | Ixodes Tick Saliva: A potent controller at the skin Interface of early Borrelia burgdorferi sensu lato transmission[END_REF]. Tick saliva may cause allergic reactions in some hosts, either by inducing an immediate reaction at the bite site -that should be distinguished from erythema migrans observed with Lyme borreliosis -or leading to ascending paralysis mainly observed with Ixodes tick saliva [START_REF] Hall-Mendelin | Tick paralysis in Australia caused by Ixodes holocyclus Neumann[END_REF]. More than 70% of tick bites in adults occur on the legs [START_REF] Wilhelmsson | Ixodes ricinus ticks removed from humans in Northern Europe: seasonal pattern of infestation, attachment sites and duration of feeding[END_REF].

Saliva of Argas soft ticks is also known to induce an anaphylactic shock in susceptible individuals [START_REF] Hilger | IgE-mediated anaphylaxis caused by bites of the pigeon tick Argas reflexus: cloning and expression of the major allergen Arg r 1[END_REF].

Cross allergy to red meat, tick saliva, and an anti-cancer drug (cetuximab) has recently been reported in Australia, the United States, and Europe. This cross allergy is associated with a reaction to galactose-alpha [START_REF] Commins | Tick bites and red meat allergy[END_REF].

Ticks of medical interest in France

Various works on ticks were initiated by French entomologists, such as Gilot, Beaucournu, Guigen, and Perez to only name a few [START_REF] Gilot | Contribution à l'étude du parasitisme humain par les tiques (Ixodidae et Argasidae), plus particulièrement dans le sud-est de la France[END_REF][START_REF] Perez-Eid | Les tiques: identification, biologie, importance médicale et vétérinaire[END_REF]. Studies thus started to be performed well before the 2016 French national plan on Lyme disease [START_REF]Plan Lyme[END_REF].

Approximately 40 species of ticks are currently identified in France. The present article only focuses on the most frequent in humans and on those that may pose public health problems. Considering the major environmental changes made by humans since the start of the 20 th century, Ixodes ticks now live in anthropogenic forest ecosystems where ticks' favorite wild animals proliferate. All ecosystems are affected, even those located in urban and suburban areas where Ixodes ticks may be found [START_REF] Gassner | Greener cities, a wild card for ticks ?[END_REF][START_REF] Medlock | Driving forces for changes in geographical distribution of Ixodes ricinus ticks in Europe[END_REF].

Ixodes ricinus

I. ricinus ticks are the most prevalent ticks in France, except around the Mediterranean basin as the climate is too dry. I. ricinus ticks are also observed in central Corsica because of a humid and continental climate. In continental climates, diapause is observed in I. ricinus ticks during winter and they are usually active from March to October depending on climatic conditions. In oceanic climates, I. ricinus ticks are active almost all year round. Most ticks wait for their host, in a position known as "questing", on the tips of grasses and leaves (Figure 2). Highly susceptible to desiccation, Ixodes ticks drop off the host on a regular basis to rehydrate on the ground. They are able to climb, up to onemeter high, and to come down on vegetation. They, however, never fall from trees. Ixodes ticks are ubiquitous and can feed from more than 300 hosts: small and large mammals, reptiles, birds (Figure 1) [START_REF] Humair | The wild hidden face of Lyme borreliosis in Europe[END_REF].

Dermacentor reticulatus and D. marginatus

Adult Dermacentor reticulatus and D. marginatus ticks are mainly found on humans, and nymphs and larvae are found in animals' hutches. They have short feeding structures and their cuticle is marbled (Figure 1). D. marginatus ticks are particularly prevalent around the Mediterranean basin. They are thermophilic ticks, commonly found in open areas such as clearings, but also in forests. D. reticulatus ticks are more frequently observed in continental climates. They are commonly found on dogs and sheep ungulates. They can also be found on humans, most often with bites on the scalp [START_REF] Bonnet | La biologie des tiques[END_REF]. Adultstage ticks are also questing ticks, just like Ixodes ticks (Figure 2).

Rhipicephalus sanguineus

This species of ticks is mainly observed in dogs (Figure 1). They are endophilic ticks found in doghouses, kennels, outside walls of houses or even inside houses. These ticks can bite humans at all stages. They have short feeding structures. R. sanguineus is mainly prevalent in warm weather regions with mild winters [START_REF] Bonnet | La biologie des tiques[END_REF].

Argas reflexus

Argas reflexus ticks usually feed on pigeons (Figure 1). They can bite humans when their usual host is not available. In that case, they leave the pigeons' nest and come into houses where they bite humans at night during short blood meals. In urban areas they are most commonly found in attic flats, close to pigeons; in rural areas houses close to dovecotes are affected [START_REF] Gilot | Contribution à l'étude du parasitisme humain par les tiques (Ixodidae et Argasidae), plus particulièrement dans le sud-est de la France[END_REF]. A. reflexus bites may be responsible for major allergic reactions to their saliva, that may even trigger an anaphylactic shock. These ticks have never been proven responsible for the transmission of infectious agents to humans.

