Insights into Bovine Tuberculosis (bTB), Various Approaches for its Diagnosis,
Control and its Public Health Concerns: An Update
Amit Kumar Verma,
Shoor Vir Singh
Bovine tuberculosis (bTB) is a zoonotic disease transmitted from animals to
human and makes significant economic impacts due to high cost of eradication
programs, trade restriction and serious consequences regarding public health
thereby causing human tuberculosis. Mycobacterium bovis is the main etiological
agent of bTB which is an acid fast staining bacterium due to waxy substance
(mycolic acid) present in its bacterial cell wall. The bacteria can be transmitted
by both aerogenous and enterogenous routes. Disease causes development of miliary
tubercular lesions, chronic cough, obstructions of air passages and alimentary
tract or blood vessels and enlargement of lymph nodes. A spectrum of Cell-Mediated
Immune responses (CMI) predominate infection, projecting the role of macrophages
and T-cell populations. In advanced stage, there is increased humoral response.
Polymerase Chain Reaction (PCR) and real time quantitative PCR (RT-qPCR) have
been widely used for the detection of M. tuberculosis complex in clinical
samples. Single intradermal test, short thermal test and Stormont tests are
the valuable delayed type of hypersensitivity tests. Gamma interferon assay,
lymphocyte proliferation assay, Enzyme Linked Immune Sorbent Assay (ELISA),
multiantigen print immunoassay (MAPIA), Fluorescent Polarization Assay (FPA),
immunochromatographic lateral flow test, single antigen as well as multiplex
chemiluminescence assays are the various blood-based laboratory tests. Attenuated
bovine-strain of tuberculosis bacterium, known as Bacillus of Calmette and Guerin
(BCG) is used as vaccine. The present review addresses important insights into
the bovine TB, a complex and multi-species disease, the etiological agent, advances
and trends in its diagnosis, vaccine development and treatment options and the
public health significance of this important disease which would altogether
help devising effective strategies for prevention and control of tuberculosis
in cattle as well as in wildlife.
to cite this article:
Amit Kumar Verma, Ruchi Tiwari, Sandip Chakraborty, Neha , Mani Saminathan, Kuldeep Dhama and Shoor Vir Singh, 2014. Insights into Bovine Tuberculosis (bTB), Various Approaches for its Diagnosis,
Control and its Public Health Concerns: An Update. Asian Journal of Animal and Veterinary Advances, 9: 323-344.
Received: January 22, 2014;
Accepted: February 28, 2014;
Published: May 23, 2014
Tuberculosis (TB) is a complex and multi-species disease which can be of three
types, bovine, avian and human TB (Dhama et al., 2011).
Among mycobacteria, there are around 120 species, most of them are saprophytic
but few are major pathogens. M. bovis is a member of Mycobacterium Tuberculosis
Complex (MTC) and based upon 16S ribosomal RNA sequence studies it shared more
than 99.95% identity with other members of MTB complex (Rastogi
et al., 2001; Garnier et al., 2003;
Smith et al., 2009; Le
Roex et al., 2013). Bovine tuberculosis is a chronic debilitating
highly contagious disease of cattle, buffaloes and many wild species (Le
Roex et al., 2013; Hardstaff et al., 2013).
Mycobacterium bovis, the causative organism is an aerobic, gram-positive,
non-motile, non-sporulating, acid-fast, rod shaped slow-growing organism, obligate
intracellular parasite. The disease is characterised by progressive development
of tubercles (or nodular granuloma) with resultant caseations and calcification
in many of the vital organs in host species except skeletal muscles.
Bovine tuberculosis (bTB) is the zoonotic disease transmitted from animal to
human and makes a significant economic impact due to high cost of eradication
programs and has serious consequences for movements of animals and their products,
biodiversity, public health and significant economic effect (Le
Roex et al., 2013; Dhama et al., 2013a;
Rodriguez-Campos et al., 2014). World Health Organization
(WHO) classified bovine tuberculosis among seven neglected zoonontic diseases
having potential to infect man (Ereqat et al., 2013).
A study conducted between 1998-2005, over european badger (Meles meles)
and cattle populations showed close association between M. bovis strain
types isolated from cattle and associated badgers indicates intraspecific transmission
(Menzies and Neill, 2000; Skuce
et al., 2011). Bovine TB is a chronic infectious disease which affects
a broad range of mammalian hosts including cattle, pigs, goats, sheep, badgers,
possums, domestic cats, deer, camelids, omnivores and wild carnivores (OReilly
and Daborn, 1995; Mathews et al., 2006;
Carslake et al., 2011). Other than domestic
animals various wildlife species such as Badgers (Meles meles), brushtail
possums (Trichosurus vulpecula), deer (Odocoileus virginianus),
bison (Bison bison) and African buffalo (Syncerus caffer) also
play role of maintenance hosts of M. bovis. Among these wild boar has
been identified in having the highest ability to transmit the disease to cattle
(Hardstaff et al., 2013). Being maintained in
the wildlife communities M. bovis may act as principal source of infection
for domestic, captive and wide range of protected wildlife species (De
Lisle et al., 2001; Hardstaff et al., 2013;
Delahay et al., 2003; Scantlebury
et al., 2004; Witmer et al., 2010;
OBrien et al., 2006; 2011;
Le Roex et al., 2013). In addition to a broad
host range, mycobacterium also occurs in numerous biotopes including water,
soil, protozoa, aerosols, and fresh tropical vegetation (Biet
et al., 2005) Bovine tuberculosis is endemic disease of cattle (Aylate
et al., 2013). Around 30 years ago as carriers of M. bovis
badgers (Meles meles) were identified for the first time and they have
been found to make an essential contribution in spreading M. bovis between
cattle herds. Between animal conservationists (who are keen for saving badgers)
and farmers (who are interested in culling badgers for reducing losses of livestock)
there is a battle currently for this reason (Krebs et
al., 1997; Delahay et al., 2007; Ward
et al., 2009).
