Tuberculosis in domestic animal species

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Tuberculosis in domestic animal species M. Pesciaroli a,b, J. Alvarez c, M.B. Boniotti d, M. Cagiola e, V. Di Marco f, C. Marianelli a, M. Pacciarini d, P. Pasquali a,g,* a

Department of Veterinary Public Health and Food Safety, Istituto Superiore di Sanità, Rome, Italy VISAVET Health Surveillance Centre, Universidad Complutense Madrid, 28040 Madrid, Spain Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St. Paul, MN, USA d National Reference Centre for Bovine Tuberculosis, Istituto Zooprofilattico Sperimentale della Lombardia e dell’Emilia Romagna, Brescia, Italy e Istituto Zooprofilattico Sperimentale dell’Umbria e delle Marche, Perugia, Italy f Istituto Zooprofialttico Sperimentale della Sicilia, Barcellona Pozzo di Gotto, Messina, Italy g FAO Reference Centre for Veterinary Public Health, Department of Veterinary Public Health and Food Safety, Istituto Superiore di Sanità, Rome, Italy b c

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Article history: Received 14 October 2013 Accepted 19 May 2014 Keywords: Mycobacterium bovis Mycobacterium caprae Tuberculosis

A B S T R A C T

M. bovis and M. caprae, members of the Mycobacterium tuberculosis complex (MTC), are the major causative agents of tuberculosis in domestic animals. Notably, M. bovis exhibits a wide host range; the infection has been reported in many domesticated animals and free or captive wildlife. Despite most of them acting as spill-over hosts in particular epidemiological scenarios, some domesticated species as pigs, camelids and goats may display high rates of infection and possibly play a role in the inter-species transmission of the disease. The aim of this review is to make an updated overview of the susceptibility and the role in the transmission of the disease of the most common domesticated animals species such as small ruminants, pigs, horses, camelids, dogs and cats. An overview of the diagnostic approaches to detect the infection in each of the species included in the review is also presented. © 2014 Elsevier Ltd. All rights reserved.

1. Introduction Two members of the Mycobacterum tuberculosis complex (MTC) are responsible to cause tuberculosis in cattle: M. bovis and, to a lesser extent, M. caprae. Tuberculosis is a chronic debilitating disease, classically characterized by formation of nodular granulomas (tubercles), most frequently observed in the lymph nodes (particularly of the head and thorax), lungs, intestines, liver, spleen, pleura, and peritoneum (Palmer and Waters, 2006). Cattle are considered the main hosts of M. bovis. Nevertheless, the infection has been reported in many domesticated animals and several free or captive wildlife species, such as buffaloes, bison, sheep, goats, equines, camels, pigs, wild boars, deer, antelopes, dogs, cats, foxes, mink, badgers, ferrets, rats, primates, South American camelids, kudus, elands, tapirs, elks, elephants, sitatungas, oryxes, addaxes, rhinoceroses, possums, ground squirrels, otters, moles, raccoons, coyotes and several predatory felines including lions, tigers, leopards and lynx (Cousins, 2001; de Lisle et al., 1990). Since M. bovis is a pathogen that can be encountered in several host populations, some of them can act as reservoir of infection. Nevertheless, in a more comprehensive and appropriate approach, a reservoir can be defined as one or more epidemiologically connected

* Corresponding author. Tel.: +39 06 49902326; fax: +39 06 49907077. E-mail address: [email protected] (P. Pasquali).

populations or environments in which the pathogen can be permanently maintained and from which infection is transmitted to the defined target population (Haydon et al., 2002). The role of several wildlife species as reservoirs of TB has been demonstrated in the past (mainly the badger in the UK) (Biek et al., 2012; Corner et al., 2011), the possum in New Zealand (Nugent, 2011), the African buffalo in South Africa (Renwick et al., 2007) and the wild boar in Spain (Gortazar et al., 2011; Naranjo et al., 2008), and therefore the impact of the infection in these species has been the subject of other reviews (Fitzgerald and Kaneene, 2013; Palmer, 2013; Palmer et al., 2012). Here, the objective was to summarize the existing knowledge about the susceptibility and therefore potential importance of other domestic species (small ruminants, pigs, horses, camelids, dogs and cats) as well as the possible diagnostic options for disease detection in these species. 2. Goat The disease in goat is mainly caused by M. bovis and M. caprae, (Alvarez et al., 2008; Crawshaw et al., 2008; Daniel et al., 2009; Sharpe et al., 2010). The infection with M. tuberculosis and NTM (Nontuberculous mycobacteria) may also lead to tuberculosis and tuberculosis-like diseases respectively, and compromise the accuracy of the TB-diagnostic tests as demonstrated for M. avium subsp. paratuberculosis (Cadmus et al., 2009; Kassa et al., 2012; Tschopp et al., 2011). The isolation of M. tuberculosis in goats highlights the

