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Review Article
 

Tuberculosis in Animals and Humans: Evolution of Diagnostics and Therapy



Vikas K. Saket,, R. Kachhi and P. Singh
 
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ABSTRACT

Tuberculosis caused by different species of genus Mycobacterium or different serotypes of various species are the leading cause of mortality among livestock, domesticated animals and humans alike. This leads to huge economic loss in terms of animal and human capital. Currently one third of global population is infected with tuberculosis (TB). There might be innumerable reasons for it being pandemic but proper diagnosis or lack of it is one of the major contributing factors for its global spread. In developing countries precise and reliable diagnosis has emerged out to be the major cause translating into high burden. The TB diagnosis has evolved over the time with changing needs from classical microscopic sputum smear analysis to rapid PCR based molecular diagnostics. Molecular techniques are becoming confirmatory diagnostic tools and advanced procedure for TB detection. Current review lays emphasis on the tuberculosis from lower animals to higher animals including human with respect to diagnostics, therapy and its improvisation over a decade.

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  How to cite this article:

Vikas K. Saket,, R. Kachhi and P. Singh, 2017. Tuberculosis in Animals and Humans: Evolution of Diagnostics and Therapy. Asian Journal of Animal and Veterinary Advances, 12: 177-188.

DOI: 10.3923/ajava.2017.177.188

URL: https://scialert.net/abstract/?doi=ajava.2017.177.188
 
Received: January 14, 2017; Accepted: February 15, 2017; Published: March 15, 2017



INTRODUCTION

Tuberculosis (TB) is a highly contagious disease that is affecting the animal as well as human population since the time immemorial. While infection in humans are chiefly from Mycobacterium tuberculosis leading to pulmonary TB (PTB), infection from other species may affect other parts of the body causing extra-pulmonary TB (ETB). Infection in domesticated livestock and wild animals from M. bovis, M. avium and rarely M. tuberculosis is responsible for the mass mortality as compared to the mortality from the combine of other infection. In the first half of 20th century, infection from animals to human through a process called zoonosis was quite common leading to the loss of both livestock as well as human capital. However, with the advent of pasteurization killing M. bovis, mortality in humans have reduced to a great extent. In the United Kingdom and other European countries farm animals or the domesticated animals are tested for the infection and are killed if tested positive for the infection1-3. Current review critically examines the array of TB diagnostic tools in terms of their accuracy, efficacy, affordability and evolution from classical TB diagnostics to modern molecular diagnostic protocols over a decade.

TUBERCULOSIS (TB) OF DOMESTICATED ANIMALS AND LIVESTOCK

Tuberculosis in horses: Equine TB is of rare occurrence nevertheless cases are reported where horse was found to be infected by M. tuberculosis and M. bovis. Infected horse displays the symptoms of granulomatous lymphadenitis in mediastinal spaces and tracheobronchial lymph nodes.

These infections are usually diagnosed by real time polymerase chain reaction (RT-PCR) and culture based techniques4.

Sheep and goats: Sheep and goats are resistant to M. tuberculosis infection but are susceptible to M. bovis infection. It usually manifests in lungs and lymph nodes of infected animal. However, it may spread to other organs as well. The TB infection is contagious and infected animals can affect other animals as well. Diagnosis is usually performed by intradermal skin test utilizing purified proteins from M. bovis and M. avium1-3,5.

Farmed and wild cervids: The visible symptoms of TB are produced by M. avium and M. bovis in the lymph nodes of the head and abscessation. Examples include farmed and wild cervids, including axis deer, fallow deer, roe deer, mule deer, sika deer, as well as red deer or elk or wapiti. Diagnosis is performed by tubercular skin test and in vitro cellular assays1,3,5.

Hoofed animals: This category includes African buffalo, wood bison, North American bison, white-tailed and mule deer, lechwe, elk, brushtail possums and European badgers. These are usually susceptible to M. bovis infection. While, fennec fox, coyote, Arabian oryx, muntjac, impala, sitatunga, springbok, moles, voles, hares, eland, yak, bactrian camel, wildebeest, European wild goat, large spotted genet, tapir, moose, otters, feral water buffalo, hedgehogs, European wild boar, greater kudu, tiger, white and black rhinoceros and giraffe etc are susceptible to M. tuberculosis mediated infection. The M. tuberculosis is isolated from oryx, black rhinoceros, Asian elephant, addax and rocky mountain goats. Visible symptoms are in the form of lesions that vary in consistency from purulent (pus like) to caseous (necrotic) in lungs and regional lymph nodes with liver, spleen and serosal surfaces acting as major sites. Diagnostics involve tuberculin skin tests performed in the cervical region using M. bovis PPD1-3,5.

Elephants: The TB infections in elephants are usually confined to captive domesticated elephants. As with other animals TB infection is usually confined to lung and the associated lymph nodes. Diagnosis via tuberculin skin test and in vitro immunologic test gives non-specific responses. Therefore, trunk washes should be used for diagnostic purposes. Combined drug therapy involving isoniazid and rifampin is recommended for treatment with continuous monitoring of blood to analyze the threshold concentration of drugs, enough to kill the TB bacilli1,3.

Pigs: The TB in pigs is usually caused by M. tuberculosis, M. bovis and M. avium complex (M. avium avium and M. avium hominissuis). Infection is spread through shared contaminated grazing. Observable symptoms are in the form of granulomatous lesions present in cervical, submandibular and mesenteric lymph nodes. Lesions in their progressive stages are present in liver and spleen. Diagnosis includes intradermal test performed on the dorsal ear surface or vulva skin1-3,5.

