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Etiology, Epidemiology, Pathogenesis and Diagnosis of Marek’s Disease in

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Poonam et al., J Vet Sci Med Diagn 2017, 6:4
DOI: 10.4172/2325-9590.1000238
Review Article
Etiology, Epidemiology,
Pathogenesis and Diagnosis of
Marek’s Disease in Chickens: A
Mini review
Poonam1, Rahul Khatri1, Hari Mohan1, Minakshi2 and Pundir
CS3*
Abstract
Marek’s disease (MD) is a worldwide tumor forming disease in
chickens, which is highly contagious and lymphoproliferative
in nature. The Marek’s disease virus (MDV) also known as
alpha- herpesvirus causes T cell  lymphoma and infiltration
of nerves and organs by lymphocytes in chickens. The disease is
diagnosed by polymerase chain reaction (PCR) for its tumor causing
Meq gene, virus isolation and antigen enzyme linked immune
sorbent assay (ELISA). New approaches of diagnosis of MDV
include Loop mediated isothermal amplification (LAMP), real time
PCR (quantitative-PCR), nested PCR and immunofluorescence,
which are proving milestones in detecting Marek’s disease at early
stage. CVI988is the gold standard for protecting chickens against
MDV This review describes the etiology, symptoms, characteristics,
epidemiology, pathogenesis, serotypes of MDV and principle,
merits and demerits of various diagnostic methods of MDV and its
prevention. A new electrochemical technique i.e. DNA biosensor/
genosensor for simple, fast, sensitive and specific detection of MDV
is proposed.
Keywords
Marek’s disease; Marek’s disease virus (MDV); Alpha-herpesvirus;
Herpesvirus of Turkey’s (HVT) vaccines; Poultry
Abbreviations: MD: Marek’s Disease; MDV: Marek’s Disease
Virus; LAMP: Loop Mediated Isothermal Amplification; TR:
Terminal Repeat; IR: Internal Repeat; CPE: Cytopathic Effects; HVT:
Herpesvirus of Turkeys; IFNs: Interferons; IL: Interleukin; iNOS:
Inducible Nitric Oxide Synthase; vv: Very Virulent; Pfu: Plaque
Forming Unit
Introduction
Marek’s disease is a highly contagious lymphoprolifative disease
in chickens. Birds like Quail and Turkeys can be affected naturally/
artificially but chickens are more prone to this disease, as they are
most important natural host for Marek’s disease virus (MDV) [1,2].
The chickens become carriers for life, once infected with MDV. The
virus exists everywhere in the environment, where chickens are
raised. This virus does not cause harm to human beings. Pioneer work
*Corresponding author: Pundir CS, Department of Biochemistry, Maharshi
Dayanand University, Rohtak, Haryana -124001, India, Tel: +91 9416492413; E-mail:
pundircs@rediffmail.com
Received: August 21, 2017 Accepted: September 11, 2017 Published:
September 15, 2017
All articles published in Journal of Veterinary Science & Medical Diagnosis are the property of SciTechnol, and is protected by
International Publisher of Science, copyright laws. Copyright © 2017, SciTechnol, All Rights Reserved.
Technology and Medicine
Journal of
Veterinary Science &
Medical Diagnosis
a SciTechnol journal
on Marek’s disease was reported by renowned veterinarian Dr. Joseph
Marek, from Royal Hungarian Veterinary School, Budapest in 1907
[3].
Marek’s disease virus (MDV) belongs to the genus Mardivirus,
a member of Alpha-herpesvirinae, subfamily, Herpesviridae family
[4,5]. In addition, herpesvirus of turkeys (HVT) also belonging to the
genus Mardivirus, has two distinct MDV species, MDV type 1 (MDV-
1) or Gallid herpesvirus 2 (GaHV-2) and MDV-2 (GaHV-3). MDV-
1 consisting all the pathogenic strains with some vaccine strains,
is derived from MDV, while MDV-2 comprises of a pathogenic
strains originally isolated from apparently normal chickens [6]. The
Mardivirus lineage was diverged from mammalian Herpesvirus about
131 million years ago (D. J. McGeoch’s, personal communication) [7].
