Veterinary Microbiology 167 (2013) 662–669

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Is the horse a reservoir or an indicator of Coxiella burnetii infection? Systematic review and biomolecular investigation Maria Luisa Marenzoni a,*, Valentina Stefanetti a, Paola Papa b, Patrizia Casagrande Proietti a, Annalisa Bietta a, Mauro Coletti a, Fabrizio Passamonti a, Klaus Henning c a b c

Department of Veterinary Medicine, University of Perugia, Via S. Costanzo 4, 06126 Perugia, Italy Istituto Zooprofilattico Sperimentale of Umbria and Marche, Via Salvemini 1, 06126 Perugia, Italy Institute of Epidemiology, Friedrich-Loeffler-Institute, Seestraße 55, 16868 Wusterhausen, Germany

A R T I C L E I N F O

A B S T R A C T

Article history: Received 31 May 2013 Received in revised form 12 September 2013 Accepted 19 September 2013

The role of the horse in Coxiella burnetii infection has not been defined. Accordingly, a twofold approach was taken to further our knowledge on this topic: (1) conduct a systematic review of the literature to establish available evidence of C. burnetii infection in the horse; (2) undertake a biomolecular investigation of 122 cases of equine abortion, stillbirth and neonatal foal death, for the presence of C. burnetii using a PCR test targeting the IS1111 gene of C. burnetii. A review of the literature turned up seven studies that identified C. burnetii DNA in equine specimens, especially aborted fetuses, while an additional 34 studies sought to determine seroprevalence of the infection in the horse. A meta-analytical approach was taken to calculate a pooled mean seroprevalence in equines based on published studies. A seroprevalence of 15.8% (95% confidence interval: 9.6–23.0%) was obtained. This figure is comparable to those previously reported in other species, especially ruminants. None of the 122 cases of equine abortion, stillbirth or neonatal foal death were positive for C. burnetii DNA. C. burnetii has rarely been looked for in equine specimens in previous studies. Cases of equine abortion should be comprehensively investigated to assess the risk of abortion in a pregnant mare infected with C. burnetii. Consideration should also be given to the possible role of the horse as a source of the organism for other animal species including humans. ß 2013 Elsevier B.V. All rights reserved.

Keywords: Coxiella burnetii Horse Q fever Abortion PCR

1. Introduction Coxiella burnetii is the causative agent of Q fever or coxiellosis, a zoonosis that occurs worldwide among a wide range of animal species, including many wild and domestic mammals, birds, and arthropods such as ticks (Maurin and Raoult, 1999). Although it is an obligate intracellular organism, the bacterium is very resistant under a variety of environmental conditions due to its

* Corresponding author. Tel.: +39 075 5857720; fax: +39 075 5857765. E-mail address: [email protected] (M.L. Marenzoni). 0378-1135/$ – see front matter ß 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.vetmic.2013.09.027

ability to form extracellular spore-like structures. It has been reported that less than 10 organisms can produce disease. Because of its widespread availability, environmental stability, non-specific nature of the symptoms or clinical signs, and low infective dose, it is considered a potential bioterrorist agent (Madariaga et al., 2003). Recent outbreaks in the Netherlands from 2007 to 2009, which resulted in thousands of human cases, have emphasized the need to detect this infection in livestock. Although not all human outbreaks occurred in close proximity to animals, many epidemiological studies have shown a high correlation between human outbreaks and livestock farms, especially those with goats and sheep

