Mycobacterium bovis is a pathogen of significant public health, animal health, and economic importance worldwide. A large proportion of the burden of M. bovis infection is borne by economically less developed countries. Mycobacterium bovis infection is preventable and treatable, but remains common. Strategies to eradicate M. bovis infection in humans include pasteurization of dairy products, public education regarding the risks of consuming
unpasteurized dairy products, and eradication of M. bovis infection in animal reservoirs. The primary challenges to eradication are lack of inexpensive, rapid, reliable means of definitive diagnosis and strain identification; antibiotic resistance of some strains of M. bovis; and a paucity of detailed information regarding the geographic distribution and epidemiology of infection. An additional challenge to eradication in livestock is the large expense associated with traditional control programs based on test and slaughter policies.
Mycobacterium bovis infection is significantly underreported, due primarily to diagnostic limitations, particularly in economically less developed countries. Widely used diagnostic methods, where available, are inadequate for M. bovis identification: tuberculin skin tests, microscopic examination of blood smears, and microbiologic culture with media that are not optimal for M. bovis growth. Distinguishing M. bovis from other members of the MTB complex, and distinguishing among M. bovis strains, are important for optimizing clinical treatment for patients, designing effective control and eradication programs, and evaluating program effectiveness.
54 More recently developed diagnostic methods, based on genetic analysis of the pathogen, can offer higher discriminatory power. The most widely used of these methods are based on analysis of polymorphisms in the mycobacterial genome. While most of the mycobacterial genome is very highly conserved, a limited number of repetitive elements are sufficiently polymorphic to be useful for genetic typing for a variety of applications: IS6110, PGRS, the DR region, and several VNTR loci.
However, these methods have important limitations. In general, the discriminatory power of any given genotyping method depends strongly on the number of genetic loci analyzed and their level of polymorphism in the study population. A high level of genetic diversity yields a larger number of different possible types and can allow for much higher resolution typing than can a low level of genetic diversity. However, geographic localization of genetic types can result in wide variation in discriminatory power of any given typing method among geographic
regions. This highlights the importance of validating typing methods for the study population, and complicates data interpretation and comparison of study results across geographic regions.
Another significant limitation of typing methods based on analysis of repetitive elements is the variable stability of these elements. The number of repeats in any given repetitive element can increase or decrease, at a rate that varies by element and by genotype. This can lead to high levels of homoplasy, i.e., identity by independent mutation instead of identity by descent, and complicates interpretation of results for phylogenetic or epidemiologic analysis. A related limitation of typing methods based on analysis of repetitive elements, and another source of homplasy, is the presence of some of the repetitive elements in transcription units or other functional units of the genome. Association of the repetitive element with a selective advantage
55 or disadvantage could contribute to convergent evolution of M. bovis strains, leading to identical typing patterns in strains that are otherwise not closely related.
Finally, many of the diagnostic methods that offer high discriminatory power can be time consuming and costly, and require the use of sophisticated laboratory equipment and well trained personnel. This can make these methods impractical or unfeasible in many regions of the world that are most severely impacted by M. bovis infection.
For the purpose of decreasing the incidence of M. bovis infection in humans, policy decisions should continue to focus on promoting strategies that have proven successful to date: widespread pasteurization of dairy products, public education regarding the risks of consuming unpasteurized dairy products, and eradication of M. bovis infection in animal reservoirs. Given the ease of spread of M. bovis infection through movement of people and animals, and the increasingly global nature of human travel and livestock trade, efforts should be increased to implement or strengthen M. bovis control and eradication programs in high-prevalence regions, in particular in economically less developed countries that lack sufficient resources or expertise to implement effective control and eradication programs without assistance. Support should focus on strengthening public health and veterinary infrastructures, with a view towards promoting long-term, sustainable program effectiveness.