The transmission of MDV occurs mainly via feather dander (white
covering wraping developing feathers), while other routes of infection
are feces, poultry house dust, litter, blood and saliva [4,7] . Initially the
disease was called as “Polyneuritis”. Dr. Joseph noted the infiltration
by mononuclear cells through the thickening of spinal routes and
sacral plexus [8].
Immunity against MDV is the combined result of both innate as
well as adaptive immune response. But the virus is cell associated, so
cell mediated immune response with vaccination is seen. Protection
is dependent upon activation of T helper (TH-cells) 1 cells and release
of pro-inflammatory cytokines [8-12]. The interferons (IFNs) - γ,
Interleukin (IL)-1β, IFN-α and inducible nitric oxide synthase (iNOS)
are also released [12-16].
Etiology
Etiological agent is Alpha-herpesvirus, which is known as Gallid
Herpesvirus 2. Three serotypes have been recognized such as serotype
1, which is more virulent, followed by serotype 2 and serotype 3,
an avirulent turkey herpesvirus [17]. Serotype 1 (MDV-1) is more
virulent and also comprises attenuated strains. Serotype 2 (MDV-2)
is avirulent virus isolated from chickens, while serotype 3 (MDV-3) is
the herpesvirus of turkeys (HVT), which is used as a vaccine against
MDV as a vaccine [18]. MDV is made of capsid with 256 capsomeres,
an outer envelope and inner core. Among these three serotypes,
serotype 1 MDVs are oncogenic (tumor causing), and on the basis
of their virulence, Serotype 1 MDVs can be classified further as mild
(m), virulent (v), very virulent (vv), and very virulent plus (vv+)
strains [16,19,20]. Several other genes and miRNAs have also shown
to promote tumour formation along with Meq. Table 1 describes the
classification of MDV serotypes [21].
Symptoms
Clinical symptoms of MD include polyneuritis,
immunosuppression, T-cell lymphoma formation in visceral and
ectoderm derived tissues. Paralysis occurs in wings and legs with
neurolymphomatosis. Iris of one or both eyes in chickens becomes
gray, because of ocular lymphomatosis. Cutaneous disease involves
round, nodular lesions upto 1 cm diameter especially on feather
follicles [22]. Nodular and lymphoid tumors can also be seen in
different organs like kidney, muscles, gonads, lungs and spleen [23,24].
Non-suppurative meningoencephalomyelitis and lymphomatous
Citation: Poonam, Khatri R, Mohan H, Minakshi, Pundir CS (2017) Etiology, Epidemiology, Pathogenesis and Diagnosis of Marek’s Disease in Chickens: A
Mini review. J Vet Sci Med Diagn 6:4.
Table 1: Classification of MDV serotypes and characters of their respective strains.
MDV serotype Characters of serotypes
Very virulent
Serotype-1 Oncogenic
Some attenuated strains as well
Non-pathogenic
Serotype-2
Non-oncogenic
Avirulent
Serotype-3
Non-oncogenic
lesions are classical histopathological changes in central nervous
system (CNS) due to vv MDV [25].
Characteristics of MDV
The infectious MDV particle comprises of more than 30 different
proteins, assembled into central capsid having viral genome,
protein layer called tegument, contain 15 proteins and 10 envelope
glycoproteins are anchored in lipid layer.
Marek’s disease virus (MDV) genome is approximately 175 kb
in size and it is linear double stranded DNA, having a unique long
(UL) sequence and a unique short (US) sequence, both are flanked
with internal repeat (IR) and terminal repeat (TR) sequences. MDV
genome contains 100 open reading frames (ORFs) and encodes more
than 70 genes, most of which are orthologous to alphaherpesvirus.
However, Meq oncoprotein or pp38 phophoprotein are specific
to MDV [25]. Compared to extensive expression of genes,
transformation during lytic infection, transcription in latent and
transformed cells are restricted to repeat region of MDV genome.