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(Enserink, 2010; Georgiev et al., 2013). While the reason for this is not yet fully understood, it is believed that massive numbers of the causal agent are probably released into the environment, disseminated by the wind and transmitted by the respiratory route, when infected fetuses are aborted or delivered. Other previously reported human outbreaks have been associated with infected dogs, cats, or birds (Maurin and Raoult, 1999; Stein and Raoult, 1999). In light of the historical epidemiological link with ruminants, greater attention has probably been paid to study the infection in these species rather than in others. Abortion and infertility caused by C. burnetii have been reported in various animal species, but since the majority of infections are generally asymptomatic, it makes the infection difficult to detect. Moreover, the specific pathogenetic mechanism involved in abortion has never been fully worked out. Even so, experimental reproduction of abortion was obtained in a number of species. Infected placentas from animals with normal deliveries have been reported (Stein et al., 2000; Martinov, 2007; Carcopino et al., 2009; Ben Amara et al., 2010; Hansen et al., 2011; Agerholm, 2013). The role of the horse as a reservoir of C. burnetii infection has not been adequately investigated. Serological evidence of infection of horses with C. burnetii has been reported for a long time. Results of studies have been variable, ranging from failure to detect any evidence of infection (Raseta and Mihajlovic, 1983) to an estimated seroprevalence of 52.5% (Joshi and Padbidri, 1978). Moreover, a recent report suggested C. burnetii as a possible abortigenic agent in horses in France (Le´on et al., 2012). C. burnetii infection can be demonstrated in different ways, depending on the type of sample and the purpose of the investigations. Serological tests are used especially for screening herds or flocks and to detect previous exposure to the bacterium but they are not appropriate for determining the infectivity status of individual animals. On the other hand, isolation of the causal agent in cell culture or embryonated eggs is laborious and timeconsuming, while its detection using stained smears has a low sensitivity. Consequently, several PCR based diagnostic assays have recently been developed to detect C. burnetii DNA in clinical samples. Techniques targeting genes of a substantial copy number, like the insertion sequence IS1111, were demonstrated to be especially sensitive (Berri et al., 2000; Klee et al., 2006; OIE, 2012). Taking into consideration all of the foregoing, the aim of this study was: (1) To conduct a systematic review of the literature to establish available evidence of C. burnetii infection in the horse; (2) To investigate the presence of C. burnetii in 122 cases of equine abortion, stillbirth and neonatal foals in order to verify whether C. burnetii could be a possible abortigenic agent in the horse. 2. Materials and methods 2.1. Literature search A literature search was carried out using Medline (from 1966), ISI’s (Thomson) Science Citation Index Expanded

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(from 1946) and CAB abstracts (from 1973) until May 2013. The algorithm of research was ‘‘(Q fever OR Query Q OR Coxiellosis OR Coxiella burnetii OR C. burnetii) AND (horse* OR equid* OR equine*)’’ in all fields. No language restrictions were used in conducting the searches. Hand searches of reference lists of published papers were used to complement the computer searches. Abstracts were translated from publications in languages other than English. Studies were included if they reported the results of serological and diagnostic investigations on equid populations (horse, donkey, mules or others) in order to find out the presence or the prevalence of the infection in different countries. When an article was not available in full-text, however the study was included in the systematic review and the quantitative analysis, in the case that the abstract contained sufficient data to establish the presence of the infection or the number of events and the population size to estimate the seroprevalence. When other species were investigated in these studies together with horses, the data on other species were also included in supplementary table. When different categories of the same species (i.e. breed, year of sampling, production area) were studied in the same paper, a mean value of the seroprevalence within the category was calculated. Supplementary material related to this article can be found, in the online version, at http://dx.doi.org/10.1016/ j.vetmic.2013.09.027. The pooled mean seroprevalence of equid populations was calculated using Stats Direct software, version 2.7.9, and the studies were included in the meta-analysis when the number of the events (numerator) and the population size (denominator) were present or inferred from the text. The descriptive data are shown in supplementary table. A random effects model was used a priori, considering the huge differences among studies and an attempt to generalize the results in a range of scenarios. The presence of bias was evaluated using the Egger’s linear regression method and the Trim and Fill method (Duval and Tweedie, 2000) using the Stats Direct Software and the Comprehensive Meta-Analysis software. 2.2. Samples, DNA extraction and PCR One hundred and five abortions, 16 foals which died within 5 days of birth and 100 placentas, collected between 2005 and 2012 from 122 mares resident on at least 35 different farms of the Central Italy, were analyzed. When possible, samples from at least two pools of different organs and from placenta were collected from each case. The placenta was available in association with fetal organs in 89 cases and was the only tissue submitted in 11 cases. DNA was extracted from 284 specimens of tissue using a commercial kit (DNeasy Tissue kit, Qiagen, Milan, Italy), in accordance with the manufacturer’s instructions. Extracted DNA was quantified using a spectrophotometer and the integrity checked by agarose gel electrophoresis with ethidium bromide staining. The PCR protocol, amplifying a fragment of 687 bp of the IS1111 insertion sequence and described by Berri et al. (2000), was used with some modifications. Briefly, 25 mL of reaction mixture contained 10 PCR buffer, 3 mM of