Cat and dogs: Dogs get TB infection chiefly from M. tuberculosis, M. bovis and rarely from M. avium complex or M. fortuitum having come from a human or bovine source. Tuberculous lesions are located in lungs, liver, kidney, pleura and peritoneum having grayish appearance with a non-calcified necrotic center. Tuberculin skin test usually gives false negative results. Since dogs lives in close proximity with human so euthanasia is recommended instead of treatment1,3. Cats show high degree of susceptibility to M. bovis, M. avium complex or M. microti, M. lepraemurium but are usually resistant to M. tuberculosis. Clinical symptoms are in the form of granulomatous lesions in mesenteric lymph. These lesions were the cause for tuberculous cat in the Europe. Blood mediated transmission to lungs and localized lymph nodes may occur. Tuberculin test, which forms the gold standard for testing TB in animals is considered unreliable in case of cats and dogs and needs to be confirmed by radiography and ELISA1-3,5.

Rabbit: The TB is extremely rare in rabbits, however, susceptibility to M. bovis and M. avium is reported. Rabbit gets the infection from exposure to infected animal or contaminated feed. The M. avium infection is caused by contact with domestic and exotic birds infected with M. avium. Tuberculin skin test forms the usual diagnostic procedure performed on abdominal skin1,3.

Guinea pigs: The TB in Guinea pigs is caused by M. tuberculosis, M. bovis, serotypes of M. bovis and M. avium. Visible symptoms are present in the form of lesions in the parenchyma of gastrointestinal tract. As with other animals diagnosis involves tuberculin skin test that utilizes Purified Protein Derivative (PPD) of M. bovis and M. avium3.

Non-primates: Non-primates get the infection from M. tuberculosis, M. bovis and M. avium in lungs (pulmonary TB and other organs (extra-pulmonary TB). Non-primates receive the infection from coming in close contact with infected human service providers. Modes of spread are aerosol with respiratory infection or the oral route. The TB bacilli may also be detected from urine. Diagnostics involve tubercular skin test where old tuberculin is preferred over Purified Protein Derivative (PPD) as it is more sensitive1-3,5.

Aquatic mammals: Marine mammals gets the infection from M. pinnipedii. The causative organism M. pinnipedii is variant of M. bovis adapted and specific to seal. This has been isolated from tubercular lesions in seals and fur seals. Symptoms are produced in peripheral lymph nodes, spleen, peritoneum and lungs1-3,5.

Bovine infection spread to humans: Infection by M. bovis or bovine infection can spread to human by contaminated unpasteurized dairy products, inhalation of infectious aerosols etc. However, it can be controlled by proper management and livestock surveillance programs. Bovine TB can be cured through antimicrobial drugs.

Tuberculosis in human: Tuberculosis (TB) is a long standing and one of the most primitive, epidemic disease of mankind6-11. Globally TB is one of the major cause for the mortality and morbidity in humans and other animals alike. Birds, rodents, reptiles and other animals can also contract Mycobacterium infection. Tuberculosis in cattles by Mycobacterium bovis is of grave concern for dairy and animal husbandry. Big animals like elephants can also get tuberculosis infection in captivity. It is believed that animals get this infection via ‘Reverse zoonosis’12-19. The TB is highly infectious disease that spread through M. tuberculosis (Table 1). Approximately, 2 million people are killed by TB annually with addition of 8.6 million per year20,21. Amongst various causes, lack of economical and reliable diagnosis has huge impact on upsurge of TB. This becomes a huge challenge particularly with MDR/XDR/TB-HIV cases in developing countries and almost in all high burden countries. The World Health Organization (WHO) has approved many diagnostic methods and has evolved a special strategy as Supranational Reference Laboratory Network (SRLN) (Fig. 1) to provide diagnostic information and technical resource in addition to the strengthening of the diagnostic methods with special laboratory capacity in many countries22-25.

Table 1: Morbidities due to different species of Mycobacterium
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Image for - Tuberculosis in Animals and Humans: Evolution of Diagnostics and Therapy
Fig. 1: WHO TB Supranational Reference Laboratory Network (SRLN)

About 36 counties are involved in SRLN network (Fig. 1) to improve and innovate the best diagnostics in terms of precision, reliability, portability and cost involved. The TB in most of the cases is often difficult to diagnose due to asymptomatic status of the patient or characters in phenotypic order for a long time. Slow progression of MTB usually take months or even year of latency. Methods are now available that facilitates direct detection of Mycobacterium tuberculosis. Basic diagnostics involve chest x-ray, sputum microscopy test, IGRA test and TB skin test. For cases where TB is associated with HIV or MDR/XDR cases, classical diagnostic methods are usually complemented with modern molecular diagnostic protocols26-29. However, these protocols are cost ineffective, not available easily and are still not optimized for commercial applications.

MYCOBACTERIUM PROFILE

Fatty acid and pathogenicity: Around 250 genes are involved in fatty acid metabolism of which 39 are involved in polyketide metabolism that produces coat of wax. The genes involved in fatty acid metabolism show evolutionary conservation that validates the importance of fatty acid in the pathogenicity. Cells stained with acid-fast staining show wrapped together due to the presence of fatty acid in the cell wall that stick together. High content of lipid, i.e., mycolic acid in the cell wall makes it highly resistant and pathogenic. Such type of cell wall prevents the fusion of bacterium containing phagosome with lysosome thus escape killing by antimycobacterial factors30-35.

Host susceptibility: Tuberculosis has a definite genetic component. A certain type of genetic makeup predisposes an individual towards the mycobacterial infection. Group of rare genetic disorder called Mendelian susceptibility to mycobacterial diseases (MSMD) increases the likelihood of an individual to contract the disease. Modern research involving Genome Wide Association Studies (GWAS) also validates this36-38.

Human-Mycobacterium co-evolution: Empirical evidences from phylogeny and phylogeography evidences have proved that Mycobacterium has migrated to distant parts of the globe along with its human host. Evolutionary history has traced back its origin to Africa from where it has migrated to other regions. Similarity found in the mitochondrial genome of Mycobacterium and human host suggests relationship between the two and co-evolutionary pattern. In any case, Mycobacterium must have evolved to increase its pathogenicity while human hosts have evolved to have better defense strategies39-41.