Some important genes, which are having role in transformation
present within repeated regions like pp38, meq gene, and antisense
ribonucleic acid (RNA) transcripts, Bam HI-H family transcripts and
ICP4 sense.
Epidemiology
Incidence of MD increased from 1930s to 1950s, as poultry
production increased and among flocks throughout the world. By
1960s MD has caused heavy economic loss in poultry industry. Most
chickens produce antibodies against MD so they survive but virus is
shed from skin and feather follicles. This dander remains infective
for many months in dust [26]. Congenital infection doesn’t occur
because chicks carry maternal antibodies for first week of a life [22,
23,27]. High mortality rate soon peaks upto 80% and later decline
[22]. Mortality rate could also vary from 1% to 50% in life span of
chicken in population [27]. Three factors such as (i) virus’s strain (ii)
genetic composition of host and (iii) age of host decides whether this
infection leads to clinical disease [28].
Pathogenesis
Infection by MDV-1 is categorized into four stages: (i) Early
cytolytic, (ii) latent, (iii) late cytolytic (iv) Transformation phase
[1]. Cytolytic and latent phase of infection is followed by virus
reactivation in birds and leads to lymphoma development and CD4+
T-cell transformation.
Inhalation of poultry house dust which is contaminated with virus
causes infection. After early cytolytic infection of B-lymphocytes in
spleen, thymus and bursa, at 5-7 days post infection virus infects
CD4+ T-lymphocytes [29-34]. MDV enters latency in cell and express
Volume 6 • Issue 4 • 1000238
doi: 10.4172/2325-9590.1000238
Strains of serotypes
Very virulent plus(VV+): 648A
Very virulent(VV): Md/5, RB-1B
Virulent(V): HPRS-16
Mild virulent: Conn, HPRS-B14
Weakly virulent: CU-2
SB-1
HPRS-24
HN-1
Herpes virus of Turkey:HVT(FC126, PB1)
various genes, one of them is meq gene, which blocks apoptosis of
latently infected CD4+ T-lymphocytes and transactivate some genes
which maintain latency [35,36]. Cytolytic infection is followed by
tumor formation about 2-3 weeks right after primary infection [1].
These latent infected cells carry the virus to others by blood [4]. Virus
can be reactivated from latency to cytolytic infection and can cause
necrosis, atrophy of tissue followed by tumor formation in kidneys,
spleen, and gonads [1]. Biochemical and genetic studies have shown
that meq gene is main oncogenic factor of MDV [37]. Transformation
leads to development of lymphomatous lesions, which appears as
early as 12-14 days post infection (d.p.i) and results in blindness,
paralysis and mortality [38]. The insertion of retroviral long terminal
repeats (LTR) into host genome causes altered host responses to
MDV which leads to cancer formation and metastasis [39].
Diagnostic Methods
Various diagnostic methods are available for detection of MD,
as given below:
Virus isolation
Principle: There is a particular morphology of cells but when
virus infects, morphology of cell or tissue is changed, this is called
as cytopathic effects (CPE). The in-vitro culturing of MDV was first
reported by Churchill et al. [40].
Infection of MDV can be detected by the isolation of virus from
tissue of infected chickens. Generally spleen cells, lymphoma cell
suspension and buffy coat cells from heparinized blood are used as a
source. Monolayer cultures of chicken kidney cells or duck embryo
fibroblasts/chicken embryo fibroblast (CEF) are inoculated with cell
suspensions. Generally 0.2 ml suspension is inoculated on duplicate
monolayer grown in plastic cell culture dishes with control at 37°C in
humid incubator containing 5% CO2. The culture medium is replaced
at 2 days interval, cytopathic effects called as plaques, appears within
3-5 days and can be counted in 7-10 days [41].
Merits: It is simple, relatively easy and specific.
Demerits: Morphological change in cell lines could also be due
to some other reasons like contamination, deprivation of nutrients.