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MgCl2, 200 mM of each deoxyribonucleotide triphosphate, 1 mM of each primer (Sigma–Genosys, Milan, Italy), 0.5 U Taq DNA polymerase (Microtech, Italy), and 5 mL of DNA of the sample. The DNA of each sample was tested in duplicate. Cycling conditions were as follows: 95 8C for 5 min, 40 cycles at 94 8C for 30 s, 59 8C for 30 s, and 72 8C for 45 s, and 72 8C for 5 min. To rule out possible PCR inhibitors in the samples and to check for successful DNA amplification, 18S ribosomal RNA gene PCR (QuantumRNATM 18S Internal Standards kit, Ambion, Cambridgeshire, UK) was performed. A positive control (C. burnetii Nine mile/I/EP1, ATCC VR-615) and a negative control (negative DNA) were used in each set of reactions. All PCRs were performed in MJ Research PTC-150 thermal cycler. The PCR products of the expected size were run on 1.5% agarose gel. 3. Results 3.1. Literature search The results of the systematic literature review are summarized in Fig. 1 (Van der Hoeden and Evenchik, 1959; Moorthy and Sdradbrow, 1985; Baldelli et al., 1995;

Bamberg et al., 2005; Torina et al., 2007; Karagiannis et al., 2009; Le´on et al., 2009; Nett et al., 2012; Socolovschi et al., 2012; Agerholm, 2013; Georgiev et al., 2013). Six articles were not found and their abstracts were not available (Zarnea et al., 1958; Toma et al., 1968; Ghosh et al., 1976; Martinov et al., 1998; AVMA, 2009; Dorko, 2012). The results of the systematic review for horses and other species reported in the same studies are summarized in supplementary table. The most recent studies (Le´on et al., 2008, 2009, 2012; Runge et al., 2012; Pan et al., 2013; Roest et al., 2013; Tozer et al., 2013) pursued a direct diagnostic approach, using real-time PCR (Table 1), while all the others were based upon serological testing. One study (Mostafavi et al., 2012) involved a systematic review on coxiellosis in different species, but was limited to Iran. It reported a generic serological positivity in horses in the country, without providing any details. Five of the studies that carried out a direct diagnostic approach (Le´on et al., 2008, 2009, 2012; Runge et al., 2012; Roest et al., 2013) involved real-time PCR testing of equine abortions or placenta. However, three of them (Le´on et al., 2008, 2009, 2012) are by the same authors and there is probably redundancy of data.

Fig. 1. Flow diagram of the systematic review (The PRISMA Group, 2009). The paper by AVMA (2009) was included in the qualitative synthesis in spite of the following lack of the fulltext.

