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1 Department of Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, Lansing, Michigan 48910–8107, USA
2 Diagnostic Center for Population and Animal Health, College of Veterinary Medicine, Michigan State University, Lansing, Michigan 48910–8107, USA
3 Michigan Department of Community Health, Tuberculosis Laboratory, Lansing, Michigan 48909, USA
4 Population Medicine Center, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan 48824, USA
5 Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan 48824, USA
6 Small Animal Clinical Sciences, Michigan State University, East Lansing, Michigan 48824, USA
7 Corresponding author (email: fitzgerald{at}dcpah.msu.edu)
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ABSTRACT |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Subsequent to discovering in 1994 that WTD in Michigan could serve as a reservoir for M. bovis, there has been ongoing surveillance of WTD and other potential reservoir hosts in this state. Several carnivorous and omnivorous species such as coyote (Canis latrans), raccoon (Procy-on lotor), bobcat (Lynx rufus), Virginia opossum (Didelphis virginiana), and red fox (Vulpes vulpes) have tested positive and have been identified as spillover hosts. In spillover hosts, infections occur sporadically but do not persist in the population (Morris et al., 1994; O’Reilly and Daborn, 1995; deLisle et al., 2001). To date, WTD are the only known reservoir host associated with the Michigan outbreak (Schmitt et al, 1997; Bruning-Fann et al., 2001). The presence of these infected wildlife species can represents an obstacle in the control or eradication of M. bovis in livestock that are in contact with infected wildlife; there also is a potential public health risk associated with human contact with infected wildlife (O’Reilly and Daborn, 1995; Nelson, 1999; Cousins, 2001; Bengis et al., 2002; Wedlock et al., 2002).
Experimental M. bovis studies to determine the susceptibility of wildlife species that are commonly associated with livestock production areas in Michigan have been completed for Virginia opossum, American crow (Corvus brachy-rhynchos), European starling (Sturnus vulgaris), rock pigeon (Columba livia), and mallard (Anas platyrhynchos; Butler et al., 2001; Diegel et al.; 2002; Fitzgerald et al.; 2003a, b, 2005). At present, there are no reported studies of M. bovis infection and attendant risk factors in three wild rodent species that might also be common on Michigan farms. These include the meadow vole (Microtus pennsylvanicus), house mouse (Mus musculus), and Norway rat (Rattus norvegicus).
The objectives of the study were: 1) to determine if the meadow vole, house mouse, or Norway rat can be infected with M. bovis by experimental inoculation, and if so, to document attendant pathologic processes/pathogenesis; 2) to detect any fecal shedding of M. bovis; and 3) to evaluate the relative susceptibility of the three species to M. bovis infection.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Inocula were prepared by the Mycobacteria/Mycology Laboratory Unit of the Michigan Department of Community Health (MDCH), Lansing, Michigan, USA. The M. bovis isolate originated from a positive WTD identified by annual surveillance and was confirmed as the Michigan strain by restriction fragment length polymorphism (RFLP; Whipple et al, 1997; Bruning-Fann et al., 1998). Aliquots of 7-day growth in Middlebrook 7H9 broth were frozen at –70 C. As needed, aliquots were thawed, diluted to 1:100 with sterile water, and colony-forming units (CFU) per unit of volume were determined by plate counts. Aliquots were diluted to attain the desired 1 x 105 dose; the final titer was confirmed by plate count at the time of inoculation. Meadow voles and house mice were anesthetized prior to inoculation with isoflurane (IsoFlo®, Abbott Animal Health, Chicago, Illinois, USA) administered in an inhalation chamber attached to a gas anesthesia machine with a precision vaporizer. Animals were dosed orally via a tomcat catheter gavage. Voles were inoculated intranasally (IN) in each nostril via a micropipette.
Study design
Each animal was weighed prior to inoculation (postinoculation day 0) and at weekly intervals thereafter. They were evaluated daily for signs of respiratory distress, weight loss or other signs of ill health (bristled hair, hunched posture, reluctance to move). When necessary for humane reasons or at the end of the experiment, animals were euthanized with an overdose of isoflurane (IsoFlo®, Abbott Animal Health). All experimental procedures were approved by the All-University Committee on Animal Use and Care at Michigan State University (MSU).