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need of further studies to understand the interspecies transmission dynamics of M. tuberculosis and highlights the possible role of goats in the epidemiology of human tuberculosis in pastoralist setting where potential epidemiological risk factors for infection and transmission between livestock and human could exist (Kassa et al., 2012). In fact the close physical contact of pastoralists with their animals, which is common in pastoralist communities of developing countries, may represent a potential risk factor for transmission of M. tuberculosis complex members from animals to human or vice versa (Boukary et al., 2012; Ereqat et al., 2013; Kassa et al., 2012). In addition watering and grazing points are often shared between goats and cattle, allowing a close interspecies interaction among these domestic animals and therefore increasing the likelihood of crossspecies transmission of mycobacteria (Biffa et al., 2010; Gumi et al., 2011; Kassa et al., 2012; Mamo et al., 2009; Muñoz Mendoza et al., 2012; Tschopp et al., 2010). Epidemiological studies indicate that TB in goat has a global distribution, and its presence has been reported in various countries of the world including, Sudan, Spain, Italy, Portugal, Nigeria, the United Kingdom, Algeria and Ethiopia (Aranaz et al., 1999; Cadmus et al., 2009; Crawshaw et al., 2008; Daniel et al., 2009; Hiko and Agga, 2011; Naima et al., 2011; Quintas et al., 2010; Shanahan et al., 2011; Sharpe et al., 2010; Tafess et al., 2011; Tag el Din and el Nour Gamaan, 1982; Tschopp et al., 2011; Zanardi et al., 2013). Goats affected with TB may initially show dry coughing, progressive emaciation, occasional diarrhoea and death (Bezos et al., 2012). Post mortem examination of animals infected with M. bovis frequently reveals circumscribed pale yellow, white, caseous or caseocalcareus lesions of various sizes, often encapsulated, especially in the lungs and mediastinal lymph nodes, or in the mesenteric lymph nodes. Similar gross lesions have been described in goats infected with M. caprae (Alvarez et al., 2008; Bezos et al., 2010). The presence of lesions in the respiratory tract and the close contact with cattle infected by the same spoligotypes, suggest that goats have the potential to act as domestic reservoir for TB (Bezos et al., 2012; Napp et al., 2013; Zanardi et al., 2013). In some European countries, including Greece, Italy, Spain and Portugal, which have high small ruminants census figures and are not officially TBfree (OTF), there may be a risk of spread of TB between cattle and small ruminants, especially when animals share pastures (EFSA, 2009). Surveillance of TB in goats in non-OTF countries is therefore important, and given its zoonotic potential, goats used for raw milk production living in mixed cattle-goat herds must be tested for TB (Regulation (EC) 853/2004). However, most non-OTF countries lack an active ante-mortem TB surveillance programme in caprine flocks that are not in close contact with cattle. In this situation, TB cases are therefore usually detected in the post mortem examination at the slaughterhouse, though TB in small ruminants is more rarely detected at the abattoir due to a lower quality of the meat inspection than that commonly carried out in cattle. In Spain, some regions have programmes for the control of tuberculosis in goats, applying the same diagnostic assays that are used for cattle (Bezos et al., 2012). Several diagnostic tests are used to ascertain individual and flock TB status. Tests measuring the CMI (cell-mediated immunity) as the single intradermal tuberculin test (SITT) or the single intradermal comparative tuberculin test (SICTT) and the IFN-γ assay have demonstrated higher sensitivity and specificity than tests relying on detection of the humoral immune response (Gutiérrez et al., 1998; Zanardi et al., 2013). However, there is a lack of standardization of SITT and SICTT in this species, and certain aspects as the site injection (neck or shoulder) or the interpretation of the results vary between the studies (Alvarez et al., 2008; Shanahan et al., 2011; Zanardi et al., 2013) and are usually applied just following the standards developed in cattle. Standard or anamnestic (sera collected 15 days after the intradermal tuberculin test) Enzyme-Linked