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Table 1 Key features and results of the studies performed molecular diagnosis for Coxiella burnetii on equine specimens and included in the systematic review. Reference

Country

Specimen

Applied test

Number positive results

Total number tested

% Positive

The present study Pan et al. (2013)a

Italy China

Aborted fetus Blood

Roest et al. (2013) Tozer et al. (2013)

The Netherlands Australia

Runge et al. (2012) Le´on et al. (2012) Le´on et al. (2009) Le´on et al. (2008)

Germany France France France

Placenta Blood Urine Aborted fetus Aborted fetus Aborted fetus Aborted fetus

Conventional PCR Real-time PCR LAMP Real-time PCR Real-time PCR

0 0 4 3 14 1 1 6 22 6

122 18 18 39b 112 14 23 407 629 407

0 0 22.2 7.7 12.5 7.1 4 1.5 3.4 1.5

Real-time Real-time Real-time Real-time

PCR PCR PCR PCR

LAMP, loop-mediated isothermal amplification. a This study tested the same samples in parallel by both employed methods. b Only 8 out of 39 placentas were from aborting animals while the others were collected during parturition with veterinary assistance, without known abortion history. Each of the 8 cases were negative for C. burnetii DNA.

Only two studies (Pan et al., 2013; Tozer et al., 2013) performed real-time PCR on different specimens (blood and urine) and they found higher number of positive results in horses compared with the other species that were investigated. The Australian study provides a new approach to explore the prevalence and the epidemiology of coxiellosis both in horses, and in other species (Tozer et al., 2013). A website described sporadic abortion and necrotic placentitis by C. burnetii in horses, but it is no longer available (AVMA, 2009). Quantitative analysis of the studies using a direct diagnostic approach was not performed because of the limited number of studies, the redundancy of some of them and the heterogeneity of the specimens. Nonetheless, the data showed that C. burnetii DNA can be present in cases of equine abortion. Apart from the papers on abortion or pregnancy loss, clinical illness associated with C. burnetii infection in horses or equids has not been investigated or reported. Only two experimental studies have been described in the literature (Zotov et al., 1956; Blinov, 1957). In the first experimental study, infection was reproduced by attaching infected ticks and by parenteral and oral administration of C. burnetii. Fever, depression, conjunctivitis and rhinitis were observed. Only fever was present after infection by ticks. Titers and onset of detection of complement-fixing antibodies varied based on method of infection and size of the dose (Zotov et al., 1956). In the other study, six horses were infected subcutaneously, intra-tracheally or via a stomach tube; all animals developed acute catarrhal gastritis and enteritis, catarrhal rhinitis, conjunctivitis, lung and bronchial infections. Fever occurred only in horses infected subcutaneously and complement-fixing antibodies were demonstrated after 25 days post infection, with titers ranging from 1:20 to 1:160 (Blinov, 1957). Seroprevalence studies were the most frequent. Geographically and temporally limited investigations, targeting specific populations, have been conducted. Accordingly, the prevalences found in each study varied widely based on year, geographic location, population tested, assay type, criteria used to define positive results and sensitivity and specificity of the tests. The estimated pooled mean seroprevalence for the equid population was 15.8% (95% interval confidence, IC: 9.6–23.0%) and is reported in Fig. 2 (Davoli and Signorini, 1951; Cordier et al.,

1953; Raska and Syrucek, 1956; Pitre, 1960; Cannistra` et al., 1967; Hrabar et al., 1971; Enright et al., 1971; Choudhury et al., 1971; Sadecky et al., 1974; Rehacek et al., 1977; Krauss et al., 1977; Sharma et al., 1978; Joshi et al., 1979; Willeberg et al., 1980; Yadav and Sethi, 1981; Raseta and Mihajlovic, 1983; Sharma et al., 1984; Padbidri et al., 1984; Somma-Moreira et al., 1987; George and Marrie, 1987; Sixl et al., 1984; Martinov et al., 1989; Ajuwape and Falade, 1993; Jaspers et al., 1994; Martinov, 2007). This was determined using random effects, assuming that there are differences in diagnostic tests and populations make it difficult to pool the data. The two experimental studies were excluded by quantitative analysis (Zotov et al., 1956; Blinov, 1957). No significant publication bias was present in the analyzed studies. 3.2. PCR All samples were positive for 18S ribosomal RNA gene PCR, excluding the presence of PCR inhibitors, but they were negative to C. burnetii DNA. 4. Discussion The present study and other five studies (Le´on et al., 2008, 2009, 2012; Runge et al., 2012; Roest et al., 2013) are the only studies that attempted to investigate the role of C. burnetii in cases of equine abortion. Positive cases provide an important opportunity to determine whether the horse can be a shedder of the microorganism and constitute a possible risk for transmission of the infection to other animals and humans. Accordingly, any C. burnetii positive cases of equine abortion should be appropriately investigated in an effort to gain an understanding of the role of this organism in equine pregnancy loss and in the epidemiology of the infection. There is the possibility that C. burnetii might not have an important role in abortion as indicated by Hansen et al. (2011) in cattle. He found that bovine placentas, positive for C. burnetii DNA, were without detectable lesions, absence of evidence of inflammation and with inactive intracellular bacteria. Consequently it would be important to investigate the significance of C. burnetii infection in animals that have