One example of support that could be helpful is training of local public and veterinary health workers in the diagnosis, epidemiology, and treatment of M. bovis infection; in
epidemiologic investigation; and in methods of effective public outreach and education regarding risk factors for infection and the importance of treatment. Other support could include improving laboratory facilities and expertise; and providing grants for equipment, reagents, therapeutics, and train-the-trainer programs. Support measures should be tailored to factors specific to the
56 target area, including the epidemiology of infection, cultural practices and sensitivities, and the availability of local resources.
Globally, efforts to prevent the spread of M. bovis infection could be strengthened by more timely, accurate diagnosis of infection; and by the availability of an effective vaccine. Policy decisions should focus on improving diagnostic methods and increasing diagnostic expertise, and on supporting the development of effective vaccines. Diagnostic education policies should focus on emphasizing the importance of carefully evaluating the target situation, and of selecting appropriate methods based on the results of the evaluation. Awareness should be increased that no single method is optimal for all situations, and training should emphasize how best to combine methods to increase the informativity of the analysis results. Factors to consider in method selection include the purpose of the investigation, the amount and types of resources and expertise available, the number of samples to be tested, and the structure and molecular characteristics of the M. bovis population under investigation.
Development of new typing methods should focus on maximizing cost and time efficiency, and reproducibility of results. Methods and protocols should be simple and easily standardized, and not require use of sophisticated equipment or expertise that is not widely available. Results should be easily portable and comparable among studies and over time. Such diagnostic methods, combined with improved vaccines that are more broadly and more reliably effective, would greatly facilitate M. bovis surveillance, control, and eradication, in particular in those regions of the world that are most severely impacted by this pathogen.
57 REFERENCES
Adams, L. G. (2001). In vivo and in vitro diagnosis of Mycobacterium bovis infection. Rev Sci Tech, 20(1), 304-324.
Advisory Council for the Elimination of Tuberculosis. (1995). Essential components of a tuberculosis prevention and control program. MMWR Recomm Rep, 44(RR-11), 1-16. Alexander, K. A., Laver, P. N., Michel, A. L., Williams, M., van Helden, P. D., Warren, R. M.,
& Gey van Pittius, N. C. (2010). Novel Mycobacterium tuberculosis complex pathogen, M. mungi. Emerg Infect Dis, 16(8), 1296-1299. doi: 10.3201/eid1608.100314
Aranaz, A., Liébana, E., Gómez-Mampaso, E., Galán, J. C., Cousins, D., Ortega, A., . . . Domínguez, L. (1999). Mycobacterium tuberculosis subsp. caprae subsp. nov.: A taxonomic study of a new member of the Mycobacterium tuberculosis complex isolated from goats in Spain. Int J Syst Bacteriol, 49 Pt 3, 1263-1273.
Australian Biosecurity Cooperative Research Center for Emerging Infectious Disease. (2009). Livestock disease surveillance. Retrieved May 19, 2012,
from http://www.abcrc.org.au/pages/About.aspx?MenuID=24
Ayele, W. Y., Neill, S. D., Zinsstag, J., Weiss, M. G., & Pavlik, I. (2004). Bovine tuberculosis: An old disease but a new threat to Africa. Int J Tuberc Lung Dis, 8(8), 924-937.
Barnes, P. F., Yang, Z., Pogoda, J. M., Preston-Martin, S., Jones, B. E., Otaya, M., . . . Cave, M. D. (1999). Foci of tuberculosis transmission in central Los Angeles. Am J Respir Crit Care Med, 159(4 Pt 1), 1081-1086.