The present review addresses important insights of the bovine TB (Mycobacterium
bovis), a complex and multi-species disease with the aims of dealing various
approaches for controlling tuberculosis in cattle as well as in wildlife.
Mycobacterium bovis is the main etiological agent of bovine tuberculosis.
It is an acid-fast bacteria having characteristic feature of acid fast staining
which is due to waxy substance (mycolic acid) present in their bacterial wall.
The recovery of M. bovis is not enhanced by addition of carbon dioxide
in the incubation atmosphere (Corner, 1994). However,
now other members of M. tuberculosis complex have also been accepted
as new species. These include M. caprae (mostly infect goats) and M.
pinnipedii (usually infect fur seals and sea lions). Badgers also act as
reservoir for spreading of bovine tuberculosis (Cousins
et al., 2003; Atkins and Robinson, 2013).
It is found that M. bovis best survive in frozen tissue and there is
adverse effects of tissue preservative i.e. sodium tetraborate on viability
(Corner, 1994). In the environment M. bovis can
survive for various months especially in cold as well as dark and conditions
which is moist. The survival period varies from 18-332 days at 12-24°C (54-75°F)
which is dependent of sunlight exposure. From soil or grazing pasture there
is infrequent isolation of this organism. It has been found that culture of
the organism can be done for approximately two years in samples that are stored
artificially. The viability of the organism has been found more recently to
be between 4-8 weeks in 80% shade whereas it can get destroyed in either summer
or winter on New Zealand pastures (Biberstein and Holzworth,
1987). The incubation period of M. bovis is 3 weeks.
The disease tuberculosis (TB) is chronic in nature affecting a wide range of
mammals that include: humans and cattle, deer, llamas, pigs, domestic cats,
carnivores (wild like foxes and coyotes), as well as omnivores (possums as well
as mustelids and rodents). Equids and sheep are comparatively more resistant
to the disease. All species including humans with various age groups are susceptible.
The bacteria primarily affect the cattle and other domestic and wild animals
along with man may also get affected. Disease is found throughout the world
including India but more prevalent in Africa, parts of Asia and America. The
prevalence of disease is high in the tropical and sub-tropical countries. Bovine
TB is distributed globally except Antarctica and those countries such as Caribbean
islands, parts of South America and Australia where it has been eradicated by
following strict test and slaughter policies. It is major health problem in
India. Chances and severity of infection depend upon several predisposing factors
like environmental variables, topographic causes, anthropogenic variables, seasonality,
immunosuppression, long antibiotic therapy, working conditions and environmental
factors. Infected cattle are the main source of infection for other cattle.
Organisms are excreted in exhaled air, sputum, faeces, milk, urine, vaginal
and uterine discharges and discharges from open peripheral lymph nodes (Gilbert
et al., 2005). Epidemiology of bovine TB is influenced from many
risk factors as genetic, behavioural, biological or environmental which have
effect on transmission, establishment of infection and expression of disease
(Gordejo and Vermeersch, 2006; Vial
et al., 2011). Male badgers are more affected as compare to female.
Male have higher risk of mortality which promote gender influence while risking
transmission of TB to cattle (Graham et al., 2013).
It is more prevalent in dairy workers exposed to poor control areas of bovine
tuberculosis. The pulmonary form of disease is more developed in occupational
groups working with animals infected from M. bovis on farm or slaughter
house, than the alimentary form of disease. Bovine tuberculosis herd prevalence
was positively related with Mycobacterium Tuberculosis Complex (MTC) and also
correlated positively with size of island, number of imported cattle and presence
of wild host but not with isolation of cattle as well as density of cattle.
Incidence of TB in cattle progeny is also affected by hereditary and maternal
influences (Petukhov, 1981). The factors associated
with tuberculosis which influence the occurrence of disease are sex, breed and
social management of livelihood conditions (OReilly
and Daborn, 1995; Biffa et al., 2012; Acevedo
et al., 2013; Torres-Gonzalez et al., 2013).