Meadow voles
Thirty-six meadow voles (19 male, 17 female) were sourced from the MSU meadow vole colony. The colony was negative for a standard profile of common pathogens (Sendai virus, pneumonia virus of mice, mouse hepatitis virus, reovirus type 3, lymphocytic choriomeningitis virus). Although previously positive for Helicobacter (Helicobacter spp., not bilis or hepaticus) the colony also tested negative for Helicobacter at the time the animals were sourced. To detect fecal shedding, fecal samples for mycobacterial culture and isolation were obtained from each vole at 1 day preinoculation, 1 day postinoculation (PI), and from surviving animals on day 30 PI. Voles were randomly assigned to one of four groups: 12 received 5 x 103 CFU of M. bovis orally in a total volume of 0.5 ml, six oral sham inoculates were given a similar volume of sterile water, 12 were given 1 x 105 CFU intranasally, a total volume of 20 µl in each nostril, and six IN sham inoculates were given a similar volume of sterile water. The voles were housed in a secure BSL-3 facility in rodent cages placed in Horsfal units. Rodent chow (Teklad 22/5 rodent diet [W] 8640, Harlan Teklad, Troy, Illinois, USA) and water were supplied ad libitum. Voles were euthanized at 30 and 60 days PI or earlier if they exhibited marked weight loss or signs of illness.
At necropsy, total body weight (TBW) in grams (g) was obtained for each animal. The weights of the lung, liver, and spleen also were recorded. Tissues harvested at necropsy were preserved in 10% neutral buffered formalin (NBF) and included brain, nasal turbinates, trachea, lung, heart, liver, kidney, spleen, gonad, adrenal gland, small intestine (SI), large intestine (LI), and cranial, thoracic, and abdominal lymph nodes. Tissues were routinely processed and sectioned (5 µm) for staining with hematoxylin and eosin (H and E). All tissues were also stained with Ziehl-Neelsen (acid-fast).
Tissues for mycobacterial culture were collected using sterile instruments and were grouped into three pools: pool A (lung, tracheobronchial lymph nodes, and cranial lymph nodes); pool B (liver, kidney, spleen); and pool C (SI, LI, and mesenteric lymph nodes).
House mice
Thirty-six house mice (18 male, 18 female) were sourced from the Geriatrics Center, University of Michigan, Ann Arbor, Michigan, USA. All mice tested negative for a standard profile of common pathogens prior to inoculation. Fecal samples were procured from each mouse as described for the voles on day 0 and day 1 PI, and from surviving animals on days 20 and 40 PI. The mice were randomly assigned to one of three groups: 12 received a high dose of M. bovis (1 x 104 CFU), 12 received a lower dose (1 x 102 CFU), and 12 were sham-inoculated controls. Each mouse received 0.25 ml total volume orally. The mice were housed and fed in a manner identical to the voles. Mice were euthanized at 20, 40, and 60 days PI or earlier if they exhibited marked weight loss or signs of illness.
The necropsy protocol for the mice was identical to that previously described for the voles. However, nasal turbinates were not included in the tissues harvested from voles. Histopathologic processing and staining in addition to the tissues harvested and pooled for mycobacterial culture were identical to that in the voles.
Norway rats
Thirty-six male Norway rats were obtained from Charles River Laboratories, Portage, Michigan, USA. All rats tested negative for a standard profile of common pathogens prior to inoculation. Fecal shedding was assessed in each rat as previously described for house mice. The rats were randomly assigned to one of three groups: 12 received a high dose of M. bovis (5 x 103 CFU), 12 a low dose (1 x 102 CFU), and 12 were sham-inoculated controls. The rats were housed and fed in a manner identical to the voles. Rats were euthanized at 20, 40, and 60 days PI.
The necropsy protocol, histopathologic processing, and staining as well as mycobacterial culture were identical to that in the mice.