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Fig. 2. Forest plot for the seroprevalence of Coxiella burnetii in equids obtained by the selected studies. The data of the studies of Sixl and Sixl-Voigt (1987) and Choudhury et al. (1971) also include donkeys.

: effect sizes calculated for each study by seroprevalence effect;

: the overall effect size

obtained for the seroprevalence across studies. The corresponding numerical data of the seroprevalence and the respective 95% confidence interval for each study and for the combined studies are reported on the right column

normal deliveries. In this respect, a recent critical review hypothesizes that the importance of C. burnetii as an abortifacient agent could be overestimated using the PCR assay. Evidence of lesions in association with presence the bacteria is necessary in implicating C. burnetii as an actual cause of abortion (Agerholm, 2013). No evidence of C. burnetii DNA was found in the cases of abortions, stillbirth and neonatal mortality in the present study, although outbreaks of Q fever and epizootics of coxiellosis have been regularly reported

in Italy, both in humans and in animals. There is reason to believe that the frequency of such disease events is probably underestimated, as no active surveillance program is currently in place (Santoro et al., 2004; Starnini et al., 2005; Masala et al., 2007; Perugini et al., 2009). The conventional PCR assay used in the present study may underestimate the presence of C. burnetii DNA compared with the use of a real-time PCR reported in previous studies. However, the conventional PCR is considered to be highly sensitive using the IS1111 gene.

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The latter is estimated to be present in a variable number of copies/microorganisms, ranging from 7 to 110 (OIE, 2012). On the other hand, the possibility of there being false negative results in the present study can be excluded because an internal control was used for each sample to verify the amplificability of DNA and the absence of inhibitors. When a pathogen is searched for but not detected, the likelihood of an infectious cause of abortion is probably low, in view of the fact that many infectious agents cause multiple cases or abortion storms (Williams, 2011). C. burnetii may only be a sporadic cause of abortion. The cause of abortion, stillbirth or neonatal mortality was previously detected in nearly half of the cases submitted in the present study (Marenzoni et al., 2012). C. burnetii may have been present in those cases lacking a specific diagnosis. It was also searched for in other samples where it could have been associated with other infectious agents, as reported by Le´on et al. (2012). Two experimental studies provided some information on the infection in horses, especially in respect of simulating the normal route of infection (Zotov et al., 1956). Another novel approach has been described by Tozer et al. (2013) in which direct diagnosis was performed on blood and urine in many different species; this yielded positive results especially in horses. However, no link with clinical signs or outbreaks/epizootics was described. Accordingly, other studies need to be carried out using these type of specimens, especially in case of outbreaks, to corroborate these findings. The result of the systematic review revealed that C. burnetii has been studied in horses for a long time (Davoli and Rosati, 1952) and in many countries, without clarifying its epidemiological role. Since the studies included in the present analysis were characterized by wide heterogeneity however, the results of the quantitative analysis must be interpreted with caution. Despite the limitations of those studies, a pooled mean seroprevalence of C. burnetii antibodies in equids was attempted based on the fact that every study performed without a random sampling is usually biased and many studies of prevalence of different infectious diseases are generally carried out without applying this kind of sampling. The pooled mean seroprevalence estimated in horses is not significantly different from the mean seroprevalence in ruminants obtained in other systematic reviews: 20% for cattle, and 15% for goats and sheep (Guatteo et al., 2011) and 15.0–21.0% for cattle, 2.5–88.1% for goats and 3.5–56.9% for sheep at animal level (Georgiev et al., 2013). Those studies were also characterized by considerable heterogeneity in aims, geographical areas analyzed, specimens, sampling methods and results. Although many papers underscored the important role of ruminants as source of C. burnetii infection (Berri et al., 2007; Rodolakis et al., 2007; Georgiev et al., 2013), the majority of these studies could be partially biased because of special attention paid to ruminants in case of coxiellosis, while horses received only marginal attention with respect to C. burnetii infection. In support of the foregoing, a reporting bias was found in the Netherlands when addressing the role of goats, where Q fever was called ‘‘goat flu’’ (Karagiannis et al., 2009).