Tick-borne diseases

Ticks are the most important vectors of vector-borne diseases in terms of human and animal health [START_REF] Dantas-Torres | Ticks and tick-borne diseases: a One Health perspective[END_REF]; they come first before mosquitoes which are in first position in terms of human health with malaria, dengue, etc. Ticks are responsible for the transmission of many infectious agents: bacteria (Borrelia, Anaplasma, etc.), viruses (tick-borne encephalitis), and even parasites (Babesia, Theileria) (Table 1). Pathologies associated with these infectious agents are mostly zoonoses for which humans are accidental hosts and represent a dead-end for the infectious agent. The host acquires the infectious agent in tick-infested habitats. Transmission usually occurs through hematophagous bites, but also through exposure to bodily fluids infected with tularemia or through blood transfusions for Babesia spp., etc. [START_REF] Piesman | Prevention of tick-borne diseases[END_REF]. The pathogen may persist for a long time in ticks because it can be transmitted from stage to stage (transstadial transmission), from females to eggs (vertical transmission), and/or from tick to tick via the host (horizontal transmission) depending on the pathogen. The co-feeding phenomenon allows some infectious agents, for instance the tick-borne encephalitis virus and bacteria responsible for Lyme disease, to be transmitted from an infected tick to an healthy tick at the site of the bite on an animal, in the absence of viremia or bacteremia in the host [START_REF] Randolph | Co-feeding ticks: Epidemiological significance for tick-borne pathogen transmission[END_REF].

Although ticks may host various microorganisms (symbiotes and pathogens) that can be detected via their DNA, their presence in ticks is not necessarily associated with an infectious risk for humans. This is explained by several reasons: DNA detection may not necessarily mean that a living pathogen is present on the vector arthropod. And, even with a living infectious pathogen, the vector arthropod does not necessarily have the ability to transmit this pathogen [START_REF] Kahl | Ecological research on Borrelia burgdorferi sensu lato: terminology and some methodological pitfalls[END_REF]. For ticks infected with bacteria or parasites, the infectious agent is not immediately transmitted as bacteria and parasites have to mature and/or migrate towards salivary glands before being transmitted to the vertebrate hosts. This process may take 24 hours [START_REF] De La Fuente | Targeting a global health problem: Vaccine design and challenges for the control of tick-borne diseases[END_REF].

Ticks have been identified for thousands of year [START_REF] Peñalver | Ticks parasitised feathered dinosaurs as revealed by Cretaceous amber assemblages[END_REF], and tick-associated pathogens have been observed for a long time as well, although most medical descriptions date from the 20 th century. One may, however, note that humans have had a major impact on the ecosystems of ticks. Forest culture -both deforestation and reforestation -has an impact on tick populations, just like changes in wildlife (disappearance of species, introduction of new species, proliferation of species attracting ticks, etc.) [START_REF] Kilpatrick | Drivers, dynamics, and control of emerging vector-borne zoonotic diseases[END_REF]. Climate change has an impact on ticks: they are now observed in northern regions of the world (Canada, Nordic countries) and at higher altitudes (above 1,500 meters), but they may also be less frequent in southern regions depending on their adaptive capacity. Better awareness of vector-borne diseases from health professionals and the general population, and improved direct diagnostic methods (mainly molecular biopsy, i.e. PCR, or culture) are associated with better management of patients and affected animals.

Although Ixodes ticks -prevalent in France -are likely to host various microorganisms, the risk of transmitting the infectious agent to humans following a tick bite is inferior to 3% according to a recent Dutch study [START_REF] Jahfari | Molecular Detection of Tick-Borne Pathogens in Humans with Tick Bites and Erythema Migrans, in the Netherlands[END_REF]. Even when the infectious pathogen is transmitted to humans, all transmissions are not necessarily associated with clinical disease, as reported by a recent French study investigating the seroprevalence of seven pathogens (Borrelia burgdorferi sensu lato, Francisella tularensis, tick-borne encephalitis virus, Anaplasma phagocytophilum, Babesia spp., and Bartonella henselae) in forestry workers [START_REF] Rigaud | Seroprevalence of seven pathogens transmitted by the Ixodes ricinus tick in forestry workers in France[END_REF].