Brosch, R., Gordon, S. V., Marmiesse, M., Brodin, P., Buchrieser, C., Eiglmeier, K., . . . Cole, S. T. (2002). A new evolutionary scenario for the Mycobacterium tuberculosis complex. Proc Natl Acad Sci U S A, 99(6), 3684-3689. doi: 10.1073/pnas.052548299
Brudey, K., Driscoll, J. R., Rigouts, L., Prodinger, W. M., Gori, A., Al-Hajoj, S. A., . . . Sola, C. (2006). Mycobacterium tuberculosis complex genetic diversity: Mining the fourth international spoligotyping database (SpolDB4) for classification, population genetics and epidemiology. BMC Microbiol, 6, 23. doi: 10.1186/1471-2180-6-23
Buddle, B. M., Wedlock, D. N., Denis, M., Vordermeier, H. M., & Hewinson, R. G. (2011). Update on vaccination of cattle and wildlife populations against tuberculosis. Vet Microbiol, 151(1-2), 14-22. doi: 10.1016/j.vetmic.2011.02.021
Cabrera, O. A., Hodge, J. G., & Gostin, L. O. (2008). Express tuberculosis control laws in selected U.S. jurisdictions. Atlanta, Georgia: United States Department of Health and Human Services, Centers for Disease Control and Prevention.
58 Campos-Outcalt, D. (2005). When, and when not, to use the interferon-gamma TB test. J Fam
Pract, 54(10), 873-875. doi: jfp_1005_5410f [pii]
Canadian Food Inspection Agency. (2012). Herds infected with bovine tuberculosis in Canada in 2011. Retrieved May 15, 2012, from http://www.inspection.gc.ca/animals/terrestrial- animals/diseases/reportable/tuberculosis/herds-infected-in-
2011/eng/1330208175739/1330208395388
Center for Food Security and Public Health. (2009). Bovine tuberculosis. Ames, Iowa: Iowa State University College of Veterinary Medicine.
Centers for Disease Control and Prevention. (2004). Guide to the application of genotyping to tuberculosis prevention and control. Handbook for TB controllers, epidemiologists, laboratorians, and other program staff: United States Department of Health and Human Services.
Centers for Disease Control and Prevention. (2010). Diagnosis of latent TB infection. Retrieved May 24, 2012, from http://www.cdc.gov/tb/publications/LTBI/diagnosis.htm
Centers for Disease Control and Prevention. (2011a). Interferon-gamma release assays (IGRAs) – Blood tests for TB infection. Retrieved May 24, 2012,
from http://www.cdc.gov/tb/publications/factsheets/testing/IGRA.pdf
Centers for Disease Control and Prevention. (2011b). Mycobacterium bovis (bovine tuberculosis) in humans. Retrieved May 17, 2012,
from http://www.cdc.gov/tb/publications/factsheets/general/mbovis.pdf
Centers for Disease Control and Prevention. (2011c). National notifiable diseases surveillance system. Retrieved May 21, 2012,
from http://www.cdc.gov/osels/ph_surveillance/nndss/nndsshis.htm
Centers for Disease Control and Prevention. (2011d). Reported tuberculosis in the United States, 2010. Atlanta, Georgia: United States Department of Health and Human Services.
Centers for Disease Control and Prevention. (2011e). TB elimination. Treatment of latent tuberculosis infection: Maximizing adherence. Retrieved May 16, 2012,
from http://www.cdc.gov/tb/publications/factsheets/treatment/LTBIadherence.pdf Centers for Disease Control and Prevention. (2011f). TB elimination: BCG vaccine. Retrieved
May 18, 2012, from http://www.cdc.gov/tb/publications/factsheets/prevention/BCG.pdf Centers for Disease Control and Prevention. (2011g). TB elimination: Diagnosis of tuberculosis
disease. Retrieved May 24, 2012,
59 Centers for Disease Control and Prevention. (2011h). TB elimination: Treatment options for
latent tuberculosis infection. Retrieved May 24, 2012,
from http://www.cdc.gov/tb/publications/factsheets/treatment/LTBItreatmentoptions.pdf Centers for Disease Control and Prevention. (2011i). Treatment for TB disease. Retrieved May
16, 2012, from http://www.cdc.gov/tb/topic/treatment/tbdisease.htm
Centers for Disease Control and Prevention. (2011j). Tuberculin skin testing. Retrieved May 24, 2012, from http://www.cdc.gov/tb/publications/factsheets/testing/skintesting.pdf
Centers for Disease Control and Prevention. (2011k). Tuberculosis treatment. Retrieved May 16, 2012, from http://www.cdc.gov/tb/topic/treatment/default.htm
Centers for Disease Control and Prevention. (2012a). 2012 nationally notifiable diseases and conditions and current case definitions. Atlanta, Georgia: United States Department of Health and Human Services.