Evolutionary spread: Mycobacterium tuberculosis complex (MTC) shows clonal spread pattern and human infecting species have been classified into seven spoligotypes (Table 2). Type 2 and 3 are closely related while type 3 is divided into two clades CAS-Kiii (Tanzania) and CAS-Delhi (Delhi and Saudi Arabia). Beijing strain is most pathogenic with population expansion of 500 fold42-44.

Table 2: Clonal variation pattern of Mycobacterium tuberculosis
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TUBERCULOSIS DIAGNOSTICS: CONVENTIONAL APPROACHES

Traditional diagnosis methods: The TB is older than 6000 years in the realms of history of mankind, referred to as phthisis or white disease. In those times information about TB were scarce; diagnosis was based on productive cough of four or more week, hemoptysis, loss of weight, chest pain, chills, night sweat, fatigue and lot of sputum production constituting the preliminary information for TB diagnosis45. However, TB diagnosis has taken a giant leap since then from microscopic analysis of sputum to PCR and isotope based protocols46-48. Diagnosis of TB bacilli depends upon smear positivity in sputum sample, chest radiography and culture. Although several TB diagnosis methods are available but with known limitations. Robert Koch had discovered the tubercle bacillus in 1882 and thereafter methods of detecting these microorganisms were developed to assist the diagnosis of the disease. Thus, Acid Fast Bacilli (AFB) remain a cost effective method for staining TB bacilli49.

Microscopy test of sputum smear or pulmonary TB test: Microscopic analysis of sputum smear is the most common method for TB diagnosis used worldwide particularly in developing or low/middle income countries making it a standard diagnostic method for detection of pulmonary TB50. This test involves microscopic analysis of sputum coughed by patient. Microscopic analysis leads to the visible detection of germs (bacilli), i.e., smear positive (Fig. 2). However, this test has its limitations when it comes to the detection of MTB that require culture test to confirm the presence of Mycobacterium tuberculosis. This test is rapid, affordable and accurate for normal pulmonary TB. Microscopic test is a common method of TB detection in Asian countries including India, Japan and China.

Culture method: Culture test requires a laboratory setup. Usually, sputum or phlegm is taken in a jar, if any MTB is present in the sample it could grow in culture medium forming colony of M. tuberculosis (Fig. 3).

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Fig. 2: Tuberculosis bacilli in Ziehl-Neelsen stain

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Fig. 3: Colonies of Mycobacterium tuberculosis grown on LJ media

This test can detect TB like normal TB and drug resistant TB51. The culture based diagnosis takes 4-10 weeks.

Culture method requires fluorescence microscopy or auramix rhodamine staining following induction of sample with bronchodilator saline solution. There are many culture method available with different type of culture media such as Lowenstein-Jensen (LJ), Middlebrook media, JH9 and 7H10 or Kirchner. Microscopic Observatory Drug Susceptibility (MODS) culture assay is faster as compared to other culture methods. This type of diagnosis is commonly used worldwide. Besides conventional laboratory culture, modern automated system are also available such as VERSA TREK, BACTEC and MGIT (mycobacterial growth indicator tube).

Chest x-ray: Radiographs of chest x-ray indicates the pulmonary TB. Lung damage shows TB infection and its location. Damage, which appears as white patches, shows the presence of TB that could be further confirmed by other tests or diagnostic protocols (Fig. 4).

Table 3: Specification of currently available IGRAs
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Image for - Tuberculosis in Animals and Humans: Evolution of Diagnostics and Therapy
Fig. 4: Chest x-ray of a patient diagnosed with advanced stage of tuberculosis

However, x-ray appears normal in case of TB associated with HIV and other immune suppressed diseases thus giving false negative response. Chest x-ray identifying MTB appear as tree in bud sign on upper lobe. Chest x-ray report needs to be aligned with other diagnostic methods to confirm TB52.

Chest x-ray is better only for acute pulmonary TB and redundant for extra pulmonary TB. Sometime other lung disease is mistakenly diagnosed as similar to pulmonary TB in X-ray called as mimicking pulmonary TB53.

Diagnosis through skin test: Mantoux test and TST (Tuberculosis/Tuberculin skin test) depend on immune response to Mycobacterium tuberculosis. At the time of TST, a small amount of TB antigen is injected inside the top layer of skin, if the immune system of body comes in contact with the bacterium, skin colour changes to pale red. This test is non-confirmatory in nature and requires other tests to complement the finding. Mantoux tuberculin test involve intra-dermal injection of Purified Protein Derivative (PPD) followed by measuring the size of tuberculin indurations of 48-72 h, which measures immune response against 72-75 bacilli10. This test is commonly used in USA and other South American countries. The TST is also a method of diagnosis in other countries like UK where it is referred to as Heaf test with 4 on point scale detection54.

Blood test for TB diagnosis: Blood test for TB diagnosis identifies parameters like hypocalcemia and hyponatremia with increased RBCs sedimentation rate. This test needs further confirmation to establish the infection. However, results are not sufficient to differentiate active or latent type. Interferon-Gamma Release Assays (IGRAs) are whole-blood tests that can aid in diagnosing M. tuberculosis infection55-58.

This test is more common in developed countries like USA, UK or other European countries where blood test is available in three types-QuartiFERON, T-SPOT TB and ELISPOT. These tests are rarely available in India and other Asian countries. Two IGRAs that have been approved by the US Food and Drug Administration (FDA) are QuantiFERON-TB Gold In-Tube test (QFT-GIT) and SPOT TB test (T-SPOT) (Table 3).