Routes or sources of infection and its transmission: In various ways
the disease can be transmitted. For instance in air that is exhaled; sputum
and urine, faeces as well as pus the bacteria can spread. Either direct contact
or contact with infected animal excreta, aerosol inhalation can spread the disease
that depends on the involvement of the species (OReilly
and Daborn, 1995; Phillips et al., 2003;
Delahay et al., 2002). The common mode of transmission
is inhalation or ingestion. Aerogenous or inhalation: it is mainly by droplet
infection, inhalation of dust contaminated by sputum, faeces, urine of infected
animals. Thus close housing and overcrowding along with improper management
predisposes to the disease. Zebu (Brahman) type cattle are thought to be much
more resistant to tuberculosis than European cattle. The dynamics of M. bovis
transmission from an effective disseminator tuberculous animal to susceptible
hosts are currently not clearly identified and are meagrely understood. Though,
infection is principally confined to the respiratory system as bacteria aim
to establish the infection within the lung. Infected cattle are considered as
possible source of infection as they shed significant amount of M. bovis
through droplet nuclei in to the environmental and may act as source of intra-herd
transmission (Perumaalla et al., 1999; Van
Rhijn et al., 2008; Humblet et al., 2009;
Raviglione and Krech, 2011). Primarily, tuberculosis
is a respiratory disease and is transmitted through mainly by air born route
within and between species during close contact (OReilly
and Daborn, 1995). In case of enterogenous route or ingestion through buccal
mucosa, pharyngeal mucosa and intestinal mucosa the organism may enter into
the animal body. It is also through the congenital route but is less common
mode of acquiring infection (OReilly and Daborn,
1995). The infected bull may also transmit disease or through artificial
insemination with the use of infected semen (Roumy, 1966).
The M. bovis is transmitted from animal to man through ingestion of unpasteurized
dairy product, milk of infected cattle and undercooked meat which was recognised
as a major public health problem (OReilly and Daborn,
Tuberculosis occurs in almost every country of the world and is of major importance
in dairy cattle due to high morbidity and loss of production as infected animals
lose 10-25% of their productive efficiency. Apart from these, advance tuberculosis
may lead to death of the animals. WHO declared tuberculosis as global emergency.
About one third of human population of the world are suffering from tuberculosis
infection (Joardar et al., 2002; 2003).
Tuberculosis has great importance regarding the economy of the livestock industry
of India because it can infect the human population due to its zoonotic nature,
therefore it is an important public health issue (OReilly
and Daborn, 1995). It is listed disease by World Organisation for Animal
Health formerly Office International des Epizooties (OIE). Tuberculosis also
has significance to the international trade of animals and animal product (Cousins,
2001; Rodriguez-Campos et al., 2014).
PUBLIC HEALTH RISKS
Human tuberculosis due to M. bovis is usually underestimated or underdiagnosed
because of no clinical, radiographicaland histopathological differentiation
of tuberculosis caused by M. tuberculosis and M. bovis (Perez-Lago
et al., 2013). M. bovis is not the major cause of human tuberculosis
but it can infect human beings too either by consuming raw milk, meat and their
products from infected animals (Dhama et al., 2013b;
Malama et al., 2013), or by inhaling infective
droplets or direct exposure to infected animals (Perez-Lago
et al., 2013). In an estimate, about 10% cases of human tuberculosis
are caused by M. bovis, while majority are caused by M. tuberculosis
(Perez-Lago et al., 2013). In countries wherein
milk is pasteurized and there is effective implementation of bovine tuberculosis
programme tuberculosis in human due to M. bovis is very rare. But in
areas where the disease in bovine is poorly controlled the reporting of the
disease is more frequently done. In farmers as well as abattoir workers and
others the incidence rate is higher. Exposure to other species apart from cattle
can cause infection in human. It has been documented that goats as well as seals,
farmed elk and rhinoceros can also act as sources of bovine tuberculosis. A
source of infection may be wildlife especially in countries where people use
to take bush meat (Fritsche et al., 2004; Corner,
2006; Etter et al., 2006; Evans
et al., 2007; Malama et al., 2013).
If the whole carcass is condemned then it indicates a high degree of tuberculosis
infection and its transmission so it requires immediate attention from both
the economic and public health point of view. (Asseged et
al., 2004; Torgerson and Torgerson, 2010).
Being cause of chronic granulomatous disease tubercle bacilli increases susceptibility
to bladder and lung cancer. Though BCG induced cytotoxicity of bladder has paved
the way towards initiation of BCG immunotherapy for treatment of bladder cancer
(Alexandroff et al., 1999; Atkinson
et al., 2000; Vento and Lanzafame, 2011).
IMMUNE RESPONSES AGAINST BOVINE TB PATHOGEN
Understanding of the immune response following infection of M. bovis
in bovines elaborates the knowledge of disease pathogenesis and development
of nodular lesions (Wang et al., 2013). Among
the immunity which persist spectrum of Cell-Mediated Immune response (CMI) predominate
projecting the role of macrophages and T-cell populations. As the tuberculosis
progresses a shift from Cell-Mediated Immune (CMI) responses to increased humoral
response develops which is evident from change of dominance from a T helper
type 1 (Th1) cell towards a Th2 type immune response signifying suppressed CMI
and amplified humoral immune response. Cytokine analysis indicates deviation
in CMI and interleukin responses as the pathological form of disease advances.