Centers for Disease Control and Prevention. (2012b). Raw milk questions and answers. Retrieved May 21, 2012, from http://www.cdc.gov/foodsafety/rawmilk/raw-milk- questions-and-answers.html#legal
Centers for Disease Control and Prevention. (2012c). Testing for TB infection. Retrieved May 25, 2012, from http://www.cdc.gov/tb/topic/testing/default.htm
Centers for Disease Control and Prevention. (2012d). Tuberculosis (TB). Retrieved May 18, 2012, from http://www.cdc.gov/tb/
Centers for Disease Control and Prevention. (2012e). Tuberculosis. Data and statistics. Retrieved May 28, 2012, from http://www.cdc.gov/tb/statistics/default.htm
Centers for Law and the Public's Health. (2009). Tuberculosis control laws and policies: A handbook for public health and legal practitioners. Atlanta, Georgia: United States Department of Health and Human Services, Centers for Disease Control and Prevention. Checkley, A. M., & McShane, H. (2011). Tuberculosis vaccines: Progress and challenges.
Trends Pharmacol Sci, 32(10), 601-606. doi: 10.1016/j.tips.2011.06.003
Chen, Y., Chao, Y., Deng, Q., Liu, T., Xiang, J., Chen, J., . . . Guo, A. (2009). Potential challenges to the Stop TB Plan for humans in China; cattle maintain M. bovis and M. tuberculosis. Tuberculosis (Edinb), 89(1), 95-100. doi: 10.1016/j.tube.2008.07.003 Cicero, R., Olivera, H., Hernández-Solis, A., Ramírez-Casanova, E., & Escobar-Gutiérrez, A.
(2009). Frequency of Mycobacterium bovis as an etiologic agent in extrapulmonary tuberculosis in HIV-positive and -negative Mexican patients. Eur J Clin Microbiol Infect Dis, 28(5), 455-460. doi: 10.1007/s10096-008-0649-5
60 Claridge, J., Diggle, P., McCann, C. M., Mulcahy, G., Flynn, R., McNair, J., . . . Williams, D. J.
L. (2012). Fasciola hepatica is associated with the failure to detect bovine tuberculosis in dairy cattle. [10.1038/ncomms1840]. Nat Commun, 3, 853.
Cleaveland, S., Shaw, D. J., Mfinanga, S. G., Shirima, G., Kazwala, R. R., Eblate, E., & Sharp, M. (2007). Mycobacterium bovis in rural Tanzania: Risk factors for infection in human and cattle populations. Tuberculosis (Edinb), 87(1), 30-43. doi:
10.1016/j.tube.2006.03.001
Collins, D. M. (2011). Advances in molecular diagnostics for Mycobacterium bovis. Vet Microbiol, 151(1-2), 2-7. doi: 10.1016/j.vetmic.2011.02.019
Cordova, E., Gonzalo, X., Boschi, A., Lossa, M., Robles, M., Poggi, S., & Ambroggi, M. (2012). Human Mycobacterium bovis infection in Buenos Aires: Epidemiology, microbiology and clinical presentation. Int J Tuberc Lung Dis. doi: 10.5588/ijtld.10.0605
Corner, L. A., O'Meara, D., Costello, E., Lesellier, S., & Gormley, E. (2012). The distribution of Mycobacterium bovis infection in naturally infected badgers [electronic publication ahead of print; journal volume, issue, and page numbers not yet assigned]. Vet J. doi:
10.1016/j.tvjl.2012.03.013
Dankner, W. M., & Davis, C. E. (2000). Mycobacterium bovis as a significant cause of tuberculosis in children residing along the United States-Mexico border in the Baja California region. Pediatrics, 105(6), E79.