ImmunoSorbent Assays (ELISA) have demonstrated their capacity to detect anergic animals in an advanced stage of infection (Gutiérrez et al., 1998; Zanardi et al., 2013). The review of tuberculosis diagnosis in goats by Bezos et al. (2012) provides an overview of current in vivo tools for diagnosis of caprine tuberculosis, including estimates of the sensitivity and specificity of tests performed in this species. This study highlighted the need to evaluate the current diagnostic tests, developed for cattle, in the target host species and to determine the performance characteristics of the tests against the individual MTC species. The literature indicates the importance of TB in goats and the need to design feasible national control strategy in livestock of countries where TB is endemic in cattle. To minimize the spread of TB among animals on the same farm, consideration should be given to (i) segregation of cattle from other ungulates where possible; (ii) active ante-mortem TB surveillance programme in goat flocks; (iii) active and accurate post mortem TB surveillance at the slaughterhouse. 3. Sheep Sheep is susceptible to the infection of M. bovis and M. caprae. However, a low incidence of TB in sheep is usually reported, and individual cases are usually detected during routine post mortem inspection at the slaughterhouse (Boukary et al., 2012; Marianelli et al., 2010). As mentioned for goat, small ruminants carcasses typically undergo a less detailed post mortem examination than that performed in cattle, and this could explain the fewer reports of TB infection in sheep (van der Burgt et al., 2013). In addition, farming practices and behaviour of sheep should be taken into account: extensive management, grazing during the daylight hours, a circumspect attitude and an allelomimetic behaviour are all factors that concur to reduce interactions between sheep and infected cattle or wildlife (Allen, 1988). However, the number of studies reporting TB infection in sheep has been increasing over the last decades, notably in non OTF countries, suggesting that the prevalence of TB infection in sheep could be currently underestimated. The infection has been described in Spain (Muñoz Mendoza et al., 2012), Italy (Marianelli et al., 2010), UK (Houlihan et al., 2008; Malone et al., 2003; van der Burgt et al., 2013), New Zealand (Cordes et al., 1981) and Ethiopia (Kassa et al., 2012). In these cases, TB lesions were mostly confined to the respiratory tract, demonstrating that the transmission of the disease in sheep can occur through aerosols. No TB lesions affected the gastrointestinal tract and the extent and the severity of the lesions observed in the lungs likely suggest that sheep were shedding high amounts of mycobacteria through nasal discharge and hence were able to transmit the disease. Nevertheless, cases of generalization of the infection have been also reported (Marianelli et al., 2010). The anatomopathological findings in sheep infected with TB suggest that sheep could act as a reservoir of infection. The infection is likely acquired by sharing pastures or cohousing with infected cattle or goats (Malone et al., 2003; Marianelli et al., 2010; Muñoz Mendoza et al., 2012) or by contact with infected wildlife (Allen, 1988; van der Burgt et al., 2013). Sheep infected with M. bovis or M. caprae show generic ill thrift, while respiratory symptoms are rare, even when large lesions affect the lungs (van der Burgt et al., 2013). Once that TB is suspected, SIT or SICCT are regarded as the first option for diagnosis. SITT performed on 281 sheep belonging to a New Zealand flock showed a sensitivity of 81.6% and a specificity of 99.6%. In fact, SICTT performed at a two months interval coupled with removal of reactors was able to eradicate the disease from two separate British flocks where an outbreak of M. bovis had occurred (Malone et al., 2003; van der Burgt et al., 2013). Although rarely applied to sheep, the IFN-γ assay yielded results in agreement with the SICCT, being able