MODERN MOLECULAR PROTOCOLS

Modified diagnostic test based on molecular and genetic based approaches: Increasing pathogenicity of tuberculosis bacterium and resistance to existing drug has made classical diagnostic protocols redundant paving the way for newer and modern PCR based molecular methods or radioisotope based fluorescence methods for detecting drug resistant TB. For instance, PCR based Ziehle-Neelsen stained sputum test, radioisotope based PCR, single PCR methods and multi-PCR SSP assay and DNA amplification of TB are available for molecular genetic analysis of TB. These improvised diagnostic protocols have facilitated the detection of more than 80% isoniazid (INH) and rifampicin (RIF) resistant TB59,60. Ziehle-Neelsen stained sputum test utilizes Ziehl-Neelsen acid fast stained slides, which uses silica based filter with PCR. The stained sputum sample on glass slide contains primer61,62. This method use two set of primers-one based on the IS6110 sequence of M. tuberculosis and other based on protein antigen b (PAB). This protocol facilitates direct detection of pulmonary tuberculosis through PCR assay63.

Multiplex allele-specific polymerase chain reaction (MAS-PCR): This protocol detects MDR/XDR TB. It is a relatively inexpensive and technically feasible technique for rapid detection of MDR-TB64. On other side, MTBDRSI assay is also available for rapid detection of drug resistance (Amikacin and almost all fluoroquinolones). This is a new type of molecular kit designed for specific detection of resistance against second line drugs. It works on a single strip and can be done directly on clinical sample65. In addition to this many Western countries use PCR-SSP (PCR-single strand conformational polymorphism) for confirmation of rifampicin resistance66.

Xpert MTB/RIF: Xpert MTB/RIF test or assay is used for the diagnosis of pulmonary TB. This assay simultaneously detects M. tuberculosis complex (MTBC). This protocol utilizes capheild’s gene Xpert Dx system that include PC, barcode scanner and software for running the test and viewing results67. Standard culture can take 2-6 weeks for MTBC to grow. This test can also detect resistance to rifampcin (RIF) and take around 3 weeks. The Xpert MTB/RIF assay is a Nucleic Acid Amplification Test (NAAT) that utilizes a disposable cartridge with the GeneXpert instrument system. A sputum sample is collected from the patient with suspected TB. The sputum is mixed with the reagent that is provided with the assay and a cartridge containing this mixture is placed in the GeneXpert machine. All processing from this point onward is fully automated. Additionally, assay can quickly identify possible multi-drug resistant TB (MDR TB). Resistance to rifampcin (RIF) is a predictor of MDR TB because resistance to RIF, in most instances co-exists with resistance to isoniazid (INH). Rapid diagnosis of RIF resistance potentially allows TB patients to start effective treatment much sooner than waiting for results from other types of drug susceptibility testing. However, this assay does not replace the need for smear with microscopy, culture of mycobacteria, acid-fast bacilli and growth-based drug susceptibility testing, in addition to genotyping for early discovery of outbreaks.

FAST-RIF or fluorometric assay: This protocol for susceptibility testing of rifampcin was developed around 2008 by the group at Stellenbosch University, South Africa. It is a fluorometric based assay to detect rifampin susceptibility of MTB. The FAST-RIF works on the principal of high resolution thermal melt analysis and determine the region of gene rpoB in MTB68.

High Resolution Melting Analysis Assay (HRMA): The HRMA detects ofloxacin, rifampcin and isoniazid resistant MTB through mutation target69,70. It is a PCR based protocol that detects mutation in the genes that imparts resistance to isoniazid, rifampcin and ofloxacin. The HRMA is a routine test for detecting MDR-TB in developing countries. It is similar to Auto MODS assay, i.e., Microscopic Observation Drug Susceptibility (MODS) assay71.

M-ARMS: The M-ARMS is utilized to detect only rifampin resistant MDR-TB. This protocol involves multiple amplification refractory mutation system PCR that works on single mutation system based on allele-specific priming. In this method, an oligonucleotide primer with a triple end complementarity to the sequence of a specific mutation coupled with a common primer is used in one PCR reaction. The M-ARMS involve chimeric primer and can detect mutation at many codon on rpoB gene of rifampin72. However, all the detection procedure including the conventional AFB-staining, skin tuberculin test and new generation modifying tests have some advantages as well as limitations (Table 4). There are some laboratory based commercially available diagnostic tests for TB that have been optimized by bio-laboratories or industries for improving diagnostic procedure (Table 5).

VACCINATION

Vaccines are permanent solution to the active and latent tuberculosis. The inherent limitations of BCG vaccination has forced scientist to look for other alternatives, the most promising being subunit vaccine73. MVA85A vaccine based on vaccinia virus is a subunit vaccine74. At global level, stop TB partnership, South African Tuberculosis Vaccine Initiative, Aeras Global TB Vaccine Foundation are spearheading the vaccine development research75-78.

A research group under Professor Raghavan Varadarajan at Indian Institute of Science (IISc), Bangalore, India is already working on the HIV-AIDS vaccine. The vaccine in question will be a epitope based sub-unit vaccine79. On similar fashion vaccine for TB can be designed based on the capsule of TB bacilli. Subunit vaccine is the logical solution for TB as it would be based on the part of TB bacilli and free from the danger of using live weakened or dead bacterium for the vaccine.

Table 4: Tuberculosis diagnostic procedures
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Table 5: List of modern diagnostic kit for TB
Image for - Tuberculosis in Animals and Humans: Evolution of Diagnostics and Therapy

Subunit vaccine approach involves techniques from proteomics and biophysics, which relies largely on protein purification, folding and dynamics and finally biophysical characterization before submitting it for immunization80-83. Surface Plasmon Resonance (SPR) based biosensors are new highly evolved tool and technique to detect protein-ligand interaction in addition to rapid and sensitive diagnosis of biomarker proteins for TB detection84.

CONCLUSION

Modern molecular diagnostic protocols require well equipped, state-of-art laboratory facilities that may not be easily available locally. Currently, most of the tools/techniques in demonstration or late-stage validation are sputum based and thus are likely to result in incremental gains in rate of TB detection. In addition to the lack of portability, cost involved is also a big deterrent before these modern protocols could realize their full potential particularly in the limited economic set up of developing countries.