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Moreover, a recent review even excluded cattle as the main reservoir for C. burnetii (Georgiev et al., 2013). Other examples of bias have been reported, like the bias of overdiagnosis, resulting in a higher incidence of Q fever in humans recorded near a reference laboratory (Frankel et al., 2011) or an overestimation of prevalence, using populations at high risk of infection (Georgiev et al., 2013). Other factors apart from species, such as farm densities of animals, seasonality of births or management, could explain the higher frequency of C. burnetii infection in ruminants. The risk factors identified for C. burnetii infection in ruminants should also be examined when studying the infection in horses. Moreover, different C. burnetii infections may have differing epidemiologic characteristics depending on the nature of specific outbreaks (Georgiev et al., 2013). An interesting consideration is that an increase in seroprevalence among ruminant herds is a useful predictor of C. burnetii outbreak in humans (Georgiev et al., 2013). This could be verified also in the case of the infection in horses. Another aspect to consider is the lack of full-text and abstracts for some articles; this made it impossible to delve more fully into some aspects of the research that has been carried out. A paper of particular interest was that of Zarnea et al. (1958) in that it is the only one that deals with horses as a source of infection. Regrettably, it was not possible to evaluate it because it was not available. Moreover, three other interesting papers (Bamberg et al., 2007; Karagiannis et al., 2009; Nett et al., 2012), which were found by systematic review, were excluded from the analysis because they did not investigate the infection in the horse. One of them (Bamberg et al., 2007), however, described an outbreak of human Q fever at a horse-boarding ranch that had horses and goats. On analysis of the risk factors of the people in the cohort study, it was found that seropositivity in humans was associated with activity and contact with goats but not with other activities, including those with horses. The second outbreak (Karagiannis et al., 2009) occurred in the Netherlands. The results of this case–control study performed during the outbreak revealed that having touched horses and ponies and frequent horse-riding were possible risk factors. Unfortunately, in both of these papers, no testing of horses was carried out. A final paper (Nett et al., 2012) described a case of Q fever in a man exposed to multiple ticks while riding a horse. This could be another way of transmission of infection linked to horses to investigate. These studies might suggest either that Q fever could be transmitted from infected horses or activities related to horse-riding (cleaning stables, handling straw or hay, brushing the animals), which could lead to exposure to contaminated dust or air from the environment. In this manner, a horse exposed to the infection could serve as a useful indicator of infection or possibly a reservoir of the etiological agent, as recently hypothesized by Roest et al. (2013). These cases should be carefully examined to determine, for example, if pregnant mares are at risk of abortion during an epizootic of coxiellosis.