Mycobacterial isolation and identification
Mycobacterial cultures were performed at the Tuberculosis Laboratory, MDCH. Tissue specimens were homogenized, digested, and concentrated (Kent and Kubica, 1985); fecal samples did not require homogenization and were cultured after digestion and concentration. For each sample, a Lowenstein-Jensen medium slant, a Middlebrook 7H11S medium slant (Remel, Lenexa, Kansas, USA), and a BACTEC 12B broth vial (Becton-Dickinson, Sparks, Maryland, USA) were inoculated. Media were examined weekly for mycobacterial growth for up to 8 wk. Cultures determined to contain acid-fast organisms by slide examination (Kent and Kubica, 1985) were tested by nucleic acid probe (Accuprobe®, Gen-Probe®, San Diego, California, USA) to ascertain if they were members of the M. tuberculosis complex (Reisner et al., 1994). Biochemical testing and high-performance liquid chromatography was performed to identify species and to differentiate M. bovis from other members of the M. tuberculosis complex (Kent and Kubica, 1985; Butler et al., 1991; Reisner et al., 1994).
Statistical analysis
The SAS version 9.1.3 statistical software was used for all analyses (SAS Institute, Inc., Cary, North Carolina, USA). The Wilcoxon rank-sum test was used to determine whether there were significant (P<0.05) changes in total body weight and organ weights within and between treatment groups. The two-tailed Fisher’s exact test was used to determine if the presence or absence of gross and microscopic lesions or positive mycobacterial cultures were dependent on route of inoculation. A Kaplan-Meier test was used to determine whether treatment and species significantly influenced survival.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Ten of the infected meadow voles exhibited respiratory distress and either died or were euthanized prior to the end of the experiment. This included six voles that were inoculated orally and four that were inoculated by the IN route. Four of the 12 house mice in the HD group died prematurely as a result of infection. After adjusting for dose (mice and rats) and route of inoculation (voles), the mortality rate was highest in voles (28%) as compared to house mice (11%) and Norway rats (0%; Cochran-Mantel-Haenszel 
2=12.36, P=0.0021) and voles died earlier than mice; the mean time to death was 26.8 days for voles and 31.5 days for mice (Fig 1
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2=5.15; P=0.0795). Lung weights for M. bovis-infected voles (IN and oral inoculates) were higher than observed in control animals (Wilcoxon rank-sum 2=11.85; P=0.0027); however, there were no differences in the liver and spleen weights of the inoculated and control voles. Four of the 12 mice in the HD group lost weight (1.7–5.4 g) during the first 30 days of the study (two of these were euthanized and two died), but after this time period, remaining mice were able to regain and maintain body weight and weights did not differ between inoculated and control mice (Wilcoxon rank-sum 2=0.39; P=0.8243). As with voles, lung weights were significantly higher in inoculated mice (HD and LD) when compared with control mice (Wilcoxon rank-sum 2=9.50; P=0.0087). Inoculated Norway rats (HD and LD) had a lower mean total body weight than sham-inoculated controls (Wilcoxon rank-sum 2=22.38; P=<0.0001) but there were no observable differences in any of the organ weights between inoculated and control rats. Gross lesions
Gross lesions suggestive of mycobacteriosis were detected in 19 of the 24 inoculated voles. In the voles with mycobacterial pneumonia, the lungs failed to collapse fully. Multifocal granulomatous to pyogranulomatous pneumonia was characterized by several pale tan foci ranging from pinpoint up to 5 mm in diameter randomly disseminated in the pulmonary parenchyma. The tan foci were friable and soft to gritty. Some animals had hepato-megaly and splenomegaly. Large numbers of granulomas were disseminated in the hepatic and splenic parenchyma (moderate to severe multifocal granulomatous hepatitis and splenitis). Lymphadenitis was evident in submandibular, parotid, cervical, tracheobronchial, and mesenteric lymph nodes. The affected lymph nodes were enlarged with multifocal to coalescing caseogranulomas that ranged from pinpoint up to 3 mm in diameter (Table 1 and Figs. 2 and 3). Nonmycobacteriosis-associated lesions were detected in two voles; severe cecal dilation and an ovarian mass were observed in one vole and a severe urogenital infection in another (cystitis with enteritis in the adjoining intestine, both transmural). In addition, two of the voles had unidentified cutaneous mites.
