Neurotropic Virus

Ning Rintiswati
Fac. Of Med, GMU

 Viral infections of the central nervous system

or neurotropic viruses are often lethal.
These diseases range from polio and
measles, to rabies, Varicella-zoster, Herpes,
West Nile, Japanese encephalitis, and AIDS.
Such infections have profound public health
consequences, and the understanding of
these diseases involves understanding the
interaction between the nervous system and
the immune system.

Polio virus

Left: Picture of
poliovirus. The
poliovirus is
extremely small,
about 50 nm
(nanometer = onebillionth of a meter)
Courtesy of David
Belnap and James
Hogle

Cross-section of the poliovirus

showing the RNA, capsid, and nerve
cell receptors Illustration courtesy
of Link Studio

GLOBAL STATUS 2004

Polio virus:
the causative agent of poliomyelitis, is a
human enterovirus
member of the family of Picornaviridae.
Poliovirus is composed of a RNA genome
and a protein capsid.
The genome is single-stranded positivesense RNA genome that is about 7500
nucleotides long.
The viral particle is about 300 ngstrm in
diameter with icosahedral symmetr y.

Pathophysiology
Poliovirus enters the body through the
mouth, infecting the first cells it comes in
contact withthe pharynx (throat) and
intestinal mucosa.
It gains entry by binding to an
immunoglobulin-like receptor, known as the
poliovirus receptor or CD155, on the cell
membrane .
The virus then hijacks the host cell's own
machinery, and begins to replicate.

Phatophysiology
Poliovirus divides within gastrointestinal cells for about a
week, from where it spreads to the tonsils (specifically the
follicular dendritic cells residing within the tonsilar
germinal centers), the intestinal lymphoid tissue including
the M cells of Peyer's patches, and the deep cervical and
mesenteric lymph nodes, where it multiplies abundantly.
The virus is subsequently absorbed into the bloodstream.

Pathogenesis and
pathology
Enter through Mouth
Multiplies in Oropharynx tonsils and
Intestines
Excreted in Stool.
Enters the CNS from Blood.
Spread along the Axons of peripheral nerves
to CNS.
Progress along the fibers of the lower motor
neurons spinal cord or brain.

Properties of Polio virus:

Polio virus is entero virus
Contains 4 viral protein VP1 to VP 4 VP1 Carries
the major antigenic site, and combines with type
specific neutralizing antibodies
Inactivated at 55 0 c for 30 mt. Chlorine at 0.1
ppm Ether is not effective.
Animal susceptibility. Monkey brain Requires
Primate specific membranes.
Contains 3 Antigenic types 1,2,3 Can be
differentiated by ELISA and CF methods.

What is Poliomyelitis?
polio= gray matter Myelitis= inflammation of the spinal
cord
This disease result in the destruction of motor neurons
caused by the poliovirus.
Polio is causes by a virus that attacks the nerve cells of
the brain & spinal cord although not all infections result
in sever injuries and paralysis. How is polio transmitted?
Poliovirus is transmitted through both oral and fecal
routes with implantation and replication occurring in
either the orapgaryngeal and or in the intestine of
mucosa.
Polio cases are most infected for 7-10 days before and
after clinical symptoms begin.

Polio infection
Incubation 3 21 days On average 14 days
Predisposing factors.
Severe muscular acitivity can lead to paralysis,
as it increases the blood flow
May produce paralysis in the limb or bulbar
region Injecting vaccines with adjuvant can
predispose to paralysis
Patients who underwent tonsillectomy have
higher incidence as Ig G secretion is reduced
Rarely oral Polio vaccine produces poliomyelitis.

RABIES Virus

Rabies virus belongs to the family:

Rhabdoviridae.
They can infect a variety of animals and
plants
it is estimated that approximately 55 000
persons die of rabies each year in the world.

Rhabdovirus
are negative strand RNA viruses; that is they have
a single strand of RNA that is anti-sense to the
messenger RNA needed to code for viral proteins.
This means that the RNA cannot code directly for
protein synthesis and must be copied to positive
strand mRNA. As a result, the virus must carry its
own RNA-dependent RNA polymerase.
are rod shaped. Each virus particle is up to 100nm
diameter and 400 nm long but this is very variable.
They have an envelope derived from the host cell
plasma membrane. The virus has only five proteins.