Reduction in in vitro CMI responses, elevated levels of IL-10 expression
and augmented HI responses involving production of anti-M. bovis immunoglobulin
G1 (IgG1) isotype have been noticed with increased pathology and disease (Villarreal-Ramos
et al., 2003). Knowledge of interactions of M. bovis with
products of immune response provides prospects for development of immune-dependent
tools as of diagnostics, vaccines and in evolving better methods/policies for
combating and controlling the disease (Pollock et al.,
2001; Welsh et al., 2005; Spencer,
BOVINE TUBERCULOSIS-THE DISEASE
Clinical signs: Basic pathogenic mechanisms are more or less same in
case of human TB and bovine tuberculosis. Developing technologies support the
fact of identical pathogenesis, because of unusually high conserved sequence
similarity in genome of TB causing bacteria in more than 99.95% animals (Smith
et al., 2006; Smith et al., 2009;
Thye et al., 2010; Verhagen
et al., 2011). TB is a chronic debilitating disease occurs in cattle.
No symptoms occur in early stage of disease that is asymptomatic. However, in
late stage, there is progressive emaciation, a mild fluctuating fever, weakness
and in-appetence. When infection is present in the lung then dyspnoea, moist
cough or trachypnoea may occur. In the terminal stage, animal become extremely
emaciated and develop acute respiratory distress. Involvement of respiratory
tract and its role in pathogenesis of disease is evidenced by the predominant
distribution of lesions present in upper respiratory tract, lung and tonsils
in affected human as well as in animals. Some cows with extensive miliary tubercular
lesions are clinically normal but in most cases progressive emaciation unassociated
with other clinical signs occur, inspite of good appetite. A capricious appetite
and fluctuating temperature are commonly associated with disease. The hair coat
may be rough. Affected animal tend to become more docile and sluggish but eyes
remain bright and alert. These general signs often become more pronounced after
calving. Pulmonary involvement is characterized by chronic cough due to bronchopneumonia.
Cough occurs only once or twice at a time and is low suppressed and moist which
is easily stimulated by squeezing the pharynx or by exercise and is most common
in morning and in cold weather.
In advanced cases, air passages, alimentary tract, or blood vessels may be
obstructed by enlargement of lymphnodes. Lymph nodes of the head and neck may
become visibly affected and sometimes rupture and drain. Involvement of the
digestive tract is manifested by intermittent diarrhoea and constipation in
some instances. There may be chances of bloat occur due to pressure of enlarged
mediastinal glands on the oesophagus. The enlargement of retropharyngeal glands
results in dysphagia. Extreme emaciation and acute respiratory distress may
occur during the terminal stages of tuberculosis. Lesions on the female genitalia
may occur, while male genitalia are seldom involved. Tuberculosis mastitis is
of major importance because of danger to public health and of spread of disease
to claves and difficulty of differentiating it from other forms of mastitis
(Radostits et al., 2000). Experiments have shown
that lions may also become susceptible to bovine TB (Trinkel
et al., 2011).
With the help of descriptive statistic and regression model on data analysis,
indicates that tuberculosis lesion are mostly occur in lung and lymph node of
respiratory system (Biffa et al., 2012).
Disease usually has a prolonged course, and symptoms take months or years to appear. The usual clinical signs include.
Weakness, loss of appetite, weight-loss, fluctuating fever, intermittent hacking cough, diarrhoea, large prominent lymph nodes, anorexia, induration of udder.
Post mortem lesions: Disease causes a chronic granulomatous, caseous-necrotising
inflammation in lungs and associated lymph nodes (Domingo
et al., 2014). On post mortem examination, tubercles are commonly
found in bronchial, mediastinal, retropharyngeal and portal lymph nodes along
with tissue affected. Apart from this, lung, liver, spleen and the surfaces
of body cavities are commonly affected. Tuberculous granuloma usually has a
yellowish appearance with caseous, caseo-calcareous, or calcified in consistency.
The efficiency of meat inspection procedure should be evaluated by conducting
detailed post-mortem examination which determines the gross lesions distribution
in cattle infected with M. bovis (Asseged et al.,
Diagnosis of this disease has various challenges and difficulties. Tentative
and presumptive diagnosis can be made by ante mortem examination on the
basis of clinical signs. However, disease can be diagnosed more clearly after
post mortem examination based on the presence of gross lesions compatible with
BTB in the lungs and/or associated lymph nodesand these are not confirmatory
(Malama et al., 2013). Typical lesion or gross
lesions are found at necropsy in macroscopic detection and histopathological
examination of lesion may confirm the diagnosis but the definitive diagnosis
is done only by isolation of Mycobacterium bovis from lesion, bacteriologically
(Corner, 1994). The confirmation of disease requires
certain laboratory examination.
Identification of agent: Organism in clinical samples and tissue
samples collected after post-mortem examination may be demonstrated by examination
of stained smears or tissue sections and confirmed by cultivation of the organism
on primary isolation medium.
Microscopic examination: M. bovis can be demonstrated microscopically on direct smears from clinical samples (blood stained purulent exudates i.e., cough and sputum, pleural fluid) and on prepared tissue materials (lung biopsy). The acid fastness of M. bovis is normally demonstrated with the classic Ziehl-Neelsen stainand a fluorescent acid-fast stain may also be used. The tentative diagnosis can be made by observing caseous necrosis, mineralisation, epithelioid cells, multinucleated giant cells and macrophages in the tissue samples on histopathology.