SIGNIFICANCE STATEMENT

Tuberculosis is the major cause of morbidity and mortality in animals and humans alike
Precise and timely diagnosis is key to the successful treatment of TB
Inaccurate diagnosis and incomplete treatment leads to drug-resistant TB (DR-TB)
DR-TB and associated co-infections (AIDS) are making TB difficult to cure
The TB diagnosis has evolved considerably from conventional SSM to DNA based molecular protocols

ACKNOWLEDGMENT

Authors gratefully acknowledge the academic inputs from various sources. The VKS acknowledges the fellowship from DST-NRDMS while PS acknowledges the financial support from DST-NRDMS and UGC Startup grants.

REFERENCES

1:  O'Reilly, L.M. and C.J. Daborn, 1995. The epidemiology of Mycobacterium bovis infections in animals and man: A review. Tubercle Lung Dis., 76: 1-46.
CrossRef  |  Direct Link  |  

2:  Delahay, R.J., A.N.S. de Leeuw, A.M. Barlow, R.S. Clifton-Hadley and C.L. Cheeseman, 2002. The status of Mycobacterium bovis infection in UK wild mammals: A review. Vet. J., 164: 90-105.
CrossRef  |  PubMed  |  Direct Link  |  

3:  Thoen, C.O., 2017. Overview of tuberculosis and other Mycobacterial infections. http://www.merckvetmanual.com/generalized-conditions/tuberculosis-and-other-mycobacterial-infections/overview-of-tuberculosis-and-other-mycobacterial-infections.

4:  Khurana, S.K. and K. Dhama, 2016. Brief Overview: Bacterial Diseases of Equines. In: Advances in Animal Sciences and Biomedicine in 21st Century, Dhama, K., Y.S. Malik, M. Munir, K. Karthik, R. Tiwari and S.K. Joshi (Eds.). International Academy of Biosciences, UK., pp: 26-43

5:  Phillips, C.J.C., C.R.W. Foster, P.A. Morris and R. Teverson, 2003. The transmission of Mycobacterium bovis infection to cattle. Res. Vet. Sci., 74: 1-15.
CrossRef  |  PubMed  |  Direct Link  |  

6:  Ryan, K.J., C.G. Ray and J.C. Sherris, 2004. Sherris Medical Microbiology: An Introduction to Infectious Diseases. 4th Edn., McGraw Hill, New York, USA., ISBN-13: 9780838585290, Pages: 979

7:  Harris, R.E., 2013. Epidemiology of Chronic Disease: Global Perspectives. Jones & Bartlett Publishers, USA., ISBN: 9780763780470, Pages: 723

8:  Southwick, F.S., 2007. Pulmonary Infections. In: Infectious Diseases: A Clinical Short Course, Southwick, F.S. (Ed.). 2nd Edn., McGraw-Hill Medical Publishing, USA., ISBN-13: 9780071593786, pp: 79-119

9:  Nicas, M., W.W. Nazaroff and A. Hubbard, 2005. Toward understanding the risk of secondary airborne infection: Emission of respirable pathogens. J. Occup. Environ. Hyg., 2: 143-154.
CrossRef  |  Direct Link  |  

10:  Lawn, S.D. and A.I. Zumla, 2011. Tuberculosis. Lancet, 378: 57-72.
CrossRef  |  Direct Link  |  

11:  Griffith, D.E. and C.M. Kerr, 1996. Tuberculosis: Disease of the past, disease of the present. J. Perianesth. Nurs., 11: 240-245.
CrossRef  |  Direct Link  |  

12:  Muller, R., C.A. Roberts and T.A. Brown, 2015. Complications in the study of ancient tuberculosis: Non-specificity of IS6110 PCRs. STAR: Sci. Technol. Archaeol. Res., 1: 1-8.
CrossRef  |  Direct Link  |  

13:  Shivaprasad, H.L. and C. Palmieri, 2012. Pathology of mycobacteriosis in birds. Vet. Clin. North Am.: Exotic Anim. Pract., 15: 41-55.
CrossRef  |  PubMed  |  Direct Link  |  

14:  Reavill, D.R. and R.E. Schmidt, 2012. Mycobacterial lesions in fish, amphibians, reptiles, rodents, lagomorphs and ferrets with reference to animal models. Vet. Clin. North Am.: Exotic Anim. Pract., 15: 25-40.
CrossRef  |  PubMed  |  Direct Link  |  

15:  Mitchell, M.A., 2012. Mycobacterial infections in reptiles. Vet. Clin. North Am.: Exotic Anim. Pract., 15: 101-111.
CrossRef  |  PubMed  |  Direct Link  |  

16:  Wobeser, G.A., 2006. Essentials of Disease in Wild Animals. 1st Edn., Wiley-Blackwell Publishing, Ames, IA., USA., ISBN-13: 978-0813805894, Pages: 256

17:  Ryan, T.J., P.G. Livingstone, D.S.L. Ramsey, G.W. de Lisle, G. Nugent, D.M. Collins and B.M. Buddle, 2006. Advances in understanding disease epidemiology and implications for control and eradication of tuberculosis in livestock: The experience from New Zealand. Vet. Microbiol., 112: 211-219.
CrossRef  |  Direct Link  |  

18:  White, P. C., M. Bohm, G. Marion and M.R. Hutchings, 2008. Control of bovine tuberculosis in British livestock: There is no 'silver bullet'. Trends Microbiol., 16: 420-427.
CrossRef  |  Direct Link  |  

19:  Ward, A.I., J. Judge and R.J. Delahay, 2010. Farm husbandry and badger behaviour: Opportunities to manage badger to cattle transmission of Mycobacterium bovis? Prev. Vet. Med., 93: 2-10.
CrossRef  |  Direct Link  |  

20:  Thoen, C.O., P. LoBue and I. de Kantor, 2006. The importance of Mycobacterium bovis as a zoonosis. Vet. Microbiol., 112: 339-345.
CrossRef  |  Direct Link  |  

21:  Jacob, J.T., A.K. Mehta and M.K. Leonard, 2009. Acute forms of tuberculosis in adults. Am. J. Med., 122: 12-17.
CrossRef  |  Direct Link  |  