Bacterial infections

Borrelia spp. Bacteria of the Borrelia genus are spiral-shaped extracellular spirochetes belonging to Spirochaetales and to the Spirochaetaceae family. The Borrelia genus is divided into two groups: [START_REF] Guglielmone | The Argasidae, Ixodidae and Nuttalliellidae (Acari: Ixodida) of the world: a list of valid species names[END_REF] Borrelia responsible for Lyme borreliosis, only transmitted by hard ticks of the Ixodes genus, and (2)

Borrelia responsible for relapsing fever, mainly transmitted by soft ticks (Ornithodoros and Argas), except for body lice for B. recurrentis or hard ticks of the B. miyamotoi group [START_REF] Stanek | Lyme borreliosis[END_REF]. Both of these groups have recently been reclassified as "Borreliella" and "Borrelia" genera, respectively, within the new Borreliaceae family [START_REF] Adeolu | A phylogenomic and molecular marker based proposal for the division of the genus Borrelia into two genera: the emended genus Borrelia containing only the members of the relapsing fever Borrelia, and the genus Borreliella gen. nov. containing the members o[END_REF]; however, for the sake of clarity, we use the former term "Borrelia" in the present article. valaisiana) [START_REF] Gern | Life cycle of Borrelia burgdorferi sensu lato and transmission to humans[END_REF], due to specificities related to the host's immune system [START_REF] Kurtenbach | Fundamental processes in the evolutionary ecology of Lyme borreliosis[END_REF]. The immune system of incompetent hosts, such as deer, is able to kill Borrelia. However, these incompetent hosts contribute to maintaining large populations of ticks in the environment as they are the preferential hosts of adult ticks.

Lyme borreliosis. Bacteria responsible for

The most frequent clinical manifestation in humans is a typical cutaneous inflammation, i.e. erythema migrans (centrifugal inflammatory lesion of at least 5 cm) (Figure 3). In the absence of antibiotic therapy, the lesion may progress to an early disseminated stage, and then to a late disseminated stage with cardiac, joint, neurological, or cutaneous involvement depending on the infectious agent [START_REF] Stanek | Lyme borreliosis[END_REF].

The diagnosis is based on an ELISA assay. Any positive result should then be confirmed by Western blot [START_REF] Stanek | Lyme borreliosis: clinical case definitions for diagnosis and management in Europe[END_REF]. The antibiotic therapy duration is two to four weeks, depending on molecules [START_REF] Borchers | Lyme disease: a rigorous review of diagnostic criteria and treatment[END_REF]. The likelihood of persisting clinical manifestations increases with diagnostic delays. However, one cannot talk about "chronic Lyme disease" because living bacteria can no longer be detected [START_REF] Sordet | Chronic Lyme disease: fact or fiction?[END_REF]. However, immunity against Lyme borreliosis is non-protective. A patient may thus be recurrently infected if frequently exposed to tick bites. The rate of Borrelia-infested ticks in France is usually around 10% to 20%. Species mainly observed in ticks and humans are B. afzelii and B. garinii [START_REF] Boulanger | Surveillance du vecteur de la borréliose de Lyme, Ixodes ricinus, en Alsace de 2013 à 2016[END_REF].

Tick-borne relapsing fever. Soft ticks such as Ornithodoros usually transmit these Borrelia species.

More recently described in human pathology, B. miyamotoi is transmitted by hard ticks of the I. ricinus complex [START_REF] Platonov | Humans infected with relapsing fever spirochete Borrelia miyamotoi, Russia[END_REF]. Although present in Europe, this species seems to be mainly pathogenic for immunodeficient people [START_REF] Hovius | A case of meningoencephalitis by the relapsing fever spirochaete Borrelia miyamotoi in Europe[END_REF][START_REF] Boden | Borrelia miyamotoi -Associated neuroborreliosis in immunocompromised person[END_REF].

A total of 22 species have been validated in this Borrelia group. They are observed in tropical areas (Africa mainly), but also in the United States [START_REF] Talagrand-Reboul | Relapsing Fevers: Neglected Tick-Borne Diseases[END_REF]. The main symptoms of the infection are successive peaks of fever or "relapsing" fever due to changes in bacterial surface antigens. Such changes enable them to temporarily escape the host's immune system. Tick-borne relapsing fever is under-diagnosed in tropical regions because of the differential diagnosis of malaria. Diagnosis is based on May-Grünwald Giemsa staining of blood smears because, unlike Lyme borreliosis, bacteremia is high during a fever peak (10 5 -10 7 bacteria/ml).

Rickettsioses. Rickettsioses are transmitted by various arthropods, including ticks. The Rickettsia genus includes small intracellular Gram-negative bacteria. Rickettsia spp. associated with ticks are observed worldwide and the distribution area of each species is similar to that of its vector [START_REF] Parola | Update on tick-borne rickettsioses around the world: a geographic approach[END_REF].