Antigen detection/ELISA
Principle
Antibody and soluble antigen when interacts in aqueous solution
forms a lattice that eventually develops into a visible line called
precipitin. This process called precipitation method.
ELISA- Churchill et al. [42] first used this method for detection
of MDV. In the method, antigen antibody interaction is viewed by
the presence of chromogenic substrate, which is converted into a
• Page 2 of 7 •
Citation: Poonam, Khatri R, Mohan H, Minakshi, Pundir CS (2017) Etiology, Epidemiology, Pathogenesis and Diagnosis of Marek’s Disease in Chickens: A
Mini review. J Vet Sci Med Diagn 6:4.
product by enzyme like horseradish peroxidase (HRP) tagged on
antibody bound to epitope of MDV antigen.
MDV antigen is detected in feather tips, which indicate the
infection. Glass slide is prepared with 0.8% agarose containing MDV
antiserum. Tips of small feathers are inserted vertically in agar and
formation of radial zones of precipitation around feather tip indicates
the presence of infection by MDV. ELISA gives the color intensity,
on which basis, the presence of antigen can be detected including its
severity in the sample [43].
Merits
Easy to perform and fast.
Demerits
Antibody must be bivalent and antigen should be either bivalent
or polyvalent.
Polymerase Chain Reaction (PCR)
Principle
A chain reaction in which a small fragment of the DNA of interest
is identified, which behaves as the template strand to produce primers
which initiate the reaction. One DNA strand is used to produce two
copies, then four, then eight and so on.
Conventional PCR
Genomes of all three serotypes of MD have been sequenced
[44,45], so PCR is used to diagnose MD, which can differentiate in
oncogenic serotype such as serotype-1 and non-oncogenic serotypes
like serotype-2 and 3 [44-50]. It also detects MDV specific meq
oncogene in feathers and tumors [44].
Nested-PCR
It specifically detects MD Meq oncogene of MDV-1 in infected
spleen, peripheral mononuclear cells [44,51].
qPCR (quantitative PCR)
qPCR can quantify MDV genome copies [52-54]. It can also
quantitate virus load in tissues or can differentiate between MDV and
HVT in feather tips or blood [53,55]. It also monitors MD vaccines.
Quencher and reporter molecule bound to probe (molecular beacon)
by a particular sequence, do not emit any light. But when reporter
molecule detach from quencher, it emits fluorescent light, which is
detected by a device and its intensity indicates the amplification of
DNA (Figure 1).
Flinders Technology Associates (FTA)
These filter cards are used for sample collection, transport and
storage for quantification of MDV viral DNA and to monitor MD
vaccines. Samples of feather pulp, solid tumor and blood are used for
the detection and quantitation of MDV genome by using qPCR [20].
Loop Mediated Isothermal Amplification (LAMP)
Principle
Six different regions on target gene are recognized by using four
distinct primers, which are specifically designed and this reaction
process proceeds at a constant temperature using strand displacement
reaction [56].
Volume 6 • Issue 4 • 1000238
doi: 10.4172/2325-9590.1000238
Bst DNA polymerase (Bacillus stearothermophilus) is used in
place of Taq polymerase. LAMP reaction is used for rapid detection
of MDV genome in feather samples. It is specific to detect Meq gene
for MDV-1 serotype.
Merits
It is a simple, fast, specific and cost-effective nucleic acid
amplification method, high amplication efficiency. DNA can be
amplified 109-1010 times in just 15-60 minutes and requires 100 times
less copy for detection of MD than conventional PCR [57].
Demerits
Less sensitive than PCR to inhibitors in complex samples such as
blood. It is only a diagnostic tool, which cannot be used for cloning
like PCR.
Immunofluorescence
Principle
In this method, the antibody is tagged with fluorescent material
like green fluorescent protein (GFP). When GFP binds to target
antigen, it gives fluorescence or a particular color at a specific
wavelength, which shows the presence of antigen. It is visualized by
fluorescence microscope. Tumor associated MDV antigen is also
visualized by tagging it with any fluorophore on some cells [23].