Herpes virus

Herpes simplex viruses

(HSV)
belong to the subfamily of Alphaherpesvirinae.
Herpes viruses consists of a relatively large linear DNA
genome of double-stranded DNA 150 kb in length,
encased within an icosahedral capsid, which is wrapped
in a lipid bilayer called the envelope.
The envelope is joined to the capsid by means of a
tegument.
The genome of Herpes viruses encodes some 100-200
genes.
These genes encode a variety of proteins involved in
forming the capsid, tegument and envelope of the virus
as well as controlling the replication and infectivity of the
virus.

 Herpes simplex virus 1 and 2 (HSV-1

and HSV-2) are two species of the
herpes virus family, which cause
infections in humans
An infection by a HSV is marked by
watery blisters in the skin or mucous
membranes of the mouth, lips or
genitals.

 Entry of HSV into the host cell involves interactions of several

glycoproteins on the surface of the enveloped virus, with
receptors on the surface of the host cell.
initial interactions occur when a viral envelope glycoprotein called
glycoprotein C (gC) binds to a cell surface particle called heparan
sulfate.
A second glycoprotein, glycoprotein D (gD), binds specifically to a
receptor called the Herpes virus entry mediator receptor (HVEM)
and provides a strong, fixed attachment to the host cell.
These interactions bring the membrane surfaces into mutual
proximity and allow for other glycoproteins embedded in the viral
envelope to interact with other cell surface molecules.
Once bound to the HVEM, gD changes its conformation and
interacts with viral glycoproteins H (gH) and L (gL), which form a
complex.

 Following infection of a cell, herpes virus proteins, called immediateearly, early, and late, are produced.
The early proteins transcribed are used in the regulation of genetic
replication of the virus.
On entering the cell, an -TIF protein joins the viral particle and aids
in immediate-early transcription.
The virion host shutoff protein (VHS or UL41) is very important to
viral replication. This enzyme shuts off protein synthesis in the host,
degrades host mRNA, helps in viral replication, and regulates gene
expression of viral proteins.
The viral genome immediately travels to the nucleus but the VHS
protein remains in the cytoplasm.
The late proteins are used in to form the capsid and the receptors on
the surface of the virus. Packaging of the viral particles - including
the genome, core and the capsid - occurs in the nucleus of the cell

 concatemers of the viral genome are separated

by cleavage and are placed into pre-formed
capsids.
HSV-1 undergoes a process of primary and
secondary envelopment.
The primary envelope is acquired by budding into
the inner nuclear membrane of the cell.
This then fuses with the outer nuclear membrane
releasing a naked capsid into the cytoplasm.
The virus acquires its final envelope by budding
into cytoplasmic vesicles.

 HSV may persist in a quiescent but persistent

form known as latent infection, notably in neural
ganglia.
During latent infection of a cell, HSV express
Latency Associated Transcript (LAT) RNA.
LAT is known to regulate the host cell genome
and interferes with natural cell death
mechanisms.
By maintaining the host cells, LAT expression
preserves a reservoir of the virus, which allows
later recurrences to produce further infections.

Japanese Enchephalitis
The causative agent JEP is an enveloped virus of the genus
flavivirus and is closely related to the West Nile virus and St Louis
enchephalitis virus.
The positive sense single stranded RNA genome is packaged in
the capsid which is formed by the capsid protein.
The outer envelope is formed by envelope (E) protein and is the
protective antigen. It aids in entry of the virus to the inside of the
cell. The genome also encodes several nonstructural proteins also
(NS1,NS2a,NS2b,NS3,N4a,NS4b,NS5).
Japanese Encephalitis is diagnosed by detection of antibodies in
serum and CSF (cerebrospinal fluid) by IgM capture ELISA
Viral antigen can also be shown in tissues by indirect fluorescent
antibody staining.
Over 60 complete genomes of this virus have been sequenced as
of 2010.