Culture of M. bovis: The tissue sample is homogenised using a pestle and mortar, followed by decontamination with either detergent, acid or an alkali, such as 0.375-0.75% hexadecylpyridiumchloride (HPC), 5% oxalic acid or 2-4% sodium hydroxide. The mixture is shaken for 10 min at room temperature and then neutralised. After that centrifuge the suspension and discard the supernatant. Sediment is used for culture and microscopic examination. For primary isolation, the sediment is usually inoculated on to a set of solid egg-based media such as Lowenstein-Jensen, Coletsos base or Stonebrinks; these media should contain either pyruvate or pyruvate and glycerol. Cultures are incubated for a minimum of 8 weeks (and preferably for 10-12 weeks) at 37°C with or without CO2. The media should be in tightly closed tubes to avoid desiccation. Slants should be examined at regular intervals for presence of any growth. When growth is visible, smears are prepared and stained by the Ziehl-Neelsen technique.
Nucleic acid recognition methods: PCR has been widely used for the detection
of M. tuberculosis complex in clinical samples (mainly sputum) in human
cases and has recently been used for the diagnosis of tuberculosis in animals.
The real time PCR determine the status of infection in cattle for bovine tuberculosis
as compare to the IFN gamma mRNA in blood culture. Another useful diagnostic
method for bovine tuberculosis in cattle is RT-qPCR (Palmer
and Waters, 2006; Collins, 2011; Gan
et al., 2013).
Bacterial culture and post-mortem confirmation of tuberculosis is insufficiently
sensitive. So, veterinarians and other health researchers have evaluated other
diagnostic approach i.e. immunological including lateral-flow devicesand Enzyme-linked
Immunosorbent Assay (ELISA), tuberculin skin test and interferon-gamma release
assay (Chambers, 2013).
Delayed type hypersensitivity reaction
Skin test or Single Intra Dermal test (SID): This is standard test for detection
of bovine tuberculosis and involves the intradermal injection of bovine tuberculin
PPD (purified protein derivative) and the subsequent detection of swelling (delayed
hypersensitivity) at the site of injection 72 h later. Generally, this test
is conducted on middle neck and the alternate site may be the caudal fold of
the tail. However, skin of the neck is preferred over tail due to higher sensitivity
of skin on neck. During initial stage of infection i.e. 3-6 weeks after infection,
this test may give negative reaction. After a SID test, the animals giving a
suspicious result should not be tested again before 60 days (Costello
et al., 1997). This test has poor specificity due to cross-reactions
with other non-pathogenic mycobacteria (Praud et al.,
2014). False-negative reactions may be given by:
||Animals in advanced stage of disease
||In initial stages i.e. 6 weeks after infection
||Cows within 6 weeks after calving
||Animals that were tested within 8-60 days after single intradermal testing
||Low-potency tuberculin or bacterial contamination of the tuberculin
||Variable dose with multi dose syringes
Short thermal test: Tuberculin (4 mL) is injected subcutaneously into the neck of cattle which have a rectal temperature of not more than 102°F at the time of injection and for 2 h later. If the temperature at 4, 6 and 8 h after injection rises above 104°F, the animal is considered as positive. The temperature peak is usually at 6-8 h and is generally over 105.8°F. In some cases, death may occur due to anaphylaxis.
Stormont test: It is performed in the same way as single intradermal
test in the neck with a second injection at the same site but after 7 days of
first injection. After 24 h of second injection, an increase in skin thickness
of 5 mm or more should be considered as positive. It is more accurate than the
Single Intra Dermal (SID) test but a practical difficulty is the necessity for
three visits to the farm (Whelan et al., 2003).
Blood based laboratory tests: These include gamma interferon assay,
lymphocyte proliferation assay, ELISA etc and require well equipped laboratory
facilities with skilled laboratory personnel (Coad et
al., 2008; Whelan et al., 2008). Interferon
gamma assay was initially developed circa 1990 for diagnosis of bovine tuberculosis
in Australian tuberculosis eradication programme (Waters
et al., 2014). As an ancillary test the interferon-gamma test is
used for diagnosing bovine tuberculosis at ante-mortem. This helps in measuring
the cellular response to antigens of mycobacteria and thereby helps in measuring
broadly similar kind of immune response as that of intradermal tests. If there
is release of interferon-gamma (a pivotal cytokine) preferentially a positive
result is indicated (Wood et al., 1991; Wood
and Jones, 2001). Printing of several antigens is done onto a membrane by
means of multiantigen print immunoassay (MAPIA) and for each animal measurement
of antibody response is done (Waters et al., 2006).
Use of tracer which is the target antigen or part of it is done in case of Fluorescence
Polarisation Assay (FPA) where in a fluorescent molecule is added to serum.