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). One mouse in the LD group (day 40 PI) had congested lungs which were mottled red and tan. Enlarged lymph nodes were detected in four mice (superficial cervical, tracheobronchial, mesenteric, inguinal, lumbar; one mouse in the HD group on day 20 PI; two mice in the HD group on day 40 PI; one mouse in the LD group on day 60 PI). Splenomegaly was present in two mice on day 60 PI (one each in HD and one LD groups). A nonmycobacteria-associated lesion was present in one mouse; a 4-mm-diameter focal pulmonary neoplasm (a mouse in the HD group on day 20 PI). There were no gross lesions suggestive of M. bovis infection in any of the rats on post-mortem evaluation.
Microscopic lesions
Histologic lesions were most extensive and severe in voles (Table 1 and Fig. 4). In each of the affected organs, lesions were moderate to severe, multifocal to coalescing, caseogranulomatous, and granulomatous to pyogranulomatous. Numbers of acid-fast bacilli ranged from abundant to rare. Of note in the microscopic lesions seen in the voles was mineralization in some of the lymph nodes with case-ogranulomatous lymphadenitis. Moderate to severe granulomatous and necrotizing rhinitis were prominent features in the IN inoculates (11 of 12) and in a single oral inoculate (Fig. 5). Nonmycobacteriosis-associated lesions detected in meadow voles included colonic nematodiasis in five animals, an ovarian teratoma in one vole, cystitis (transmural chronic fibrosing, pyogranulomatous, and necrotizing with in-tralesional bacteria), and adjacent transmural enteritis in one vole.
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). Acute to subacute lesions were seen in mice that were euthanized on days 20 and 40 PI and presented as severe coagulative necrosis (sequestrum) with moderate to massive numbers of acid-fast bacilli (also macrophages on day 40 PI). Chronic granulomatous pneumonia with infiltrates of macrophages, epithelioid cells, and rare multinucleated giant cells were evident in mice euthanized on day 60 PI. Acid-fast bacilli were present in small numbers in macrophages in small numbers or were rare. Other organs affected were lymph nodes (three tracheobrochial and one mesenteric) and spleen in four mice, and liver in one animal. In each of these tissues acid-fast bacilli were present in macrophages, but tissue architecture was otherwise unaffected. The only nonmycobacteriosis lesion detected microscopically was a focal pulmonary bronchiogenic adeno-carcinoma in one mouse day 20 PI. In a single Norway rat (HD group, 20 days PI) there was focal aggregation of small numbers of multinucleate giant cells which contained a few acid-fast bacilli within a tracheobronchial lymph node. In another rat (LD group, day 60 PI), sections of cerebrum and a single blood vessel (vein) contained a few acid-fast bacilli. Nonmycobacteriosis-associated lesions seen in the Norway rat included a meningeal granular cell tumor (control rat day 40 PI) and a focal sperm granuloma in the testis in another control rat (day 40 PI).
Mycobacterial isolation and identification
In the voles all fecal cultures were negative prior to inoculation; sham-inoculated controls remained negative on days 1 and 30 PI. Eight of the 12 IN inoculated voles and nine of 12 oral inoculates had positive fecal cultures on day 1 PI. Two of the five surviving IN inoculates had positive fecal cultures on day 30 PI, whereas fecal cultures from the five surviving oral inoculates sampled at 30 days PI were negative. All fecal cultures taken prior to inoculation and on days 1, 20, and 40 PI for the house mice and rats were negative.
Positive tissue cultures were obtained in all 12 of the IN inoculated voles and in seven of the oral inoculates. Tissues from control voles were negative. Tissues from 14 of 24 (nine HD and five LD) inoculated mice were positive by culture. All tissues from sham-inoculated mice were negative. A single HD rat had a positive culture for tissues in pool A on day 20 PI. Tissues in pools B and C were negative. Cultures from tissues of all other rats were negative (Table 2).
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A difference in the frequency of M. bovis culture-positive animals was observed between species (Fisher’s exact test, P<0.0001); meadow voles and mouse mice were most susceptible. Meadow voles were infected by both inoculation routes, and there was a significant difference in the number of gross lesions present in intranasal versus orally-inoculated animals (Fisher’s exact test, P<0.05). Voles also had a higher prevalence of histologic lesions (Fisher’s exact test, P<0.05).