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to recognize 4/4 skin reactors from which 3/4 had visible TB lesions at necroscopy. 4. Pigs Pigs are susceptible to M. bovis infection. The oral route is considered the most important route of infection in domestic pigs, which acquire infection most frequently through the ingestion of milk, milk products or offal from infected cows. In the last century, when control and eradication measures had not been implemented in cattle yet, M. bovis was commonly found in pigs and prevalence in pig population was usually correlated to that in cattle. Not surprisingly the implementation of eradication campaigns in cattle reduced the prevalence of pig tuberculosis in many countries. In the USA, for example, the rate of tuberculosis lesions due to M. bovis in slaughtered pigs declined from 15.2% in 1924 to 1.09% in 1970 (Acha and Szyfres, 1987) and in Australia from 17% in 1913 to 0.84% in 1928 (Cousins et al., 1998). Tuberculosis is now rare in domestic pigs in countries that have successfully applied tuberculosis control programmes. Nevertheless, the increasing spread of outdoor pig farming systems has led to the reemergence of M. bovis infection in this animal species in non OTF countries, as recently demonstrated in British study (Bailey et al., 2013). Available information nowadays is mainly related to feral pigs and wild boars, with a limited number of studies performed in domestic pigs. However the close resemblance in ecology, behaviour and management of wild boars and pigs raised in free ranging conditions allows to combine here the evidences resulting from both species as a single background to address the problem of TB in free ranging or semi domesticated pigs. Tuberculosis is not particularly contagious amongst pigs and in most cases is self-limiting, leading to the consideration of this species as a spill-over host. However, their role in the epidemiology of TB is somewhat controversial. In Australia and New Zealand, in fact, the low prevalence of generalized lesions in feral pigs, as well as management and genetic findings, suggested that feral pigs are spillover hosts rather than sources of infection (Corner, 2006; Corner et al., 1981; Nugent, 2011; Nugent et al., 2011). Similarly, Eurasian wild boar (Sus scrofa) in northwestern Italy has been excluded to be a reservoir (Serraino et al., 1999). Conversely, new insights suggest the possibility that pigs may play a different role in defined epidemiological scenarios characterized by several connected animal species populations or particular environments. This hypothesis is supported by the demonstrated role of the closely related wild boar in the epidemiology of TB in Spain and Portugal, (Aranaz et al., 2004; Martín-Hernando et al., 2007; Naranjo et al., 2008; Santos et al., 2009). As observed in other animals species the proportion of M. bovis infected pigs and pigs with gross lesions increases with age, as already observed in wild boars (Vicente et al., 2006). Lesions in feral pigs can be localized in the mandibular lymph nodes (Corner et al., 1981) or may be generalized (Di Marco et al., 2012; Martín-Hernando et al., 2007) with involvement of mandibular, retropharyngeal and thoracic lymph nodes. The involvement of those lymph nodes, whose afferents drain the nasal cavities, the nasopharynx, the auditory tubes and the lung, suggests that both respiratory and food-borne transmission may occur. A fibrous layer surrounds granulomas (encapsulation) in pigs (Bollo et al. 2000; Gortazar et al., 2011, Santos et al., 2009). Recently, miliary lesions and caseous necrotic-calcified tubercles were described (Di Marco et al., 2012). Histologically, granulomas showed peripheral fibroplasia and central necrosis, with different degrees of calcification (types 4 and 5). In addition, numerous granulomas without peripheral fibroplasia were also frequently detected. The fibrous layer of encapsulated tuberculous lesions reduces the likelihood of excretion (Santos et al., 2009). Conversely, caseous necrosis contributes to the formation of

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infectious material that might be spread to other individuals, through sputum, mucus, or stool by way of coughing, sneezing or defecation (Co et al., 2004). Reports from Spain and Portugal have shown that the same M. bovis spoligotypes were circulating in pig, wild boar and cattle (Parra et al., 2003; Santos et al., 2009; mycoDB-Spanish Database of Animal Mycobacterosis) suggesting a multi-directional interspecies transmission of M. bovis. A more detailed investigation about the potential role as reservoir of pigs should be warranted since Di Marco et al. (2012) demonstrated in a free ranging pig population of Sicily the presence of spoligotypes never detected in the coexisting cattle population nor described in the international scientific literature, suggesting that TB likely circulates among pigs and that new variants could be generated within the pig population. The diagnosis of tuberculosis in pigs is based on the post mortem analysis of organs followed by microbiological isolation of M. bovis, coupled with the detection of acid-fast bacilli by histology or by polymerase chain reaction (OIE, 2012). Due to the similarity of the lesions caused by members of the MTC and M. avium complexes (Thorel et al., 2001) a differential diagnosis between these two groups of bacteria should be performed by the isolation of the causative agent whenever possible. Intra vitam diagnosis can be based on ELISA as demonstrated in wild boars by Boadella et al. (2011), intradermal tuberculin test (Jaroso et al., 2010) or the IFN-γ assay, as recently suggested (Pesciaroli et al., 2012), although the specificity of these tests may be compromised by the high degree of exposure to nontuberculous mycobacteria. 5. Horses Horses are considered highly resistant to mycobacterial infections (O’Reilly and Daborn, 1995; Pavlik et al., 2004). However, infections in this species caused from M. bovis were reported until the first half of the last century in several European countries due to the widespread of disease in cattle that occasionally was transmitted to horses (Pavlik et al., 2003) Then, as mentioned for swine, the application of measures aimed at controlling M. bovis in cattle led to a significant reduction of incidence of infection in horses. Nowadays, sporadic cases of horse infection occur in countries where TB still represents an unresolved problem in livestock. Monreal et al. (2001) reported a case of bovine tuberculosis in an Andalusian mare in Spain. More recently, Keck et al. (2010) diagnosed M. bovis infection in a stallion native from the marshlands of the French region of Camargue. In the latter case, the horse was suspected to have acquired the infection sharing contaminated pastures with a cattle herd infected with M. bovis. In fact, the ingestion is regarded as the preeminent route of transmission for horses (Keck et al., 2010; Pavlik et al., 2004), unless the animals are subjected to an exceptionally high infection pressure (housed with other infected animal species). In this case, occurrence of respiratory transmission cannot be ruled out (Keck et al., 2010). Clinical symptoms, extremely generic and variable, are dependent on the extent of lesions in the organs affected by tubercles. Typically, preliminary lesions show up in the mesenteric lymph nodes and once the infection is established, generally tends to evolve spreading to other gut organs and involving other anatomical systems. The two cases previously reported were characterized by caseous necrosis of most of the lymph nodes of thorax and abdomen and a severe presence of granulomatous lesions in the lungs (Keck et al., 2010; Monreal et al., 2001). In case of advanced stages of disease, haematogenous dissemination of mycobacteria determines the appearance of miliary or nodular tubercles in spleen, liver, pancreas and kidney (Monreal et al., 2001). Signs of tuberculous disease may be observed less frequently in skin and eyes (Pavlik et al., 2004). Advanced tuberculous granulomas in horse usually have a lardaceous appearance differing from the extensive caseification and calcification typical of bovine tubercles (Monreal