22:  Van Zyl Smit, R.N., M. Pai, W.W. Yew, C.C. Leung, A. Zumla, E.D. Bateman and K. Dheda, 2010. Global lung health: The colliding epidemics of tuberculosis, tobacco smoking, HIV and COPD. Eur. Respir. J., 35: 27-33.
CrossRef  |  Direct Link  |  

23:  Golden, M.P. and H.R. Vikram, 2005. Extrapulmonary tuberculosis: An overview. Am. Fam. Physician, 72: 1761-1768.
Direct Link  |  

24:  Kommareddi, S., C.R. Abramowsky, G.L. Swinehart and L. Hrabak, 1984. Nontuberculous mycobacterial infections: Comparison of the fluorescent auramine-O and Ziehl-Neelsen techniques in tissue diagnosis. Hum. Pathol., 15: 1085-1089.
CrossRef  |  Direct Link  |  

25:  Ahmed, N. and S.E. Hasnain, 2011. Molecular epidemiology of tuberculosis in India: Moving forward with a systems biology approach. Tuberculosis, 91: 407-413.
Direct Link  |  

26:  O'Brien, R.J., 1994. Drug-resistant tuberculosis: Etiology, management and prevention. Semin. Respir. Infect., 9: 104-112.
PubMed  |  Direct Link  |  

27:  Velayati, A.A., M.R. Masjedi, P. Farnia, P. Tabarsi, J. Ghanavi, A.H. ZiaZarifi and S.E. Hoffner, 2009. Emergence of new forms of totally drug-resistant tuberculosis bacilli: Super extensively drug-resistant tuberculosis or totally drug-resistant strains in Iran. Chest, 136: 420-425.
CrossRef  |  PubMed  |  Direct Link  |  

28:  Rattan, A., A. Kalia and N. Ahmad, 1998. Multidrug-resistant Mycobacterium tuberculosis: Molecular perspectives. Emerg. Infect. Dis., 4: 195-209.
PubMed  |  Direct Link  |  

29:  Lambert, M.L., E. Hasker, A. van Deun, D. Roberfroid, M. Boelaert and P. van der Stuyft, 2003. Recurrence in tuberculosis: Relapse or reinfection? Lancet Infect. Dis., 3: 282-287.
CrossRef  |  Direct Link  |  

30:  Lienhardt, C., M. Espinal, M. Pai, D. Maher and M.C. Raviglione, 2011. What research is needed to stop TB? Introducing the TB Research Movement. PLoS Med., Vol. 8.
CrossRef  |  Direct Link  |  

31:  Segal, W. and H. Bloch, 1956. Biochemical differentiation of Mycobacterium tuberculosis grown in vivo and in vitro. J. Bacteriol., 72: 132-141.
PubMed  |  Direct Link  |  

32:  Wipperman, M.F., N.S. Sampson and S.T. Thomas, 2014. Pathogen roid rage: Cholesterol utilization by Mycobacterium tuberculosis. Crit. Rev. Biochem. Mol. Biol., 49: 269-293.
CrossRef  |  Direct Link  |  

33:  Houben, E., L. Nguyen and J. Pieters, 2006. Interaction of pathogenic mycobacteria with the host immune system. Curr. Opin. Microbiol., 9: 76-85.
CrossRef  |  PubMed  |  Direct Link  |  

34:  Glickman, M.S. and W.R. Jacobs Jr., 2001. Microbial pathogenesis of Mycobacterium tuberculosis: Dawn of a discipline. Cell, 104: 477-485.
CrossRef  |  Direct Link  |  

35:  Niederweis, M., O. Danilchanka, J. Huff, C. Hoffmann and H. Engelhardt, 2010. Mycobacterial outer membranes: In search of proteins. Trends Microbiol., 18: 109-116.
CrossRef  |  Direct Link  |  

36:  Keane, J., M.K. Balcewicz-Sablinska, H.G. Remold, G.L. Chupp, B.B. Meek, M.J. Fenton and H. Kornfeld, 1997. Infection by Mycobacterium tuberculosis promotes human alveolar macrophage apoptosis. Infect. Immunity, 65: 298-304.
PubMed  |  Direct Link  |  

37:  Hirsh, A.E., A.G. Tsolaki, K. DeRiemer, M.W. Feldman and P.M. Small, 2004. Stable association between strains of Mycobacterium tuberculosis and their human host populations. Proc. Natl. Acad. Sci. USA., 101: 4871-4876.
CrossRef  |  PubMed  |  Direct Link  |  

38:  Moller, M. and E.G. Hoal, 2010. Current findings, challenges and novel approaches in human genetic susceptibility to tuberculosis. Tuberculosis, 90: 71-83.
CrossRef  |  Direct Link  |  

39:  Hershberg, R., M. Lipatov, P.M. Small, H. Sheffer and S. Niemann et al., 2008. High functional diversity in Mycobacterium tuberculosis driven by genetic drift and human demography. PLoS Biol., Vol. 6.
CrossRef  |  Direct Link  |  

40:  Niobe-Eyangoh, S.N., C. Kuaban, P. Sorlin, P. Cunin and J. Thonnon et al., 2003. Genetic biodiversity of Mycobacterium tuberculosis complex strains from patients with pulmonary tuberculosis in Cameroon. J. Clin. Microbiol., 41: 2547-2553.
CrossRef  |  PubMed  |  Direct Link  |  

41:  Comas, I., M. Coscolla, T. Luo, S. Borrell and K.E. Holt et al., 2013. Out-of-Africa migration and Neolithic coexpansion of Mycobacterium tuberculosis with modern humans. Nat. Genet., 45: 1176-1182.
CrossRef  |  Direct Link  |  

42:  Barnes, I., A. Duda, O.G. Pybus and M.G. Thomas, 2011. Ancient urbanization predicts genetic resistance to tuberculosis. Evolution, 65: 842-848.
CrossRef  |  Direct Link  |  