These bacteria interact with endothelial cells, thus increasing vascular permeability which is responsible for clinical manifestations [START_REF] Blanton | Rickettsial infections in the tropics and in the traveler[END_REF]. A total of 25 pathogenic species have been identified, divided into three groups: typhus group (mainly transmitted by lice and fleas), spotted fever group, and a transitional group. Twenty of the 21 species of the spotted fever group are transmitted by ticks, acting both as the vector and main reservoir. Four main species are observed in France:

(1) R. conorii, responsible for Mediterranean spotted fever, is transmitted by Rhipicephalus sanguineus in the south of France, although also present in Europe, Asia, and Africa. After a one-week incubation period, acute fever onset is observed with headaches, arthralgia, and muscular pain. A black spot is observed at the bite site, followed by a rash after three to five days of fever (mainly on extremities). Severe cases have been reported with multiple organ dysfunction syndrome, mainly in Portugal [START_REF] Oteo | Tick-borne rickettsioses in Europe[END_REF];

(2) R. slovaca, R. raoultii (and R. rioja) are responsible for TIBOLA (tick-borne lymphadenopathy) or SENLAT (scalp eschar and neck lymphadenopathy) or DEBONEL (Dermacentor-borne necrosis erythema lymphadenopathy). They are transmitted by the Dermacentor tick. This is currently the most frequent rickettsiosis in Europe. After approximately a week of incubation (1 to 15 days), cervical adenopathy and black spots -most often on the scalpare observed; fever is not always present.

(3) R. helvetica, first described in 1993 in Switzerland and seemingly less pathogenic, is transmitted by Ixodes ricinus [START_REF] Oteo | Tick-borne rickettsioses in Europe[END_REF]. Pathogenicity varies by patient.

Treatment is based on doxycycline or azithromycin.

Imported from Africa, R. africae is observed in France; it is transmitted by Amblyomma variegatum.

Human granulocytic anaplasmosis. The Anaplasmataceae family (Rickettsiales order) includes

strictly intracellular bacteria of the Anaplasma and Ehrlichia genera, which are transmitted by ticks [START_REF] Dumler | Reorganization of genera in the families Rickettsiaceae and Anaplasmataceae in the order Rickettsiales: unification of some species of Ehrlichia with Anaplasma, Cowdria with Ehrlichia and Ehrlichia with Neorickettsia, descriptions of six new species combi[END_REF].

Human monocytotropic ehrlichiosis is caused by Ehrlichia chaffeensis. This species was first identified in humans in the 1990s and is only present in the United States. Its main reservoirs are white-tailed deer and its vector is the Amblyomma americanum tick.

Among species of the Anaplasma genus, A. phagocytophilum -responsible for human granulocytic anaplasmosis (HGA) -is the most important from a clinical standpoint [START_REF] Koenen | Tick borne infections (including zoonoses) in Europe and the Mediterranean Basin[END_REF]. A. phagocytophilum invades white cells (neutrophils, monocytes, and macrophages) and is usually found in vacuole as a morula. HGA has first been reported in 1994 on the eastern coast of the United States [START_REF] Woldehiwet | The natural history of Anaplasma phagocytophilum[END_REF]. HGA is prevalent in temperate regions as it has been reported in both animals and humans in Europe, Asia, the United States, and Australia. Bacterial prevalence rates vary by country and by tick species, with rates between <1% and 20% for I. ricinus in Western Europe and between 1.7% and 16.7% for I. persulcatus in Eastern Europe [START_REF] Stuen | Anaplasma phagocytophilum--a widespread multi-host pathogen with highly adaptive strategies[END_REF]. In France, 1-2% of ticks are infected and human infections are mainly observed in Eastern France [START_REF] Boulanger | Surveillance du vecteur de la borréliose de Lyme, Ixodes ricinus, en Alsace de 2013 à 2016[END_REF]. Differences in Anaplasma ecotypes could be responsible for prevalence disparities in humans. After one to three weeks of incubation following an infected tick bite, disease onset presents as fever and is frequently associated with chills, faintness, or generalized musculoskeletal pain with headaches and myalgia. Biological results usually show increased transaminase level, increased C-reactive protein level, and cytopenia (thrombopenia, neutropenia).

The diagnosis of anaplasmosis is based on bacterial DNA detection on whole blood PCR. It can also be based on the detection of increased antibody levels after a four-week period. HGA treatment is based on doxycycline [START_REF] Koebel | Human granulocytic anaplasmosis in eastern France: clinical presentation and laboratory diagnosis[END_REF].