Merits
Easy method to detect and provide clear location of antibody and
sensitive.
Demerit
Costlier than PCR and require expertise handling.
Future diagnostic method for detection of MDV
Biosensor
Principle: The “biosensor” is an analytic device, composed of
a transducer and a biological element that can be an enzyme, an
antibody, nucleic acid, cell or cell organelles. The analyte interacts
with biological element and this biological response is converted into
an electrical signal with the help of transducer. In biosensor, biological
component acts as the sensor and detection and transmission of
signals is done by electronic component [58,59].
DNA biosensor/genosensor can be very effective to diagnose
Marek’s disease, because it is very rapid, sensitive,specific and cost
effective. In DNA based biosensor/ genosensor, a complementary
single stranded (ss) oligonucleotide probe is synthesized and
immobilized onto a suitable working electrode. When this probe
modified electrode is dipped into a reaction buffer consisting
denatured/ss genomic DNA, it binds with the complementary
sequence present in genomic DNA isolated from the clinical sample.
This hybridization of DNA can be detected in different ways,
of which measurement of decrease in cyclic voltammetric (CV)
current of methylene blue (MB), a redox dye, is most popular. As
the concentration of genomic DNA increases, the concentration of
free Guanine (G) bases also increases. This free G base binds with
MB dye, which results into generation of oxidation current. Such
electrochemical DNA biosensors not only reduce the detection/assay
time and simplify the method but also provide highly specificity
and sensitivity [60]. A number of DNA biosensors have been
• Page 3 of 7 •
Citation: Poonam, Khatri R, Mohan H, Minakshi, Pundir CS (2017) Etiology, Epidemiology, Pathogenesis and Diagnosis of Marek’s Disease in Chickens: A
Mini review. J Vet Sci Med Diagn 6:4.
Figure 1: Concept of Real-time polymerase chain reaction (qPCR).
reported for detection of pathogenic viruses in human like Human
Papilloma Virus (HPV), a cause for cervical cancer [61]. To the best
of our knowledge, there has been no report on construction of an
amperometric genosensor for detection of MDV. However, the
development of an amperometric genosensor based on MDV’s Meq
gene for simple, rapid, higly sensitive and specific detection of MDV
is in progress in our laboratory (Figure 2).
Merits: Fast, specific, cost effective, require less sample and
reagents for calibration.
Demerits: No heat sterilization.
Table 2 summarizes different diagnostic methods used for
detection of Marek’s disease virus (MDV).
Vaccination
Marek’s disease (MD) is prevented by vaccination at 1 day or
in-ovo. Both inactivated and tumor associated antigen can induce
resistance to virulent MDV [62-64]. It is reported that non-oncogenic
viruses (HVT and SB-1) are suitable as MD vaccine, as these do not
induce cytolytic infection in lymphoid organs [65]. HVT (serotype-3)
can be present in a cell free (lyophilized form) or cell associated (wet)
Volume 6 • Issue 4 • 1000238
doi: 10.4172/2325-9590.1000238
form, which is widely used vaccine. Attenuated vaccine of serotype-1
is also widely used vaccine. Serotype-2 vaccine has been employed in
bivalent form with HVT vaccine [40]. Following vaccines are used
for MD:
Attenuated virulent serotype-1 vaccines
Attenuated mildly virulent serotype-1 vaccines
It is less virulent for highly succeptible chickens and has ability to
spread by contact [66,67].
Attenuated serotype 1 vaccines derived from highly virulent
strains
Serotype-2 MDV vaccines
Serotype-3 MDV vaccines, also known as HVT vaccine
Polyvalent vaccines
The better protection from MD is by using combination of all
three serotypes, called trivalent vaccine and used for high risk flocks,
E.g.: FC126 +SB-1 + CVI988/C and FC126 + 301/B + CVI988/C
(serotypes 1, 2 and 3 respectively) were introduced in 1990.