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et al., 2001). Microscopically, the tuberculous granuloma contains cell types typical of a granulomatous inflammatory response, as epithelioid macrophages, multinucleated giant cells, lymphocytes plasma cells and fibroblasts. However, with time, necrosis does not occur or develops to a minimal extent conferring to the lesions a lardaceous appearance when compared with those observed in bovine, in which caseous necrosis becomes a distinguishing macroscopical feature. In humans and mice development of necrosis has been associated to different cell death pathways triggered in macrophages during infection and necrosis represents a mechanism to evade host response. This association has not been demonstrated in horses, but a similar mechanism could be hypothesized in this species, what could explain at least in part their higher resistance to infection (Divangahi et al., 2013). The intradermal tuberculin test was shown to be unreliable in horse due to the lack of specificity and sensitivity (Keck et al., 2010; Pavlik et al., 2004). The risk of transmission of Mycobacterium bovis from horse to humans appears negligible. Nevertheless, in epidemiological scenarios where a high infectious pressure is suspected, it cannot be ruled out. Therefore, horses used in pettherapy activities or in contact with immunocompromised humans should be subjected to a careful observation. 6. Camelids The wide range of species susceptible to M. bovis infection includes also camelids, conventionally distinguished in New World Camelids (NWCs) or South America Camelids (SACs) and Old World Camelids (OWCs). NWCs (mainly llamas – Lama glama – and alpacas – Vicugna pacos), in which outbreaks of M. bovis are rarely reported in their natural habitat, show a high susceptibility when reared in intensive conditions, suggesting that exposure in a confined area and the stress associated to an artificial environment may lead to an increased disease transmission in these species (Barlow et al., 1999). On the other hand, although M. bovis infection in OWCs (Bactrian camel – Camelus bactrianus – and dromedary – Camelus dromedaries) has been reported since the 19th century (Mustafa, 1987), it generally appears as a rare event. Recent literature reports cases caused by strains belonging to the antelope clade of the MTC (Kinne et al., 2006; Wernery et al., 2007). A cross sectional study conducted by Mamo et al. (2011) on 906 healthy camels slaughtered in two Ethiopian abattoirs reports a prevalence of 10.4% based on lesions presumptive of TB infection. However, genus typing, RD4 deletion typing and spoligotyping of the isolates cultured from diseased animals demonstrated that the majority of lesions were caused by NTM and only two isolates were M. bovis. The currently available ante mortem diagnostic tools are not able to accurately detect M. bovis infection in OWC (Alvarez et al., 2012). The intradermal tuberculin tests have demonstrated a lack of specificity when applied following the protocol used for cattle (Paling et al., 1988). However a better diagnostic performance of the SCITT (single comparative intradermal tuberculin test) was observed when the test was performed at the axillary sites and read after 5 days the injection (Wernery et al., 2007). However, in the latter study, a large portion of the animals of a dromedary herd under investigation reacted also to avian PPD. Studies involving larger groups of animals with a confirmed infectious status are needed to evaluate the efficacy of SCITT in light of the frequent exposure of OWC to environmental mycobacteria that can bias the results of the test. On that account, the diagnosis of M. bovis infection may benefit from complementing diagnostic approaches based on the cellular immune with those relying on the detection of the humoral immune response. The number of llamas and alpacas reared as pet or productive purposes has increased largely in several countries (D’Alterio et al., 2006). Outbreaks of M. bovis infection in NWCs have been increas-