There is binding of antibody (if present) in the serum. There is increase in
the measurable fluorescent polarisation because of the increase in size of the
antigen-antibody complex in combination (Jolley et al.,
2007). There is use of latex beads (coloured and antigen-impregnated) mixed
with serum in case of immunochromatographic lateral flow test. Along a membrane
the material flows by means of capillary action across a line where impregnation
of antigen is done onto the membrane. There is formation of a coloured line
where there is binding of coated latex beads to serum antibody (Lyashchenko
et al., 2006). There is use of magnetic iron beads coated with antigen
of choice in case of single antigen chemiluminescence wherein magnetic collection
is done. Detection of any bound antibody is then done by the use of a anti-bovine
antibody specifically followed by identification of by the use of a chemiluminescent
reaction (Green et al., 2009; Foddai
et al., 2010a; 2010b). There is printing
of individual antigens in small dots on a multi-well plate (96 well) in case
of multiplex chemiluminescence immunoassay viz., Enferplex. To each of the well
serum samples are used individually and detection of antibody to each spotted
antigen is done by immunoassay detection method. There is colour change in each
spot that indicates specific antibodys presence to that antigen (Whelan
et al., 2008). The assessment of the performance of such newer tests
just began in recent years but on their potential value certain optimisms have
been followed cautiously by seeing preliminary results.
Antibody detection in milk: In dairy animals, milk samples can also
be used for measuring antibodies against M. bovis antigens such as MPB70
and MPB83 using ELISA kits (Buddle et al., 2013).
Milk samples can be pooled from 10-20 animals but this may result in 50% decrease
in sensitivity. This test is unlikely to be useful in nations with low prevalence
of disease and large herd sizes.
Animal inoculation test: Mostly Guinea pig and rabbit are used. The clinical sample (exudates, CSF, sputum or centrifuge milk) is deposit in the thigh region of Guinea Pig produces or results into typical tuberculosis lesion of spleen, liver and lymph nodes of infected animal.
Genetic fingerprinting technique: The different strains of M. bovis
can also be distinguished with the help of genetic fingerprinting technique,
VNTR typing, spoligotyping and current molecular diagnostic techniques. Variable
Number Tandem Repeat (VNTR) typing and spoligotyping are DNA typing schemes
developed in 1990 for M. bovis (Kamerbeek et
al., 1997; Filliol et al., 2002; Boehme
et al., 2010; Dhama et al., 2012).
The genomic detection analysis and spoligotyping is another method used in identification
of M. bovis (Biffa et al., 2012).
The primarily screening test for bovine tuberculosis is tuberculin skin test
having low sensitivity. In comparison to tuberculin test the interferon gamma
assay is found to be more sensitive (Schiller et al.,
2011). The necessity of new-fangled and improved diagnostic for Bovine tuberculosis
(TB) has driven researchers to develop specific tests with significant sensitivity
(Pollock and Neill, 2002; Singh
et al., 2014).
In human tuberculosis, drugs like isoniazid, combinations of streptomycin and
para-aminosalicylicand other acids are commonly used. The treatment of animals
with tuberculosis is not a favoured option in eradication-conscious countries.
Being long term therapy chances of development of multidrug resistant (MDR),
extremely drug resistant (XDR) and even Totally Drug Resistant (TDR) bacterial
strains are more if treatment regime is not properly followed. Alternative therapeutic
approaches involve panchgavya therapy, cytokine therapy, egg yolk antibody,
herbal medication, immunomodulation and b acteriophage therapy etc. (Mahima
et al., 2012; Dhama et al., 2013c,
Tiwari et al., 2014c; Rahal
et al., 2014). The fruit extracts of black pepper (Piper longum)
and way bread, a perennial herb (Plantago major) is known for its significant
valid anti-mycobacterial and antitubercular activity even against MDR strains
of Mycobacterium tuberculosis also (Stuckler et
al., 2008; Ford et al., 2011; Mahima
et al., 2012; Dhama et al., 2013d,
2013e; Tiwari et al., 2013;
2014a, 2014d). Being equipped
with peptidoglycan hydrolase, lipolytic action and growth inhibition activity
endolysins and mycobacteriophage have broad spectrum of demolishing efficiency
against mycobacteria. Functional analysis of mycobacteriophage Ms6 revealed
presence of lysis gene lysine A which encodes endolysin, lysine B and the holin-like
enzymatic proteins with lipolytic activity (Garcia
et al., 2002; Gil et al., 2008; Payne
et al., 2009; Catalao et al., 2011a,
b; Tiwari et al., 2014b).
PREVENTION AND CONTROL
Control of bovine tuberculosis can be done by test-and-slaughter or test-and-segregation
methods. There is periodic re-testing of affected herds for eliminating cattle
shedding the organism. For this purpose the test which is generally used is
tuberculin test. Quarantine programme is followed for the infected herds thereby
helping in tracing the animals found in contact with reactors. From domesticated
animals only test-and slaughter policy can eradicate bovine tuberculosis. There
may be reduction in the spread of the agent within the herd by means of sanitation
as well as disinfection. To disinfectants M. bovis is relatively resistant
thereby requiring long contact time for inactivating. 5% phenol, iodine solutions
(having presence of iodine at high concentration), glutaraldehyde as well as
formaldehyde are found to be effective disinfectants. If the concentration of
organic material is low in environment the efficacy of 1% sodium hypochlorite
with a long contact time is efficacious. Moist heat of 121°C (250°F)
for a minimum period of 15 min can kill M. bovis. In affected farms it
is also advisable to perform control of rodents. Experimental infection of meadow
voles as well as house mice can be done and in vole feces the organism can be
shed (USDA/APHIS, 1995; DEFRA, 2003;
Ryan et al., 2006).