43:  Comas, I. and S. Gagneux, 2009. The past and future of tuberculosis research. PLoS Pathog., Vol. 5.
CrossRef  |  Direct Link  |  

44:  Wirth, T., F. Hildebrand, C. Allix-Beguec, F. Wolbeling and T. Kubica et al., 2008. Origin, spread and demography of the Mycobacterium tuberculosiscomplex. PLoS Pathog., Vol. 4.
Direct Link  |  

45:  Frothingham, R. and W.A. Meeker-O'Connell, 1998. Genetic diversity in the Mycobacterium tuberculosis complex based on variable numbers of tandem DNA repeats. Microbiology, 144: 1189-1196.
CrossRef  |  PubMed  |  Direct Link  |  

46:  Mason, P.H., A. Roy, J. Spillane and P. Singh, 2016. Social, historical and cultural dimensions of tuberculosis. J. Biosocial Sci., 48: 206-232.
CrossRef  |  Direct Link  |  

47:  Jaiswal, S., J.P. Sah and B. Sharma, 2013. Standard diagnostic procedure for tuberculosis: A review. Res. Rev.: J. Life Sci., 3: 34-40.
Direct Link  |  

48:  Bento, J., A.S. Silva, F. Rodrigues and R. Duarte, 2011. Diagnostic tools in tuberculosis. Acta Medica Portuguesa, 24: 145-154.
Direct Link  |  

49:  Steingart, K.R., L.L. Flores, N. Dendukuri, I. Schiller and S. Laal et al., 2011. Commercial serological tests for the diagnosis of active pulmonary and extrapulmonary tuberculosis: An updated systematic review and meta-analysis. PLoS Med., Vol. 8.
CrossRef  |  Direct Link  |  

50:  Amicosante, M., M. Ciccozzi and R. Markova, 2010. Rational use of immunodiagnostic tools for tuberculosis infection: Guidelines and cost effectiveness studies. New Microbiol., 33: 93-107.
PubMed  |  Direct Link  |  

51:  Birhanu, T. and E. Ejeta, 2015. Review on convectional and advanced diagnostic techniques of human tuberculosis. J. Med. Leb. Diagn., 6: 9-16.
CrossRef  |  Direct Link  |  

52:  Steingart, K.R., M. Henry, V. Ng, P.C. Hopewell and A. Ramsay et al., 2006. Fluorescence versus conventional sputum smear microscopy for tuberculosis: A systematic review. Lancet Infect. Dis., 6: 570-581.
CrossRef  |  Direct Link  |  

53:  Rossi, S.E., T. Franquet, M. Volpacchio, A. Gimenez and G. Aguilar, 2005. Tree-in-bud pattern at thin-section CT of the lungs: Radiologic-pathologic overview. RadioGraphics, 25: 789-801.
CrossRef  |  Direct Link  |  

54:  Chaturvedi, N. and A. Cockcroft, 1992. Tuberculosis screening in health service employees: Who needs chest X-rays? Occup. Med., 42: 179-182.
CrossRef  |  Direct Link  |  

55:  Dacso, C.C., 1990. Skin Testing for Tuberculosis. In: Clinical Methods: The History, Physical and Laboratory Examinations, Walker, H.K., W.D. Hall and J.W. Hurst (Eds.). 3rd Edn., Chapter 47, Butterworths, Boston, USA., ISBN-13: 9780409900774, pp: 245-248

56:  Menzies, D., 1999. Interpretation of repeated tuberculin tests: Boosting, conversion and reversion. Am. J. Respir. Crit. Care Med., 159: 15-21.
CrossRef  |  Direct Link  |  

57:  Starke, J.R., 1996. Tuberculosis skin testing: New schools of thought. Pediatrics, 98: 123-125.
PubMed  |  Direct Link  |  

58:  Froeschle, J.E., F.L. Ruben and A.M. Bloh, 2002. Immediate hypersensitivity reactions after use of tuberculin skin testing. Clin. Infect. Dis., 34: e12-e13.
CrossRef  |  Direct Link  |  

59:  Metcalfe, J.Z., C.K. Everett, K.R. Steingart, A. Cattamanchi, L. Huang, P.C. Hopewell and M. Pai, 2011. Interferon-γ release assays for active pulmonary tuberculosis diagnosis in adults in low- and middle-income countries: Systematic review and meta-analysis. J. Infect. Dis., 204: S1120-S1129.
CrossRef  |  Direct Link  |  

60:  Akselband, Y., C. Cabral, D.S. Shapiro and P. McGrath, 2005. Rapid mycobacteria drug susceptibility testing using Gel Microdrop (GMD) growth assay and flow cytometry. J. Microbiol. Methods, 62: 181-197.
CrossRef  |  Direct Link  |  

61:  Rosilawati, M.L. and A. Yasmon, 2012. Detection of multidrug-resistant Mycobacterium tuberculosis directly from sputum samples of patients from Jakarta, Indonesia by radioisotope-based PCR-dot blot hybridization. S. Afr. J. Trop. Med. Public Health, 43: 89-95.
PubMed  |  Direct Link  |  

62:  Tansuphasiri, U., P. Boonrat and S. Rienthong, 2004. Direct identification of Mycobacterium tuberculosis from sputum on Ziehl-Neelsen acid fast stained slides by use of silica-based filter combined with polymerase chain reaction assay. J. Med. Assoc. Thailand, 87: 180-189.
PubMed  |  Direct Link  |  

63:  Forbes, B.A. and K.E. Hicks, 1993. Direct detection of Mycobacterium tuberculosis in respiratory specimens in a clinical laboratory by polymerase chain reaction. J. Clin. Microbiol., 31: 1688-1694.
Direct Link  |  

64:  Chia, B.S., F. Lanzas, D. Rifat, A. Herrera and E.Y. Kim et al., 2012. Use of Multiplex Allele-Specific Polymerase Chain Reaction (MAS-PCR) to detect multidrug-resistant tuberculosis in Panama. PLoS ONE, Vol. 7.
CrossRef  |  