Dankner, W. M., Waecker, N. J., Essey, M. A., Moser, K., Thompson, M., & Davis, C. E. (1993). Mycobacterium bovis infections in San Diego: A clinicoepidemiologic study of 73 patients and a historical review of a forgotten pathogen. Medicine (Baltimore), 72(1), 11-37.
de Kantor, I. N., LoBue, P. A., & Thoen, C. O. (2010). Human tuberculosis caused by
Mycobacterium bovis in the United States, Latin America and the Caribbean. Int J Tuberc Lung Dis, 14(11), 1369-1373.
de la Rua-Domenech, R. (2006). Human Mycobacterium bovis infection in the United Kingdom: Incidence, risks, control measures and review of the zoonotic aspects of bovine
tuberculosis. Tuberculosis (Edinb), 86(2), 77-109. doi: 10.1016/j.tube.2005.05.002 de la Rua-Domenech, R., Goodchild, A. T., Vordermeier, H. M., Hewinson, R. G., Christiansen,
K. H., & Clifton-Hadley, R. S. (2006). Ante mortem diagnosis of tuberculosis in cattle: a review of the tuberculin tests, gamma-interferon assay and other ancillary diagnostic techniques. Res Vet Sci, 81(2), 190-210. doi: 10.1016/j.rvsc.2005.11.005
Driscoll, J. R. (2009). Spoligotyping for molecular epidemiology of the Mycobacterium
tuberculosis complex. Methods Mol Biol, 551, 117-128. doi: 10.1007/978-1-60327-999- 4_10
61 Drobniewski, F., Strutt, M., Smith, G., Magee, J., & Flanagan, P. (2003). Audit of scope and
culture techniques applied to samples for the diagnosis of Mycobacterium bovis by hospital laboratories in England and Wales. Epidemiol Infect, 130(2), 235-237.
Durnez, L., Sadiki, H., Katakweba, A., Machang'u, R. R., Kazwala, R. R., Leirs, H., & Portaels, F. (2009). The prevalence of Mycobacterium bovis-infection and atypical
mycobacterioses in cattle in and around Morogoro, Tanzania. Trop Anim Health Prod, 41(8), 1653-1659. doi: 10.1007/s11250-009-9361-4
Esteban, J., Robles, P., Soledad Jiménez, M., & Fernández Guerrero, M. L. (2005).
Pleuropulmonary infections caused by Mycobacterium bovis: A re-emerging disease. Clin Microbiol Infect, 11(10), 840-843. doi: 10.1111/j.1469-0691.2005.01225.x
Etchechoury, I., Valencia, G. E., Morcillo, N., Sequeira, M. D., Imperiale, B., Lopez, M., . . . Romano, M. I. (2010). Molecular typing of Mycobacterium bovis isolates in Argentina: First description of a person-to-person transmission case. Zoonoses Public Health, 57(6), 375-381. doi: 10.1111/j.1863-2378.2009.01233.x
European Food Safety Authority and European Center for Disease Prevention and Control. (2012). The European Union summary report on trends and sources of zoonoses, zoonotic agents and food-borne outbreaks in 2010. EFSA Journal, 10(3), 2597. doi:
10.2903/j.efsa.2012.2597
Evans, J. T., Smith, E. G., Banerjee, A., Smith, R. M., Dale, J., Innes, J. A., . . . Sonnenberg, P. (2007). Cluster of human tuberculosis caused by Mycobacterium bovis: Evidence for person-to-person transmission in the UK. Lancet, 369(9569), 1270-1276. doi:
10.1016/S0140-6736(07)60598-4
Fritsche, A., Engel, R., Buhl, D., & Zellweger, J. P. (2004). Mycobacterium bovis tuberculosis: From animal to man and back. Int J Tuberc Lung Dis, 8(7), 903-904.