With house mice, the frequency of gross lesions differed between the high dose low dose treatments (Fisher’s exact test, P=0.04). However, a difference in the frequency of microscopic lesions observed in these treatment groups was not detected (Fisher’s exact test, P>0.05).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Evidence in support of meadow voles being more susceptible than house mice and Norway rats to experimental inoculation with M. bovis include lethal infections in 10 of the 24 inoculated animals, extensive gross and histologic lesions (19 animals), and positive mycobacterial cultures (19 animals). Sensitivity of voles to M. bovis seen in this study supports the work of Jespersen (1974, 1975, 1976, 1977a, b) and Jespersen et al. (1977) in common voles (Microtus arvalis), field voles (Microtus agrestis), bank voles (Clethrionomys glareolus), and the vole rat (Arvicola terrestris), all of which developed lethal infections following experimental inoculation of M. bovis. Similar results were obtained earlier by Griffith (1937, 1939) and Wells (1938). Gross lesions including caseous lymphadenitis as well as granulomatous pneumonia, splenomegaly, and hepatitis were observed in these earlier studies and are consistent with results from this study.
The results of our study demonstrate that infected voles are capable of disseminating M. bovis via their feces. The isolation of M. bovis in feces from 17 voles on day 1 PI most likely resulted from passive transit through the gastrointestinal tract. Although the majority of these (nine) positive results came from voles that were inoculated orally, eight positive fecal cultures were obtained from IN inoculated voles. This suggests that the inoculum was either swallowed during administration or was coughed up from the respiratory tract and subsequently swallowed. Two of the IN inoculates had positive fecal cultures at 30 days post-inoculation, which indicates both dissemination of M. bovis and the potential for longer-term fecal shedding.. Fecal shedding does occur with the closely related M. microti, or vole bacillus, which like M. bovis is a member of the M. tuberculosis complex. Mycobacterium microti can be spread from vole to vole via ingestion of the excreta from infected voles (Rankin and McDiarmid, 1968) and acid-fast bacilli have been reported in the feces of field voles experimentally inoculated with M. microti (Griffith, 1939); however, these acid-fast bacilli were not identified as M. microti through culture.
Meadow voles were more susceptible to infection via the oral route than the IN route. Six of the animals in the oral treatment group died or were euthanized in less than 21 days PI as compared to loss of a single IN inoculate on day 19 PI and three other animals between days 46 to 52 PI.
Positive fecal cultures and the ability to survive M. bovis infections, suggest that meadow voles could represent a potential reservoir host. However, this potential is not supported by field data and it is not known if M. bovis infections can persist in meadow vole populations.
The results of this study are the first to document oral infection of a wild-type house mice with M. bovis. Although Lefford (1984) states that adult mice cannot be infected by virulent tubercle bacilli via the gastrointestinal tract, Pierce et al. (1947) did demonstrate that immature house mice (4–6 wk old) were susceptible to oral infection with M. tuberculosis. Extensive gross and microscopic lesions in orally-infected mice as well as positive mycobacterial cultures from the lungs, liver, and spleen are indicative of M. bovis dissemination from the gastrointestinal tract. Gross and microscopic lesions in these mice were most severe in the lung, which is similar to previously published studies of M. bovis-infected laboratory mouse strains (Griffith, 1907b; Glover, 1944; Ratcliffe 1952; Ratcliffe and Palladino, 1953; Gunn, Nungester and Hougen, 1933–34, cited in Darzins 1958). Similar to what has previously been reported in mice experimentally infected with M. tuberculosis (Cosma et al., 2003), caseation or calcification of pulmonary granulomas was not evident in the lungs of infected mice in this study. Although experimental infections are possible, results from field studies provide no evidence that house mice are naturally infected with M. bovis (Little et al., 1982; Wilesmith et al., 1986; Fischer et al., 2000; Pillali et al., 2000).