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5. Conclusion This review revealed that only limited and fragmentary knowledge is available on the epidemiology of C. burnetii infection in horses. Further studies both on healthy equine populations and during outbreaks/epizootics involving horses, and investigation of positive cases of equine abortion are important if we are to further our understanding of the role of the horse in C. burnetii infection and in time, be able to prevent an epizootic involving horses. Increased surveillance of infection and disease outbreaks is the way to improve our knowledge on this topic. Conflict of interest None of the authors of this paper has financial or personal relationship with other people or organization that could inappropriately influence or bias the content of the paper. Acknowledgement The authors acknowledge Prof. Peter J. Timoney for his skillful English revision of the manuscript. References Agerholm, J.S., 2013. Coxiella burnetii associated reproductive disorders in domestic animals – a critical review. Acta Vet. Scand. 55, 13. Ajuwape, A.T.P., Falade, S., 1993. Serological evidence for Q fever in horses and pigs in Nigeria. Trop. Vet. 11, 79–81. AVMA, 2009. Backgrounder: Q Fever. American Veterinary Medical Association. http://www.avma.org/public_health/biosecurity/qfever_ bgnd.asp (accessed 07.05.09). Baldelli, R., Calistri, P., Battelli, G., Cavone, D., Di Francesco, A., Musti, M., 1995. Seroepidemiological studies on zoonoses in farm workers in Apulia. Ann. Ig. 7, 445–450 (in Italian). Bamberg, W.M., Pape, W.J., Beebe, J.L., Nevin-Woods, C., Ray, W., Maguire, H., Nucci, J., Massung, R.F., Gershman, K., 2007. Outbreak of Q fever associated with a horse-boarding ranch, Colorado, 2005. Vector Borne Zoonot. 7, 394–402. Ben Amara, A., Ghigo, E., Le Priol, Y., Le´polard, C., Salcedo, S.P., Lemichez, E., Bretelle, F., Capo, C., Mege, J.L., 2010. Coxiella burnetii, the agent of Q fever, replicates within trophoblasts and induces a unique transcriptional response. PLoS One 5 (12) e15315. Berri, M., Rousset, E., Champion, J.L., Russo, P., Rodolakis, A., 2007. Goats may experience reproductive failures and shed Coxiella burnetii at two successive parturitions after a Q fever infection. Res. Vet. Sci. 83, 47–52. Berri, M., Laroucau, K., Rodolakis, A., 2000. The detection of Coxiella burnetii from ovine genital swabs, milk and fecal samples by the use of a single touchdown polymerase chain reaction. Vet. Microbiol. 72, 285–293. Blinov, P.N., 1957. Experimental Q fever in horses. Veterinaria 34, 34–40 (in Russian with English abstract). Cannistra`, S., Sanzi, G., Curro`, G., 1967. Survey of the epidemiological serology of Q fever in the Province of Catanzaro. G. Mal. Infett. Parassit. 19, 530–533 (in Italian). Carcopino, X., Raoult, D., Bretelle, F., Boubli, L., Stein, A., 2009. Q Fever during pregnancy: a cause of poor fetal and maternal outcome. Ann. N. Y. Acad. Sci. 1166, 79–89. Choudhury, S., Balaya, S., Mohapatra, L.N., 1971. Serological evidence of Coxiella burnetii function in domestic animals in Delhi and surrounding areas. Indian J. Med. Res. 59, 1194–1202. Cordier, G., Kovalenko, C., Harouni, B., 1953. Q fever in animals in Tunisia (La fievre Q animale, en Tunisie). Recueil Me´d. Vet. (Alfort) 129, 565 (in French with English abstract). Davoli, R., Signorini, L.F., 1951. Antibodies against Rickettsia burnetii in serum of animals slaughter house in Tuscany. Ann. Sanita` Publ. 12, 67 (in Italian).

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Is the horse a reservoir or an indicator of Coxiella burnetii infection? Systematic review and biomolecular investigation.

The role of the horse in Coxiella burnetii infection has not been defined. Accordingly, a twofold approach was taken to further our knowledge on this ...
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