ingly reported during the last decades, especially in areas where a high prevalence of tuberculosis in cattle is observed (García-Bocanegra et al., 2010; Ryan et al., 2008; Twomey et al., 2012). Furthermore, NWCs have also demonstrated to be highly susceptible to M. microti, another member of the MTC whose recognized reservoir are the voles but that is able to infect other animals species as cats and badgers (Smith et al., 2009), meerkats (Suricata surucatta) (Palgrave et al., 2012) and even humans (Emmanuel et al., 2007; Panteix et al., 2010). Infection with either M. bovis or M. microti may go unnoticed in NWCs until one or few animals in the herd die after showing general distress and respiratory symptoms. Nonetheless, sudden deaths without any premonitory sign have been also reported (Lyashchenko et al., 2007; Twomey et al., 2010). Lesions observed at the post mortem examination might address the diagnosis towards the genus Mycobacterium. The suspect is often confirmed by isolation of the causative agent from tissues of infected animals. Microbiological diagnosis of M. microti infection may be impaired by its slow and sometimes fastidious isolation (Smith et al. 2009; Zanolari et al. 2009). The reports of M. bovis infection in NWCs have drawn concern from veterinary public health authorities since the transmission of M. bovis to a veterinary surgeon has been documented (Twomey et al., 2010) but also because camelids might act as reservoirs of the disease for cattle or wildlife hampering the eradication programmes implemented in several developed countries. However, TB testing of NWCs is not performed on a mandatory basis in the European Union. Great Britain, in which the majority of the outbreaks have been reported due to the co-existence of a notable number of NWCs in areas where tuberculosis infection is endemic in cattle and wildlife, imposes TB testing in case of exportation of NWCs or when M. bovis infection is confirmed in a herd by microbiological isolation. The ante mortem tools that have been successful in the eradication of M. bovis in cattle, mainly the intradermal tuberculin test, proved to be ineffective in NWCs offering a scant ability to discriminate infected animals (Alvarez et al., 2012). Single intradermal tuberculin test (SITT) or SICTT applied to animals naturally infected with M. bovis repeatedly demonstrated low sensitivity (Lyashchenko et al., 2011; Stevens et al., 1998; Twomey et al., 2010). Conversely, animals experimentally infected with M. bovis showed positive reactions to the SITT or SICTT performed at the axillary site (Stevens et al., 1998). In vitro diagnostic methods based on assessing the CMI, as the IFN-γ assay, or on the humoral immune response, as the rapid serological test (RT), the Dual Path Platform (DPP) and different ELISAs have been evaluated (Rhodes et al., 2012; Twomey et al., 2010, 2012). The specificity of all the serological tests was greater than that observed with the IFN-γ assay (Rhodes et al., 2012). However, the serological tests were not able to identify correctly all diseased animals in any of the above indicated studies. The authors conclude that different in vitro tests can detect different groups of M. bovis-infected animals thus supporting the suitability of a combination of antibody and IFN-γ testing to maximize the detection of diseased animals. The same conclusion was reached in another study evaluating the usefulness of the single and comparative skin tests performed in different inoculation sites and read at different times along with an experimental serological test, in which the ancillary use of serology significantly increased the number of infected reactors (Bezos et al., 2013). Interestingly, the use of serum samples collected 15–30 days after the intradermal test (IDT) increased the sensitivity of the test. The development or the validation of any reliable diagnostic approach must be coupled with a more detailed knowledge of the hostpathogen interaction between M. bovis and the camelid host. The evidence of a greater susceptibility of NWCs towards M. bovis infection when reared in intensive conditions if compared to their natural habitat suggests the existence of risk factors that need to be identified and characterized. NWCs experimentally inoculated