• Page 4 of 7 •
Citation: Poonam, Khatri R, Mohan H, Minakshi, Pundir CS (2017) Etiology, Epidemiology, Pathogenesis and Diagnosis of Marek’s Disease in Chickens: A
Mini review. J Vet Sci Med Diagn 6:4.

doi: 10.4172/2325-9590.1000238

Figure 2: Principle of biosensor.

Table 2: A comparison of different diagnostic techniques used for detection of Marek’s disease virus (MDV) along with their merits and demerits.
Method Principle
Cytopathic effects (CPE) of cells Plaque forming unit (Pfu) can
or tissues changed, which is
specific for every virus
Virus isolation
Antigen detection
Antigen-Antibody precipitation or
agglutination formation
Enzyme convert chromogenic
substrate into a product
ELISA
Fluorescent proteins or dyes are
used which emits a particular
color at a specific wavelength
Immunofluorescence
of light
PCR
DNA molecule is amplified in a
chain reaction by annealing the
specific primers against desired
gene
Real-time PCR
Merits Demerits Reference
CPE effects can also be seen
due to contamination, lack of
be counted, easy interpretation, nutrients, also require skillful OIE [47]
sensitive and specific method handling of cell culture, time
taking
Antigen must be bivalent or Churchill et al.
Easy to perform, time saving
polyvalent in precipitation [43]
Easy to detect and visualize,
Costly and require expertise for
sensitive method, give clear location Clarence et al. [23]
handling
of antibody
Temperatue dependent, (Lee et al.[44]
unspecific primer binding Afonso et al. [45]
Preliminary method of detection, fast
Becker et al. [46];
Bumstead et al.
Very specific and usually used
Costlier than conventional PCR [47], Handberg
for meq gene detection, no post-
et al. [48]; Abdul
PCR processing, qualitative and
careem et al. [52];
quantitative method
Baigent et al. [53];
Islam et al. [54];
Davidson et al. [55]

Primers are used which make it Silva [49]; Zhu et

more specific for a desired gene al. [50]; Murata et
Primer sequence must be known
amplification al. [51]
Nested PCR
4 different primers are used to Rapid, time saving, very specific, Only a diagnostic method, less
Loop mediated isothermal (Notomi et al. [56].
detect 6 regions of target gene cost effective, high amplification sensitive than PCR to inhibitor
amplification (LAMP) Wei et al. [57]
at a constant temperature efficiency complex

Recombinant vaccines
Recombinant vaccine is prepared by using HVT [68], Fowlpox
[69,70] and Newcastle disease viruses as vectors [71-74].
Conclusion and Future Perspectives
Marek’s disease (MD) is a contagious lymphoproliferative disease,
which infects chickens on large scale. The virus causing Marek’s disease
(MDV) serotype 1 is oncogenic but serotype-2 and 3 are not oncogenic.
Various diagnostic methods are used for detection of MD such as
PCR, virus isolation, ELISA, qPCR, LAMP and immunofluorescence.
The proposed DNA biosensor could be a better diagnostic tool for
analyzing MD in samples, as it is simple, very rapid, sensitive, specific
and less expensive. Marek’s disease vaccines like Herpesvirus of Turkey
(HVT) are widely used but this disease is growing day by day and affects
worldwide. Immunization of embryos against infectious poultry disease
does not help to prevent its infection permanently or transmission to
higher virulence and is only temporary solution [75]. So, there must
be some rapid tools to diagnose this disease like biosensor in order
to cure chickens. Till now, it has not shown any sign in human but it
could be transmitted in future, so, we need to take care of this disease,
as soon as possible.

Volume 6 • Issue 4 • 1000238 • Page 5 of 7 •

Citation: Poonam, Khatri R, Mohan H, Minakshi, Pundir CS (2017) Etiology, Epidemiology, Pathogenesis and Diagnosis of Marek’s Disease in Chickens: A
Mini review. J Vet Sci Med Diagn 6:4.
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