Candidatus Neoehrlichia mikurensis. This species has been described in Japan and belongs to the Anaplasmataceae family [START_REF] Kawahara | Ultrastructure and phylogenetic analysis of "Candidatus Neoehrlichia mikurensis" in the family Anaplasmataceae, isolated from wild rats and found in Ixodes ovatus ticks[END_REF]. However, several reports such as in the Netherlands with I. ricinus ticks feeding on deer [START_REF] Schouls | Detection and identification of Ehrlichia, Borrelia burgdorferi sensu lato, and Bartonella species in Dutch Ixodes ricinus ticks[END_REF] as well as in Italy [START_REF] Kawahara | Ultrastructure and phylogenetic analysis of "Candidatus Neoehrlichia mikurensis" in the family Anaplasmataceae, isolated from wild rats and found in Ixodes ovatus ticks[END_REF], had already highlighted the presence of gene sequences in this bacterium. The main reservoir is made of rodents and the vector is Ixodes spp., among which the prevalence is 1%-20% depending on European regions. Although a few human cases of infection have been reported, Candidatus Neoehrlichia mikurensis is mainly considered an emerging pathogen [START_REF] Silaghi | Neoehrlichiosis: an emerging tick-borne zoonosis caused by Candidatus Neoehrlichia mikurensis[END_REF]. The bacterium invades endothelial cells. This pathogen is responsible for atypical symptoms, mainly in immunodeficient patients: fever, sepsis, and weight loss [START_REF] Silaghi | Neoehrlichiosis: an emerging tick-borne zoonosis caused by Candidatus Neoehrlichia mikurensis[END_REF][START_REF] Grankvist | Infections with the tick-borne bacterium "Candidatus Neoehrlichia mikurensis" mimic noninfectious conditions in patients with B cell malignancies or autoimmune diseases[END_REF]. Infections caused by this bacterium are treated with doxycycline. Ticks are also likely to transmit other bacteria, but their role as vectors is less important as there are other more effective transmission modes: e.g., for bacteria of the Coxiella, Bartonella, Francisella (etc.) genera.

Q fever.

Coxiella burnetii is a Gram-negative, obligate, intracellular bacterium, commonly found in animal and human monocytes and macrophages. This bacterium is responsible for Q fever, a worldwide zoonosis, and can infect numerous animal species [START_REF] Roest | Clinical microbiology of Coxiella burnetii and relevant aspects for the diagnosis and control of the zoonotic disease Q fever[END_REF]. Humans are contaminated through the respiratory route, when directly in contact with infected animals (mainly ruminants), or through the digestive route following consumption of dairy products or unpasteurized or poorly pasteurized derived dairy products. Ticks only play a secondary role in the transmission. Clinical manifestations of human Q fever are influenza-like illness (fever, headaches, arthralgia, myalgia), atypical pneumonia, or hepatitis. Severity is related to the potential onset of a chronic infection (mainly endocarditis).

Tularemia. Francisella tularensis is a Gram-negative intracellular bacterium. Its prevalence is low, but it is highly virulent and contagious because of an easy dissemination and transmission via aerosols. F. tularensis is observed in various regions of the world, mainly in the Northern Hemisphere, and most often as sporadic cases [START_REF] Steiner | Host-pathogen interactions and immune evasion strategies in Francisella tularensis pathogenicity[END_REF]. It is mainly a zoonosis: the most receptive species are rodents and lagomorphs (hares). Dermacentor and Ixodes ticks can transmit tularemia. However, direct transmission is most frequent, with various transmission modes: direct contact with animals (scratches, bites, licks), ocular route, oral route (undercooked meat consumption), inhalation. The clinical presentation is highly varied and depends on the bacterial portal of entry. Disease onset is abrupt with an influenza-like illness. The ulceroglandular presentation is most frequent. Increased However, ticks are believed to also transmit various Bartonella species, but the vector ability of I. ricinus has only been proven with B. henselae [START_REF] Cotte | Transmission of Bartonella henselae by Ixodes ricinus[END_REF] and B. birtlesii [START_REF] Reis | Vector competence of the tick Ixodes ricinus for transmission of Bartonella birtlesii[END_REF]. Little human data is available to describe the role of ticks in Bartonella transmission.

Viral infections

Numerous viruses may be transmitted to humans and animals by ticks. Most of these viruses belong to three families of viruses transmitted by hard ticks: Bunyaviridae, Flaviviridae, and Reoviridae [START_REF] Lani | Tick-borne viruses: A review from the perspective of therapeutic approaches[END_REF].

The most important tick-borne viral infection in humans are: tick-borne encephalitis virus (TBEV), endemic in Central and Eastern Europe; and Crimean-Congo hemorrhagic fever (CCHF) virus.

Tick-borne encephalitis. The tick-borne encephalitis virus (TBEV) is an RNA virus belonging to the

Flavivirus genus. Ticks acquire the virus during blood meals on a vertebrate host at the viremic phase, and then transmit it to their host during the following meal. Ticks may also acquire the virus when co-feeding on non-viremic or poorly viremic vertebrate hosts [START_REF] Randolph | Co-feeding ticks: Epidemiological significance for tick-borne pathogen transmission[END_REF]. Vertical transmission (from female animals to newborn animals) has been reported in vector ticks, although not frequent (<0.5%) [START_REF] Lindquist | Tick-borne encephalitis[END_REF].