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with M. bovis are able to react to SITT and SCITT. On the contrary, poor results are obtained when SITT or SICTT are applied to naturally infected NWCs (Stevens et al., 1998). Since the natural transmission of M. bovis within members of a llama herd has been documented, a valuable approach to validate any diagnostic test would be mimicking natural within-herd transmission of M. bovis by placing in a single environment experimentally infected animals and disease-free animals. 7. Dog M. bovis infection in dog was relatively common in the past century (Hawthorne et al., 1957; Jennings, 1949; Lovell and White, 1941). Again, the decrease of the prevalence of M. bovis in cattle as a consequence of implementation of eradication campaigns, along with the pasteurization of milk, have reduced canine cases. However, M. bovis infection in dog is still reported in non OTF countries as UK (Ellis et al., 2006; Shrikrishna et al., 2009; van der Burgt et al., 2009) and New Zealand (Gay et al., 2000). Dog can acquire the infection through consumption of infected raw milk (although pasteurization has decreased the importance of this route). The transmission via aerosols seems to occur only when dogs live in close contact with heavily diseased cattle (Snider et al., 1971) as Wilkins et al. (2008) did not detect the infection in dogs living in farms with M. bovis infected cattle herd at a low prevalence of infection and mild lesions. The transmission of M. bovis from infected wildlife to dog through biting has been reported (van der Burgt et al., 2009). The close contact between dogs and human being creates scenarios of inter-species transmission in which humans could act as a source of infection for dogs both for M. bovis and M. tuberculosis. Reports suggest the probable transmission of M. bovis (Shrikrishna et al., 2009) and M. tuberculosis (Erwin et al., 2004; Parsons et al., 2012) from owner to dog. The course of M. bovis infection in dogs is characterized by non specific symptoms and the in vivo diagnosis of the disease is difficult since IDT proved to be unreliable (Bonovska et al., 2005). Conversely, an IFN-γ-based assay was able to effectively recognize dogs with a previous exposure to TB human patients (Parsons et al., 2012). The transmission of M. tuberculosis from experimentally infected dogs to uninfected animals kept in close contact has been demonstrated (Bonovska et al., 2005). Moreover, M. tuberculosis was isolated from fluids (nasal secretions, urine, and faeces) of a dog with a generalized infection (Martinho et al., 2013). These findings suggest that dogs can shed mycobacteria in the environment and potentially act as a source of infection for other animals and humans. On that account, M. bovis or M. tuberculosis infections should be considered in dogs showing respiratory symptoms and living in areas in which mycobacterial infections are widespread in wildlife, farm animals or humans. 8. Cats Tuberculosis in cats is considered uncommon, but case series or case reports from different European countries, United States, Argentina, Australia and New Zealand have been published before (de Lisle et al., 1990; Gunn-Moore et al., 1996, 2013; Isaac et al., 1983; Kaneene et al., 2002; Monies et al., 2000; Orr et al., 1980; Snider et al., 1971; Willemse and Beijer, 1979; Zumárraga et al., 2009). The causative agents of tuberculosis in cats are M. bovis and M. microti, but non-tuberculous mycobacteria may also cause mycobacterial infections. A recent retrospective study from the UK evaluating 339 cases of mycobacterial disease in cats found that 19% were due to M. microti infection and 15% by M. bovis, while 7% was caused by Mycobacterium avium complex members, 6% by nontuberculous mycobacteria and no growth was achieved in 53% (Gunn-Moore et al., 2011).