In 1906, Albert Calmette and Camille Gueringot success for the first time in
immunization against tuberculosis, a serious zoonotic disease using attenuated
bovine-strain tuberculosis, which was later known as Bacillus of Calmette and
Guerin (BCG) (Waters et al., 2014). BCG is a live,
laboratory-attenuated vaccine (M. bovis) strain derived from a virulent
French M. bovis field isolate which has been in use against M. tuberculosis
for nearly a century (Dhama et al., 1998; 1999;
2004). It is noteworthy that BCG provides solid protection
against miliary TB (generalized form of human TB) in young children but is less
effective in adults against pulmonary form of human TB. Contribution of BCG
vaccination in global TB control programme is still controversial because mostly
TB infection occurs in pulmonary form (Segal-Maurer and
Kalkut, 1994; Orme, 2010; Margaret
and Anthony, 2011).
Trials have been conducted on a number of deletion mutants and other vaccinesand
none has been shown to induce a superior protection to BCG (Dhama
et al., 2008). Experimental vaccine trials have shown that vaccine
prepared from M. bovis strain Amce2 (M. bovis strain deleted in
mce2A and mce2B genes) tested in cattle calf have proved this strain as promising
vaccine candidate in controlling bovine TB pathogenesis in cattle. Post-vaccination
challenge immune response was assessed by measuring IFN-γ concentration
using an Interferon-gamma Release Assay (IGRA), cytometry and cytokine responses
of bovine Purified Protein Derivative (PPD) re-stimulated Peripheral Blood Mononuclear
Cells (PBMCs) (Blanco et al., 2013). Based upon
several trials most effective vaccination strategy against bovine TB has been
suggested to first prime the immune system with BCG vaccine and after initiation
of immune response booster dose should be administered with subunit, DNA or
protein vaccines containing any protective antigen which was a component of
BCG vaccine. This vaccination strategy is referred as heterologous prime-boost
strategy (Skinner et al., 2003; 2005;
Wedlock et al., 2005; Vordermeier
et al., 2004; 2006).
In countries where test and slaughter control scheme is not possible, vaccination
may be used but before implementing vaccination programme, the vaccination schedule
must be optimised according to local conditions. In countries like UK, BT persisted
in cattle herds even after following test and slaughter policies due to close
proximity with wildlife reservoir. Due to maintenance of bacteria in wild life,
there is difficulty in eradicating this disease using well proved control strategies,
so there is need of some alternate control strategies (Le
Roex et al., 2013; Hardstaff et al., 2013).
Hence, immunological approaches of developing an effective vaccine and careful
strategies for its delivery for the control of M. bovis infection in
wildlife may act as potential alternative tools (Buddle
et al., 2000; 2003; Woodroffe
et al., 2009; Blanco et al., 2013;
Hutchings et al., 2013; Malama
et al., 2013). Ideally, the dose of vaccine is 104 to
106 Colony-Forming Units (CFU) through subcutaneous route. It is
important to recognise that use of vaccine will compromise tuberculin skin tests
or other immunological tests. Thus, in countries where control or trade measures
are based on this testing, the vaccine should not be used. This fact indicates
limitations that still a long road has to be crossed to achieve full protection
against bovine TB (Kao et al., 1997; Clifton-Hadley
and Hewinson, 2003). The results show that the vaccine combination of BCG
and the vaccinating moiety (adjuvant subunit, DNA vaccines) are more effective
or superior in protection as compared to the use of BCG alone. DIVA vaccines
are also under development for bovine tuberculosis. Specific antigens such as
prototype DIVA antigens ESAT-6, CFP-10 and others should be identified to facilitate
the differentiation of BCG-vaccinated and M. bovis infected bovines for
differential diagnosis of infected from vaccinated cattle and to define differentiating
infected from vaccinated animals (DIVA) antigens. (Buddle
et al., 2011; Vordermeier et al., 2011a;
2011b). Another important factor that can affect the
pathogen is the hosts genome. The identification of genetic variability
responsible for susceptibility and resistance to bacteria may be useful in selection
of drug target and development of disease resistant animals (Le
Roex et al., 2013). Because the bovine tuberculosis is a notifiable
or reportable disease so if bovine tuberculosis is suspected in animals then
notification should be given to higher authorities to take recommended action
Control measures: The methods of controlling M. bovis in wildlife
are limited and dependent on sound disease control principles and judicious
use of diagnostic tests. Though population control and vaccination are potential
alternative control methods but not applicable in all the situations:
||The primary tool used for screening of bovine tuberculosis
is the tuberculin test (Schiller et al., 2011).
The standard control measure applied to tuberculosis is test and slaughter
or abattoir surveillance (Schiller et al., 2010).