 Japanese encephalitis has an incubation period of 5 to 15 days and

the vast majority of infections are asymptomatic: only 1 in 250
infections develop into encephalitis.
Severe rigors mark the onset of this disease in humans.
Fever, headache and malaise are other non-specific symptom
of this disease which may last for a period of between 1 and 6 days.
Signs which develop during the acute encephalitic stage include neck
rigidity, cachexia, hemiparesis, convulsions and a raised body
temperature between 38 and 41 degrees Celsius.
Mental retardation developed from this disease usually leads to
coma.
Mortality of this disease varies but is generally much higher in
children. Transplacental spread has been noted.
Life-long neurological defects such as deafness, emotional lability
and hemiparesis may occur in those who have had central nervous
system involvement.
In known cases some effects also include nausea, headache, fever,
vomiting and sometimes swelling of the testicles.

HIV virus
roughly spherical particles
(sometimes called virions).
The surface of each particle is
studded with lots of little spikes.
An HIV particle is around 100-150
billionths of a metre in diameter
surround with a coat of fatty
material known as the viral
envelope
Projecting from this are around 72
little spikes, which are formed from
the proteins gp120 and gp41.
Just below the viral envelope is a
layer called the matrix, which is
made from the protein p17.

Assembly, Budding and

Maturation
Among the strands of messenger RNA produced
by the cell are complete copies of HIV genetic
material. These gather together with newly made
HIV proteins and enzymes to form new viral
particles, which are then released from the cell.
The enzyme protease plays a vital role at this
stage of the HIV life cycle by chopping up long
strands of protein into smaller pieces, which are
used to construct mature viral cores.
The newly matured HIV particles are ready to infect
another cell and begin the replication process all
over again.
In this way the virus quickly spreads through the
human body. And once a person is infected, they
can pass HIV on to others in their bodily fluids.

Creutzfeldt-Jakob disease
(CJD)
is a rare, degenerative
invariably fatal brain disorder.
onset of symptoms occurs about age 60, and
about 90 percent of individuals die within 1 year.
In the early stages of disease, people may have
failing memory, behavioral changes, lack of
coordination and visual disturbances.
As the illness progresses, mental deterioration
becomes pronounced and involuntary
movements, blindness, weakness of extremities,
and coma may occur.

 In sporadic CJD, the disease appears even though the person has no
known risk factors for the disease. This is by far the most common
type of CJD and accounts for at least 85 percent of cases.
In hereditary CJD, the person has a family history of the disease
and/or tests positive for a genetic mutation associated with CJD. About
5 to 10 percent of cases of CJD in the United States are hereditary.
In acquired CJD, the disease is transmitted by exposure to brain or
nervous system tissue, usually through certain medical procedures.
There is no evidence that CJD is contagious through casual contact
with a CJD patient.
Since CJD was first described in 1920, fewer than 1 percent of cases
have been acquired CJD.

 CJD belongs to a family of human and animal diseases known

as the transmissible spongiform encephalopathies (TSEs).
Spongiform refers to the characteristic appearance of infected
brains, which become filled with holes until they resemble
sponges under a microscope.
CJD is the most common of the known human
Kuru was identified in people of an isolated tribe in Papua New
Guinea and has now almost disappeared.
These include bovine spongiform encephalopathy (BSE), which
is found in cows and is often referred to as mad cow
disease; scrapie, which affects sheep and goats; mink
encephalopathy; and feline encephalopathy.
Similar diseases have occurred in elk, deer, and exotic zoo
animals.

Prions
Prions propagate by transmitting a misfolded protein
state.
When a prion enters a healthy organism, it induces
existing, properly-folded protein
s to convert into the disease-associated, prion form; the
prion acts as a template to guide the misfolding of more
protein into prion form.
prions induce the formation of an amyloid fold, in which
the protein polymerises into an aggregate consisting of
tightly packed beta sheets.
Amyloid aggregates are fibrils, growing at their ends, and
replicating when breakage causes two growing ends to
become four growing ends