TBEV infection is the most important neuroinvasive disease transmitted by ticks in Europe and Asia, with thousands of human cases per year. Three virus subtypes have been reported, with geographical distributions more or less correlated with the vector geographical distributions: European subtype transmitted by I. ricinus and I. hexagonus ticks, and Siberian and Far Eastern subtypes both transmitted by I. persulcatus [START_REF] Süss | Tick-borne encephalitis 2010: epidemiology, risk areas, and virus strains in Europe and Asia-an overview[END_REF]. This virus is present as more or less stable microclusters, defined based on autochthonous human cases and/or on its detection among field-collected ticks. Other animals may act as competent reservoirs: wild animals such as micromammals (field mice, voles), foxes, wild boars, deer [START_REF] Mansfield | Tick-borne encephalitis virus -a review of an emerging zoonosis[END_REF], but also domestic animals (goats, cows, sheep, and dogs) [START_REF] Ecdc | Tick-borne encephalitis in Europe[END_REF]. TBEV prevalence rates among I. ricinus ticks in Europe usually vary from 0.1% to 1.22% depending on countries, studied areas, and analyzed tick stages [START_REF] Lommano | Prevalence and genotyping of tick-borne encephalitis virus in questing Ixodes ricinus ticks in a new endemic area in western Switzerland[END_REF].

The human infection is seasonal, with a peak during spring and summer due to the activity of vector ticks. Another contamination mode has been reported, through the ingestion of raw dairy products (cheese, milk) from infected domestic animals [START_REF] Mansfield | Tick-borne encephalitis virus -a review of an emerging zoonosis[END_REF].

The infection may be asymptomatic. Following incubation, the typical manifestation presents as an influenza-like illness. Following temporary improvement for a few days, meningitis symptoms may be inconsistently observed and may be associated with encephalitis signs in 50% of patients and with myelitis signs in less than 10% of patients. The case fatality is 0.5%-3% for the European and Siberian subtypes, but reaches 35% for the Far Eastern subtype [START_REF] Mansfield | Tick-borne encephalitis virus -a review of an emerging zoonosis[END_REF]. An effective vaccine is available for this infection. A sharp increase in tick-borne encephalitis cases was reported in 2016 in Eastern France [START_REF] Velay | A new hot spot for tick-borne encephalitis (TBE): A marked increase of TBE cases in France in 2016[END_REF].

Crimean-Congo hemorrhagic fever. The disease was first characterized in the 1940s in the Crimea when a severe hemorrhagic fever epidemic sparked. The virus was then coined "Crimean-Congo hemorrhagic fever virus" (CCHFV), following isolation of the antigenically identical Congo virus in 1956. The virus belongs to the Nairovirus genus from the Bunyaviridae family. It is a large, enveloped, double-stranded DNA virus (group I).

CCHFV distribution reflects the geographical distribution of vector tick species, mainly those of the Hyalomma genus but also of the Dermacentor and Rhipicephalus genera. The virus is observed in Africa, Europe, and Western Asia, but it has never been reported in the New World. Little data is available on the virus prevalence among ticks, and results vary (0.7% to 33%) depending on the detection technique and on the tested tick species. The virus circulates via an enzootic cycle including a large panel of vertebrate hosts among which the virus is asymptomatic; only humans contract the disease. The main vertebrate hosts of the virus are hares, hedgehogs, rodents, and domestic species (bovine animals, sheep, caprines, horses, and pigs). Domestic hosts are considered viral enhancers: they are viremic for at least one week following contamination and develop specific antibodies targeting the virus that can be detected by serological testing. Tick bite remains the main infectious route in humans. However, contacts with infected bodily fluids or tissues from viremic animals may lead to contaminations [START_REF] Mertens | The impact of Crimean-Congo hemorrhagic fever virus on public health[END_REF]. CCHF human infection is characterized by epidemic flares in summer, enabling cluster identification. This is an emerging infection. The clinical presentation is characterized by fever that may lead to a fatal hemorrhagic syndrome in 50% of cases. Two cases of CCHF were reported in 2016 in Spain following tick bites, including one death [START_REF] Lindquist | Tick-borne encephalitis[END_REF]. The prevalence of the virus among ticks is relatively low in Europe (Turkey is particularly affected though). The presence of H. marginatum vector has been confirmed in Camargue and in the area of Montpellier, France [START_REF] Lindquist | Tick-borne encephalitis[END_REF]. Migratory birds from Africa also play a role in the virus circulation [START_REF]Plateforme ESA: Epidémiosurveillance en Santé Animale: Fièvre Criéé-Congo septembre 2016[END_REF].

Parasitic infections

Babesiosis or piroplasmosis. Ticks may transmit parasites (helminths and Apicomplexa protists); members of the Babesia genus are the most pathogenic for humans. Babesia sp. is highly similar to Plasmodium sp. (responsible for malaria), but sporozoites of Babesia sp. are present in the salivary glands of ticks and directly penetrate into red blood cells (no hepatic cycle).