65:  Feng, Y., S. Liu, Q. Wang, L. Wang, S. Tang, J. Wang and W. Lu, 2013. Rapid diagnosis of drug resistance to fluoroquinolones, amikacin, capreomycin, kanamycin and ethambutol using genotype MTBDRsl assay: A meta-analysis. PLoS ONE, Vol. 8.
CrossRef  |  

66:  Cheng, X., J. Zhang, L. Yang, X. Xu and J. Liu et al., 2007. A new Multi-PCR-SSCP assay for simultaneous detection of isoniazid and rifampin resistance in Mycobacterium tuberculosis. J. Microbiol. Methods, 70: 301-305.
CrossRef  |  Direct Link  |  

67:  Bodmer, T. and A. Strohle, 2012. Diagnosing pulmonary tuberculosis with the Xpert MTB/RIF test. J. Visualized Exp., Vol. 62.
CrossRef  |  

68:  Hoek, K.G.P., N.G. van Pittius, H. Moolman-Smook, K. Carelse-Tofa and A. Jordaan et al., 2008. Fluorometric assay for testing rifampin susceptibility of Mycobacterium tuberculosis complex. J. Clin. Microbiol., 46: 1369-1373.
CrossRef  |  Direct Link  |  

69:  Chen, X., F. Kong, Q. Wang, C. Li, J. Zhang and G.L. Gilbert, 2011. Rapid detection of isoniazid, rifampin and ofloxacin resistance in Mycobacterium tuberculosis clinical isolates using high-resolution melting analysis. J. Clin. Microbiol., 49: 3450-3457.
CrossRef  |  Direct Link  |  

70:  Ramirez, M.V., K.C. Cowart, P.J. Campbell, G.P. Morlock, D. Sikes, J.M. Winchell and J.E. Posey, 2010. Rapid detection of multidrug-resistant Mycobacterium tuberculosis by use of real-time PCR and high-resolution melt analysis. J. Clin. Microbiol., 48: 4003-4009.
CrossRef  |  Direct Link  |  

71:  Wang, L., S.H. Mohammad, B. Chaiyasirinroje, Q. Li and S. Rienthong et al., 2015. Evaluating the auto-MODS assay, a novel tool for tuberculosis diagnosis for use in resource-limited settings. J. Clin. Microbiol., 53: 172-178.
CrossRef  |  Direct Link  |  

72:  Shi, X., C. Zhang, M. Shi, M. Yang and Y. Zhang et al., 2013. Development of a single multiplex amplification refractory mutation system PCR for the detection of rifampin-resistant Mycobacterium tuberculosis. Gene, 530: 95-99.
CrossRef  |  Direct Link  |  

73:  Bell, E., 2005. A souped-up version of BCG. Nat. Rev. Immunol., 5: 746-746.
CrossRef  |  Direct Link  |  

74:  Ibanga, H.B., R.H. Brookes, P.C. Hill, P.K. Owiafe and H.A. Fletcher et al., 2006. Early clinical trials with a new tuberculosis vaccine, MVA85A, in tuberculosis-endemic countries: Issues in study design. Lancet Infect. Dis., 6: 522-528.
CrossRef  |  Direct Link  |  

75:  Kaufmann, S.H., 2010. Future vaccination strategies against tuberculosis: Thinking outside the box. Immunity, 33: 567-577.
CrossRef  |  Direct Link  |  

76:  Montanes, C.M. and B. Gicquel, 2011. New tuberculosis vaccines. Enfermedades Infecciosas Microbiologia Clinica, 29: 57-62.
CrossRef  |  Direct Link  |  

77:  Bonah, C., 2005. The 'experimental stable' of the BCG vaccine: Safety, efficacy, proof and standards, 1921-1933. Stud. History Philos. Sci. Part C: Stud. History Philos. Biol. Biomed. Sci., 36: 696-721.
CrossRef  |  Direct Link  |  

78:  Hawn, T.R., T.A. Day, T.J. Scriba, M. Hatherill and W.A. Hanekom et al., 2014. Tuberculosis vaccines and prevention of infection. Microbiol. Mol. Biol. Rev., 78: 650-671.
CrossRef  |  Direct Link  |  

79:  Bhattacharyya, S., P. Singh, U. Rathore, M. Purwar and D. Wagner et al., 2013. Design of an Escherichia coli expressed HIV-1 gp120 fragment immunogen that binds to b12 and induces broad and potent neutralizing antibodies. J. Biol. Chem., 288: 9815-9825.
CrossRef  |  Direct Link  |  

80:  Gautam, S., P. Dubey, P. Singh, S. Kesavardhana, R. Varadarajan and M.N. Gupta, 2012. Smart polymer mediated purification and recovery of active proteins from inclusion bodies. J. Chromatogr. A, 1235: 10-25.
CrossRef  |  Direct Link  |  

81:  Gautam, S., P. Dubey, P. Singh, R. Varadarajan and M.N. Gupta, 2012. Simultaneous refolding and purification of recombinant proteins by macro-(affinity ligand) facilitated three-phase partitioning. Anal. Biochem., 430: 56-64.
CrossRef  |  Direct Link  |  

82:  Singh, P., L. Sharma, S.R. Kulothungan, B.V. Adkar and R.S. Prajapati et al., 2013. Effect of signal peptide on stability and folding of Escherichia coli thioredoxin. PLoS ONE, Vol. 8.
CrossRef  |  

83:  Singh, P., 2015. Study of signal peptide mediated folding-unfol ding kinetics of Escherichia coli thioredoxin. Int. J. Pharmacol. Biol. Sci., 9: 161-168.
Direct Link  |  

84:  Singh, P., 2016. SPR biosensors: Historical perspectives and current challenges. Sen. Actuators B: Chem., 229: 110-130.
CrossRef  |  Direct Link  |  

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