Screening of meat at slaughterhouses along with detection of slaughtered
animal's herd of origin will be helpful in reducing the disease (Smith
et al., 2014)
||Slaughter of diseased cattle can be an effective policy for tuberculosis
eradication, if no other reservoirs of infection are maintained in near
surroundings (Verma et al., 2014)
||In early stage of disease, test and segregation method is followed while
in later or terminal stage of disease, test and slaughter method is recommended
||The animal which is import from other state or country should be strictly
||DNA fingerprinting is an epidemiological tool in cattle for control measure
(OReilly and Daborn, 1995)
||Quality control produces quality product (Duignan
et al., 2012)
||Novel diagnostic biomarkers as specific antigens should be identified
to support the development of DIVA skin tests (Vordermeier
et al., 2011a)
||The Bovigam assay is an in vitro diagnostic test, based on the measurement
of interferon gamma (IFN-gamma) after stimulation of blood with avian and
bovine tuberculin PPD used for diagnosis of bovine TB (Rothel
et al., 1990; 1992)
||It is difficult to eradicate and control where wild population is established
and also when once it spread into the ecosystem with free ranging maintenance
host. (Miller and Sweeney, 2013)
||The routine inspection of abattoir also play important role for national
surveillance. (Probst et al., 2011; Aylate
et al., 2013)
||Reintroduction of bovine tuberculosis and its eradication is done by premovement
testing which act as central tool for eradication (Schiller
et al., 2011)
||Post mortem examination, meat inspection, intensive surveillance, gamma
interferon assay, systematic individual testing of animals, followed by
removal of infected and in contact animals for reducing or eliminating the
disease (De La Rua-Domenech, 2005)
||Ancillary diagnostic techniques, herd testing, health surveillance, ante
mortem diagnosis including tuberculin testing and immunization are effective
in controlling the TB incidences (De La Rua-Domenech
et al., 2006; Torgerson and Torgerson, 2010)
||Post mortem meat inspection of animals looks for the tubercles in the
lungs and lymph nodes. Detecting these infected animals preve/AQW Knts unsafe
meat from entering the food chain and allows veterinary services to trace-back
to the herd of origin of the infected animal which can then be tested and
eliminated if needed
||Pasteurisation of milk of infected animals
||Treatment of infected animals is not economically feasible because of
the high cost, lengthy time and the larger goal of eliminating the disease.
||Hygienic measures to prevent the spread of infection should be instituted
as soon as the first group of reactors is removed. Feed troughs should be
cleaned and thoroughly disinfected with hot, 5% phenol or equivalent cresol
disinfectant. Water troughs and drinking cups should be emptied and similarly
disinfected (Woolhouse et al., 1997)
||It is important that calves being reared as herd replacements be fed on
tuberculosis-free milk, either from known free animals or pasteurized
||Farm attendants should be checked as they may provide a source of infection
||Rodent population should be decreases on herd which also help in transmission
||Bio-security measures should be followed on herd/farm which helps in decreasing
or reducing the interaction between domestic animals and wildlife animals
||Carcasses of infected animals should be buried at least four feet under
||Notification, surveillance by effective implementation of TB control programmes
like Revised National Tuberculosis control programme
||Vaccination of animals along with vector control may be more effective
than only vaccination
||Wear protective cloth during handling of the diseased animal and infected
||In the control and eradication programmes, must consider or incorporated
the data collection and epidemiological analysis of disease so that progress
and the constraints to progress may be evaluated
||Epidemiological approaches, including case-control studies are helpful
to provide the information regarding various sources of M. bovis
and further cost-effective techniques as control measures can be designed
for eradication of tuberculosis
||Monitoring of the control and eradication programme should be done continuously
to know the progress of the programme and for the implementation of necessary
modification as required to the programme. Application of advanced genotyping
tools and co-operation and co-ordination in human as well as veterinary
health care professionals will ultimately help in eradication of bovine
tuberculosis especially in developing nation like India (Dhama
et al., 2013f; Verma et al., 2014)
CONCLUSION AND FUTURE PERSPECTIVES
In almost every country of the world, bovine tuberculosis is prevalent and accounts for 10-25% loss in productivity. It is a listed disease in world organization for Animal Health. The disease has an important public health issue due to its zoonotic significance. In certain species of animals, antimicrobial treatment has been attempted but as long term treatment is required so in eradication conscious countries practicing anti-tubercular treatment is not a wise option. Programs involving eradication of the disease consists of: inspection of meat at post mortem and conducting surveillance programme intensively. This include, on-farm visits, individual testing of cattle systematically along with infected as well as in contact animals removal and control of movement. The advances in development of bovine tuberculosis diagnostics and vaccines for cattle are offering valuable insights in the use of vaccination for the control of tuberculosis in a range of bovines and captive wildlife species. In human medicine, vaccination is practiced but as a preventive measure it is not widely used in animals. There is variation in the efficacy of existing vaccines in animals thereby interfering with testing for elimination of the disease. Testing of new candidate vaccines is underway. Combination of BCG vaccine along with vaccine moiety viz., adjuvant subunit and DNA vaccines are more efficacious or superior in providing protection in comparison to BCG alone. DIVA vaccines are also under development. Application of advanced genotyping tools and co-operation and co-ordination in human as well as veterinary health care professionals will ultimately help in eradication of bovine tuberculosis especially in developing nations.
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