Download Marek`s Disease Virus - Cal State LA

Marek’s Disease Virus
(And correlation of resistance to
Marek’s disease virus with the
chicken B21 haplotype)
What is Marek’s Disease?

A highly contagious infection in chickens
caused by a specific herpes virus that results
in a rapidly fatal polyclonal lymphoma.
What is Marek’s disease
virus?


A herpes virus – genome is double
stranded, linear DNA
May be oncogenic; i.e. it may be
capable of causing cancer
What kinds of viruses are
oncogenic?

RNA viruses – Of the RNA viruses, only the
retroviruses are oncogenic.



Acute transforming retroviruses carry in their own
genome the gene that causes the development of
cancer (see following slides).
Chronic transforming retroviruses integrate next to
a host cell gene to turn on its expression, and this
is what causes the development of cancer (see
following slides).
DNA viruses – Many different DNA viruses are
capable of being oncogenic.
Examples of chronic and acute
transforming RNA viruses.
Chronic
Acute
How chronic retroviruses act
How do Chronic Retroviruses
Transform Animal Cells?
Insertional activation
How
acute
transfor
ming
viruses
are
thought
to have
formed
How are RNA oncogenic viruses different
from DNA oncogenic viruses?
RNA

Oncogenesis requires
integration of the whole
viral cDNA into host cell
DNA. Integration is
random and is required
for viral replication.
What virus does this remind
you of?
DNA

Oncogenesis requires
integration of whole or
part of the viral
genome into the host
cell DNA. Integration is
random, but is not
required for viral
replication.
How are RNA oncogenic viruses
different from DNA oncogenic
viruses?
RNA

Oncogenesis occurs
when the virus infects
its normal permissive
host cells. Permissive
cells are cells in which
there is a productive
infection, i.e., cells in
which new virus is
produced.
DNA

Oncogenesis occurs
when the virus infects a
non-permissive host
cell, i.e., a cell that
lacks something
required for viral
replication.
How are RNA oncogenic viruses
different from DNA oncogenic
viruses?
RNA


In acute transforming RNA
viruses, the genes that are
involved in the development of
cancer are normal or modified
cellular genes that have been
permanently incorporated into
the viral RNA genome. They
are not viral genes, nor are
they required for viral
replication.
The genes are usually genes
that are involved in cell growth
control.
DNA


The genes that are involved
in the development of cancer
are normal viral genes that
are required for viral
replication.
The genes involved are
normally genes whose
products complex with
cellular tumor suppressor
gene products to inactivate
their function.
Marek’s disease viruses cause
three types of infection


Productive infection
Non-productive infection


Long latency
Transforming following short latency
What types of infections does
Marek’s disease virus cause?


Productive infection – A productive, lytic
infection occurs in cells other than
lymphocytes.This leads to cell death
and the development of necrotic
lesions.
This type of infection is caused by both
oncogenic and non-oncogenic variants
of Marek’s disease virus.
What types of infections does
Mareks disease virus cause?

Non-productive infections
EITHER
 Latent infection by a non-oncogenic serotype or variant

occurs predominantly in T lymphocytes. No virus is produced,
and there are no visible symptoms.
OR
 Transforming infection by an an oncogenic serotype

occurs predominantly in T cells and is characterized by a
polyclonal T cell lymphoma. No new viruses are produced, but
there are visible symptoms. The malignant cells infiltrate



the peripheral nerves and spinal cord leading to paralysis
the iris, leading to blindness
and the skin, leading to skin lesions.
What is the difference between a
monoclonal and a a polyclonal T cell
lymphoma?


A monoclonal lymphoma would result
from the proliferation of a single T cell
that became malignant.
A polyclonal lymphoma would result
from the proliferation of several
different T cells, each having become
independently malignant from infection
by the Marek’s disease virus.
Lymphoma, and leukemia, are both
cancers of white blood cells.
What is the difference?


In a lymphoma, the malignant cells
originate in tissues other than the bone
marrow (i.e., the lymph nodes, spleen,
thymus, liver, etc.)
In a leukemia, the malignant cells
originate in the bone marrow.
How does Marek’s disease
virus cause a lymphoma?




An oncogenic variant of the virus enters through the
respiratory route.
An early productive infection occurs in non-lymphocytic cells.
(At this stage, virus can spread rapidly through a chicken
population.)
The virus particles enter the lymphoid organs and causes
short nonproductive latent infections, mainly in T cells.
Nonproductive infection of these T lymphoid cells leads to
lymphoma formation in each infected T cell, giving rise to a
polyclonal lymphoma.
What viral proteins are involved in
the development of the malignant
lymphoma?



A viral transcriptional activator that
transactivates both viral and cellular
genes may be involved.
A viral protein may bind the tumor
suppressor protein, p53, leading to
entry of the cell into the cell cycle,
causing it to multiply when it shouldn’t.
A viral protein may block signal-induced
apoptosis, causing the cell to survive
longer than usual and replicate.
What are the MHC genes of chickens
called and how are they related to
resistance to Marek’s disease virus?




Class I genes are called B-F and they encode MHC molecules
found on the surface of all nucleated cells.
Class II genes are called B-L and they encode MHC
molecules found on the surface of cells involved in immune
function.
The B21 haplotype, which maps to the B-F region, appears
to confer resistance to Marek’s disease virus.
Remember that the MHC genes are closely linked and are
inherited as a haplotype.

The haplotype numbers are assigned to specific combinations of MHC
alleles.
What are the MHC genes of chickens
called and how are they related to
resistance to Marek’s disease virus?



There are 2-3 different genes encoding the
alpha chains found in the B-F region.
The primers that you are using in the SSCP
analysis are consensus primers for the alpha
chains in the B-F region, so they will amplify
all 2-3 genes in that region.
The chicken DNAs that you are analyzing are
homozygous, so you should ideally see 4-6
bands in your analyses.