More than 100 species have been characterized and classified as small or large Babesia spp. The most pathogenic species for humans are B. microti and B. divergens, and more recently B. venatorum (Babesia sp. EU1). Ixodes ticks are the vectors of these species. Transmission of the parasite at the sporozoite stage occurs only a few days after attaching to the host as they first need to mature inside salivary glands. Natural hosts of these species, acting as reservoirs, are rodents, bovine animals, and deer [START_REF] Vannier | Human babesiosis[END_REF].

Human babesiosis cases are rare but severe; they are mainly observed in immunodeficient individuals (40% case fatality). Two B. divergens infection cases have been reported in immunocompetent patients in 2009 in Eastern France [START_REF] Martinot | Babesiosis in immunocompetent patients, Europe[END_REF]. Humans and animals may also be contaminated via blood transfusions [START_REF] Koenen | Tick borne infections (including zoonoses) in Europe and the Mediterranean Basin[END_REF]. The clinical presentation depends on the host's immune status and on the involved Babesia species. The main symptoms of human babesiosis are fever, jaundice, anemia, and hemoglobinuria. Treatment in humans depends on the patient's immune system: combination of atovaquone and azithromycin in immunocompetent patients, and clindamycin and quinine for severe cases [START_REF] Vannier | Human babesiosis[END_REF].

Prevention

Individual-based prevention

Physical prevention. Larva and nymph bites from Ixodes ticks are the most difficult to detect because of their small size (Figure 4). Primary prevention against ticks is mainly based on simple measures such as wearing long and bright clothes (Figure 5), tucking one's trousers inside socks, wearing a cap for children to avoid bites on the scalp -although it should be noted that ticks do not fall from trees.

People should also check their body for ticks after being outdoors in infested areas: any warm and humid body parts, skin folds, belly button, genitals, ears, and scalp.

Skin repellents. Primary prevention against ticks may also rely on the use of skin repellents [START_REF] Pages | Tick repellents for human use: prevention of tick bites and tick-borne diseases[END_REF]. Data update is currently underway on the effectiveness of skin repellents against tick bites [START_REF]répulsifs et tiques[END_REF][START_REF] Krober | A standardised in vivo and in vitro test method for evaluating tick repellents[END_REF].

Specificities for the use of these skin repellents are updated every year in the monthly epidemiological report (French acronym BEH) published by the French national agency for public health (Santé publique France) [START_REF]BEH[END_REF].

Repellents do not kill ticks; they only repel them, preventing them from biting humans or animals. The choice of repellent depends on various factors, including the individual's status (age, pregnant woman), and on the intention for use. For all repellents, attention should be paid to the nature and proportion of active ingredients, to the duration of action, and to the maximum daily applications. The pharmaceutical form also plays an important role in the repellent activity.

Current repellents are based on external application molecules (on skin or clothes). Four molecules are known to be effective against tick bites:

(1) PMD (P-menthane-3, 8-diol), Corymbia citriodora eucalyptus extract;

(2) DEET (diethyltoluamide) has been largely used for several decades and is the reference molecule. However, it is known to impair synthetic fibers (rayon, spandex, vinyl, etc.) and plastic materials (glasses, watch strap);

(3) IR35/35® (N-butyl, N-acetyl-3-ethylaminopropionate);

(4) KBR 3023 or picaridin (piperidine-1-carboxylic acid).

Other natural products are being studied, such as 2-undecanone (BioUD ® ) derived from tomatoes, decanoic acid (Contrazek ® ) derived from coconut or palm kernel, geraniol, Margosa extract or margosa (Neem), and lavender extract. The other essential oils are usually not recommended or very rarely recommended as they are highly volatile. Their repellent effect is limited to 20 minutes to one hour. Some components of these essential oils are skin irritants (citral, farnesol, trans-2-hexenal) or carcinogenic (eugenol) [START_REF] Strickman | Prevention of bug bites, stings and disease[END_REF].

Repellent-treated clothing. Repellent-treated clothing is an alternative to skin repellents. Permethrin is widely used. It may be applied as a spray (on the external side of clothes in a ventilated area, and must be left to dry), with a 6-week effectiveness. Cloth immersion in a permethrin bath is more effective. The repellent effect lasts six months and resists to several washings.

Other individual-based protection measures. Following a tick bite, mechanical extraction of the tick is the best effective method and must be performed as rapidly as possible to avoid any potential transmission of pathogens [START_REF] Pages | Tick repellents for human use: prevention of tick bites and tick-borne diseases[END_REF]. Tick removers are particularly useful and should be recommended (Figure 5). However, using products such as oil, ether, or nail polish to facilitate the tick removal is useless. No study has demonstrated the effectiveness of such products.