Garnier, T., Eiglmeier, K., Camus, J. C., Medina, N., Mansoor, H., Pryor, M., . . . Hewinson, R. G. (2003). The complete genome sequence of Mycobacterium bovis. Proc Natl Acad Sci U S A, 100(13), 7877-7882. doi: 10.1073/pnas.1130426100
González-Duarte, A., Ponce de León, A., & Osornio, J. S. (2011). Importance of differentiating Mycobaterium bovis in tuberculous meningitis. Neurol Int, 3(3), e9. doi:
10.4081/ni.2011.e9
Grange, J. M. (2001). Mycobacterium bovis infection in human beings. Tuberculosis (Edinb), 81(1-2), 71-77. doi: 10.1054/tube.2000.0263
Groenen, P. M., Bunschoten, A. E., van Soolingen, D., & van Embden, J. D. (1993). Nature of DNA polymorphism in the direct repeat cluster of Mycobacterium tuberculosis;
Application for strain differentiation by a novel typing method. Mol Microbiol, 10(5), 1057-1065.
62 Gumi, B., Schelling, E., Firdessa, R., Aseffa, A., Tschopp, R., Yamuah, L., . . . Zinsstag, J.
(2011). Prevalence of bovine tuberculosis in pastoral cattle herds in the Oromia region, southern Ethiopia. Trop Anim Health Prod, 43(6), 1081-1087. doi: 10.1007/s11250-010- 9777-x
Haddad, N., Masselot, M., & Durand, B. (2004). Molecular differentiation of Mycobacterium bovis isolates. Review of main techniques and applications. Res Vet Sci, 76(1), 1-18. doi: S003452880300078X [pii]
Hewinson, R. G., Vordermeier, H. M., Smith, N. H., & Gordon, S. V. (2006). Recent advances in our knowledge of Mycobacterium bovis: a feeling for the organism. Vet Microbiol,
112(2-4), 127-139. doi: 10.1016/j.vetmic.2005.11.050
Hlavsa, M. C., Moonan, P. K., Cowan, L. S., Navin, T. R., Kammerer, J. S., Morlock, G. P., . . . LoBue, P. A. (2008). Human tuberculosis due to Mycobacterium bovis in the United States, 1995-2005. Clin Infect Dis, 47(2), 168-175. doi: 10.1086/589240
Humblet, M. F., Boschiroli, M. L., & Saegerman, C. (2009). Classification of worldwide bovine tuberculosis risk factors in cattle: A stratified approach. Vet Res, 40(5), 50. doi:
10.1051/vetres/2009033
Ingram, P. R., Bremner, P., Inglis, T. J., Murray, R. J., & Cousins, D. V. (2010). Zoonotic tuberculosis: On the decline. Commun Dis Intell, 34(3), 339-341.
Jalava, K., Jones, J. A., Goodchild, T., Clifton-Hadley, R., Mitchell, A., Story, A., & Watson, J. M. (2007). No increase in human cases of Mycobacterium bovis disease despite
resurgence of infections in cattle in the United Kingdom. Epidemiol Infect, 135(1), 40-45. doi: 10.1017/S0950268806006509
Kamerbeek, J., Schouls, L., Kolk, A., van Agterveld, M., van Soolingen, D., Kuijper, S., . . . van Embden, J. (1997). Simultaneous detection and strain differentiation of Mycobacterium tuberculosis for diagnosis and epidemiology. J Clin Microbiol, 35(4), 907-914.
Kanduma, E., McHugh, T. D., & Gillespie, S. H. (2003). Molecular methods for Mycobacterium tuberculosis strain typing: A users guide. J Appl Microbiol, 94(5), 781-791. doi: 1918