Infections were more severe in mice that received a HD inoculum. A total of eight mice (67%) in the HD group had gross and microscopic lesions consistent with mycobacteriosis compared to four (33%) mice in the LD group. Results from house mice also suggest that those animals receiving an HD oral inoculum of M. bovis might be able to control infection. Adverse effects in this group occurred up to day 40 PI. By this time, severe pulmonary disease had occurred in seven of eight animals in this group. All eight animals were culture positive and four deaths due to mycobacteriosis occurred between days 28 and 35 postinoculation. After day 40, only one of four surviving mice tested positive by culture. The converse was seen in mice receiving the LD oral inoculum; chronic pulmonary disease was detected at day 60 PI and tissues from three of the four animals in this group were culture positive. These differences might relate to dose dependent variation in stimulating a cell-mediated immune response. House mice might serve as an ideal animal model for tuberculosis in humans infected with M. tuberculosis and M. bovis because there is evidence that some of these mice were able to recover from their infection.
Although fecal cultures in the house mice were consistently negative, M. bovis was cultured from the intestinal tissue pools of six mice. This confirms infection or retention of M. bovis following oral exposure, and suggests that some fecal shedding might have occurred despite the negative culture results from fecal samples. These negative results might have resulted from the sampling methods used in our study.
The lack of gross lesions and negative fecal cultures in Norway rats indicates resistance to oral infection with M. bovis. However, there was one positive tissue culture (lung, tracheobronchial, and cranial lymph nodes) in a single rat in the HD group on day 20 PI. This rat also had histologic lesions consistent with mycobacterial persistence/colonization as multinucleated giant cells with acid-fast bacilli were present in the tracheobronchial lymph node. This is indicative of dissemination of the mycobacteria from the site of infection within this rat. Lack of gross and microscopic lesions and negative culture attempts from Norway rats in this study beyond 20 days PI is consistent with prior reports of resistance in rats; this is related to the cell-mediated immune response to Mycobacterium spp. infection (Thorns et al., 1982). In a recent study with female Lewis rats, Sugawara and associates (2004) report that animals infected by aerosol with M. tuberculosis developed granulomatous lesions in the lungs, spleen, lymph nodes, and liver. Although rats might be susceptible to Mycobacterium spp. via a respiratory route, it is unlikely that wild type rats would be naturally exposed to such a large dose (2 x 106 CFU) of M. tuberculosis by aerosol.
It is unclear why a decreased total body weight in inoculated rats was observed when none of these rats exhibited any other adverse clinical signs (respiratory distress, bristled hair, reluctance to move, etc.). A similar lack of clinical signs in rats infected with M. bovis following experimental inoculation is reported by Griffith (1907a) with intraperitoneal (IP) and subcutaneous (SQ) routes as well as by Wessels (1941) who utilized the IV route. In these studies, M. bovis was detected in several tissues (lungs, liver, spleen, lymph nodes, kidneys, omentum, and bone marrow) which was not observed in our study. Accordingly, one can conclude that Norway rats are essentially resistant to infection with M. bovis at high oral doses and are incapable of disseminating this organism laterally via fecal shedding. Support for rats being dead-end hosts for M. bovis is gleaned from previously reported environmental survey studies in which rats were negative on culture (Wilesmith et al., 1986; Pillai et al., 2000) or lacked lesions in the face of positive cultures (four animals total) (Bosworth, 1940; Little et al., 1982).
In conclusion, the results of this study indicate that meadow voles are highly susceptible to infection with M. bovis via both oral and intranasal routes and can shed M. bovis in their feces. In voles, lesions consistent with mycobacteriosis occurred in several tissues, including the lungs, liver, and spleen, various lymph nodes, and in the intranasal inoculates and nasal turbinates. House mice are also susceptible to infection with M. bovis via the oral route but are apparently less efficient in transmitting mycobacteria via fecal shedding when compared to the vole. Most lesions in affected mice were associated with the lungs. Of the three rodent species tested in this study, the Norway rat is the most resistant to oral infection with M. bovis.
Although meadow voles and house mice are unlikely to encounter M. bovis in their natural environment at doses equivalent to the HD inocula used in this study, it is recommended that appropriate measures be taken to eliminate these animals or at least control their numbers on premises where bovine tuberculosis-positive animals are present. Further, it would be strongly advised that access of voles and mice to food and water sources of domestic animals be restricted wherever possible.
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Received for publication 1 February 2006.
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