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M. microti infection is mainly related to direct contact with small rodents like voles and mice (Burthe et al., 2008), while M. bovis infection has been historically associated to direct contact with infected animal or consumption of contaminated animal products (Jennings, 1949). In particular, farm cats were considered at very high risk of acquiring M. bovis from infected cattle especially if they were fed unpasteurized milk, raw meat or offal (Zumárraga et al., 2009). In a study conducted during 1966–1968 in Pennsylvania, 24 out of 52 cats were affected after exposure to positive cattle (Snider et al., 1971). However, the increasing use of commercial foods for pets and the lower prevalence of bovine tuberculosis due to the eradication campaigns have contributed to a reduction in the incidence of feline infections caused by M. bovis (Green and Gunn-Moore, 2006). In Michigan, 18 cats living in bTB positive cattle farm were found negative to M. bovis infection (Wilkins et al., 2008). Authors suggested that the low prevalence of infected cattle in the herds (1.6%) and the absence of advanced, heavily diseased cattle might explain the apparent lack of transmission to cats. However, other risk factors can contribute to the occurrence of tuberculosis infection in cats. Wildlife reservoirs, as the badger in UK (Monies et al., 2000), the white-tailed deer in USA (Kaneene et al., 2002) or the possum in Australia (Ragg et al., 2000) could play a role in tuberculosis transmission to this animal species. This was one of the probable sources of a recent cluster of cases detected in the UK, in which a possible cat-to-cat transmission could not be also ruled out (Roberts et al., 2014). Moreover, people who adopt and rear many cats, together with the increase of immunosuppressing diseases (feline immunodeficiency virus and feline leukaemia virus), are new risk factors for tuberculosis transmission in felines (Monies et al., 2000). In contrast, cats are supposed to pose a very limited risk as sources of TB for humans, although cases of cat-to-human transmission has been reported (British Governement, 2014). The real prevalence of mycobacterial infections in cats is still unknown. A 2009 survey from diagnostic laboratories in the UK evaluating tissue samples with a histological diagnosis of mycobacterial infection showed a significant incidence of around 1% (Gunn-Moore et al., 2013). The primary sites of infection may be the digestive tract, lungs or skin (Malik et al., 2000) while the clinical signs of the disease are unspecific and affect several organs or fluids. The most common are digestive as loss of weight and mesenteric lymphadenopathy, or respiratory as pneumonia, hilar lymphadenopathy, pneumothorax, pleural or pericardial effusions (Gunn-Moore et al., 1996; Lloret et al., 2013). Frequently a moist skin lesion is associated with M. bovis and M. microti infections (de Lisle et al., 1990; Gunn-Moore et al., 2011). The disease can evolve in dissemination and systemic infection that leads to the death within 10 to 20 days from the onset of symptoms. Fever, ocular signs, splenomegaly, hepatomegaly, generalised lymph adenopathy, bone lesions and central nervous system signs may accompany this stage. Lesions are usually characterized by granulomatous inflammation, consisting of multifocal to coalescent infiltration with large numbers of foamy macrophages containing variable numbers of acid fast bacilli (Kaneene et al., 2002; Snider, 1971). The diagnosis of suspected tuberculosis in cats is based on the detection of acid-fast bacilli by histology or by polymerase chain reaction (Aranaz et al., 1996). However, species confirmation is essential for treatment and prognosis, so culture isolation, that still remains the gold standard for diagnosis of feline tuberculosis, is extremely important. The intradermal tuberculin test was shown to be completely unreliable in cats (Fenton et al., 2010; Kaneene et al., 2002; Snider, 1971). That is why, in the past few years, efforts have been made to develop both cellular and humoral mediated diagnostic tests to be used as ante mortem assays. The IFN-γ test developed by Rhodes

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et al. (2008) was shown to detect infections caused by the MTC in domestic cats. This test could distinguish M. bovis from M. microti infection when positive responses to the specific proteins ESAT6/ CFP10 (present only by M. bovis) were detected. Regarding serological tests, a recent study showed that a rapid lateral-flow antibody test could identify 66.7% of M. bovis-sensitized cats (Fenton et al., 2010). Moreover, a comparative study of IFN-γ and serological rapid antibody tests showed a 100% specificity of both tests and a higher sensitivity of IFN-γ (70–100%) compared to serological tests (41–90%) (S. G. Rhodes et al., 2011). 9. Conclusion The knowledge achieved in the last decades has demonstrated the ability of certain MTC members (particularly M. bovis) to infect a wide range of host species other than cattle, including not only the well-described wildlife reservoirs (badger, deer and wild boar) but also other livestock and pet species, in spite of the lack of reliable diagnostic techniques in some of them. The importance of the detection of the disease in these alternative host species is derived from the consequences of the tuberculosis itself (in most of them it is also a devastating process that may lead to dead) and their potential role as reservoirs of infection for the cattle and human populations. However, their role in the epidemiology of bovine tuberculosis may vary largely depending on the epidemiological context, so a given species may act as a true reservoir in a certain location while being a spill-over host in another. Nevertheless, the possible role of alternative host species should be always considered in the epidemiological investigations and, generally speaking, in the design of eradication programmes for bovine tuberculosis. Uncited references Cordes, D.O., Bullians, J.A., Lake, D.E., Carter, M.E., 1981. Observations on tuberculosis caused by Mycobacterium bovis in sheep. New Zealand Veterinary Journal 29, 60–62. European Union. Regulation (EC) No. 853/2004 of the European Parliament and of the Council laying down specific hygiene rules for the hygiene of foodstuffs. .

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