Collective measures

Environmental treatment of at-risk housing areas may be performed, and mainly consists of getting rid of falling leaves and of mowing lawns. Green areas are more and more frequent in urban areas, and may represent targeted ecosystems [START_REF] Gassner | Greener cities, a wild card for ticks ?[END_REF]. Building up fences around housing areas helps keep deer at bay, as they are the main carriers of adult ticks [START_REF] Kilpatrick | The relationship between deer density, tick abundance, and human cases of Lyme disease in a residential community[END_REF].

Conclusion and perspectives

  Lyme disease belong to the B. burgdorferi sensu lato (sl) group, with 21 species identified. Lyme disease is the most prevalent vector-borne disease in the Northern Hemisphere. The vector is I. scapularis on the eastern coast of the United States and I. pacificus on the western coast. The main vectors in Europe are I. ricinus, and I. persulcatus in eastern Europe and Asia. The most pathogenic species for humans in Northern America is B. burgdorferi sensu stricto (ss), although other species of the complex are active in this region. In Europe, five species are observed in human pathologies: three are frequently observed (B. burgdorferi ss, B. garinii, B. afzelii) and two are only rarely observed (B. spielmanii and B. bavariensis) [24]. The animal reservoir is highly varied, with rodents (B. afzelii and B. bavariensis) and birds (B. garinii and B.

  transmission of this bacterium by ticks has been reported in Switzerland in April 2018 by the Federal Office of Public Health [50]. Bartonellosis. Bacteria of the Bartonella genus are Gram-negative hemotrophic bacteria transmitted by arthropod vectors (sandflies -B. bacilliformis; body lice -B. quintana). A total of 13 species have been identified as potentially pathogenic for humans over the past 20 years: mainly B. henselae and B. quintana. Three species are commonly found on cats (B. henselae, B. clarridgeiae, B. koehlerae).

Figure 1 .Figure 1 .Figure 2 .Figure 2 .Figure 3 .

 11223 Figure 1. Various genera of ticks. From left to right: dorsal side of ticks with Ixodes ricinus,

Figure 3 .

 3 Figure 3. Érythème migrant lors d'une borréliose de Lyme, (A) Typique, (B) Non typique (C) Réaction

Figure 4 .Figure 4 .Figure 5 .Figure 5 .

 4455 Figure 4. Tick bites from Ixodes ricinus (A) Larva and (B) Nymph. (Photo credit: N. Boulanger)

Table 1 .

 1 Main human infectious diseases transmitted by ticksTableau 1. Principales pathologies infectieuses humaines transmises par les tiques

	Diseases	Infectious agents	Vector ticks	Hosts acting as	Geographical
				reservoirs	distribution
			Virus (arbovirus)
	Tick-borne		Ixodes ricinus	Wild mammals,	Asia, Europe
		Flavivirus
	encephalitis		I. persulcatus	vectors
	Crimean-Congo		Hyalomma	Wild mammals,	Europe, Asia,
		Nairovirus
	hemorrhagic fever		marginatum	vectors	Africa
			Bacteria
			Rhipicephalus
			spp.
	Q fever or coxiellosis Coxiella burnetii		Mammals	Worldwide
			Dermacentor
			spp.
		Borrelia
				Small mammals,	Northern
	Lyme borreliosis	burgdorferi sensu	Ixodes spp.
				birds, reptiles	Hemisphere
		lato
					Europe, Northern
	Borrelioses/tick-		Ornithodoros
					America, tropical
	borne recurrent	Borrelia spp.	spp.	Rodents
					and subtropical
	fever		Ixodes spp.
					regions
	Mediterranean		Rhipicephalus		Africa, Asia,
		Rickettsia conorii		Dogs
	spotted fever		sanguineus		Europe
	Tick-borne African		Amblyomma		Sub-Saharan
		Rickettsia africae		Mammals
	fever		spp.		Africa
		Rickettsia
	TIBOLA (tick-borne		Dermacentor
		slovaca,		Sheep, deer	Europe
	lymphadenopathy)		spp.
		R. raoultii, R. rioja
		Francisella	Various	Jackrabbits,
	Tularemia				Worldwide
		tularensis	genera of ticks	rabbits, rodents

Vector-borne diseases transmitted by ticks have been on the rise worldwide since the start of the 20 th century because of increased human activities with an impact on forest ecosystems, wild life animals, and domestic animals. In the Northern Hemisphere, human diseases such as Lyme borreliosis are the most prevalent. However, in southern countries vector-borne veterinary diseases have an impact on socio-economic issues, due to invasive ticks which are disease vectors for livestock. Most of these tick-borne diseases are zoonotic diseases, and the interaction between hosts-vectors-pathogens is still poorly understood for most of them. Tick and tick-borne disease research has been neglected compared with mosquito-borne diseases (malaria, dengue, Zika, etc.). It must be developed to further knowledge on tick circulation and persistence in the environment, infectious agent transmission and persistence among vectors and vertebrate hosts to develop effective multidisciplinary control measures (tick control, diagnosis, vaccine).

Diseases