|
 


 
` |

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`  |
|
 |


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 r |

|
` small (20-
(20-30 nm) nonenveloped, icosahedral, +ve
ssRNA viruses
` Replicate in the cytoplasm
` resist lipid solvents (e.g. ether) because they do not
have an envelope
` The family includes 2 groups:
1- Enteroviruses
2- Rhinoviruses
Among the major enteroviruses are poliovirus,
coxsackieviruses, echoviruses, and hepatitis A virus .
` Enteroviruses infect primarily the enteric tract,
` whereas rhinoviruses are found in the nose and throat
(rhino = nose).
ántroduction
Picornaviruses are among the most diverse
(more than 200 serotypes) and 'oldest' known
viruses (temple record from Egypt ca. 1400
B.C.).
FMDV (foot and mouth disease virus) was
one of the first viruses to be recognised -
Loeffler and Frosch 1898.
` Poliomyelitis as a viral disease was first
recognised by Landsteiner and Popper, 1909
(though the virus was not isolated until the
1930's.
Name: 'Pico (Greek very small ) RNA Viruses'.

` iriginally based on physical properties (particle
density & pH-
pH-sensitivity) & serological
relatedness,
` more recently based on nucleotide sequence.
There are there are nine genera within the
Picornaviridae.. Five of these infect humans:
Picornaviridae
` Enteroviruses
` Rhinoviruses
` Hepatoviruses
` Parechoviruses
` Kobuviruses
` Parechoviruses were formerly classified
among the Echoviruse
Echovirusess and cause
gastrointestinal and respiratory tract
infections, and occasionally cases of
encephalitis and flaccid paralysis.
` Kobuviruses also cause gastroenteritis.
  |
|
Enterovirus infections are common in humans;
seasonal peak in autumn; frequently undiagnosed:
Enteroviruses
Virus family Serotypes
Polio 1-3
Coxsackie A 1 - 22, 24
Coxsackie B 1-6
Echovirus 1 - 9, 11 - 27, 29 - 34
Hepatitis A Enterovirus 72
Other Enteroviruses 68 - 71
 ˜enera of Picornaviruses
˜

 


Enterovirus
Polio Diseases of the human
Coxsackie A and B (and other) alimentary
Echo tract (e.g. polio virus)
Other enteroviruses
Disease of the
Rhinovirus(HRV) nasopharyngeal region
(e.g. common cold virus)

Hepatovirus
Human hepatitis virus A
Parechovirus
Parechovirus Formerly echoviruses
22 and 23.

Disease of x
x x

respiratory tract

Kobuvirus Aichi virus is the type

` species
 
` Cardiovirus Mainly found in rodents
Murine encephalomyocarditis,
` Theiler's murine encephalomyelitis
` virus
`
` Aphthovirus Foot and mouth disease in (FMDV )
` cloven footed animals
` Erbovirus
` Teschovirus
`
 Properties of Rhino- and Entero-viruses
Optimum
Site of
growth Detergent Transmissio
pH sensitivity Serotypes primary
temperatur sensitivity n
infection
e

33
upper
Rhino labile to acid degrees
>100 aerosol respirator
viruses pH C
y tract
(approx)

37
Entero resistant to degrees
Resistant 72 oro-fecal gut
viruses acid pH C
(approx)
  !
` The genome consists of one s/s (+)sense RNA
molecule of between 7.2kb (HRV14) to 8.5kb
(FMDV).
` A number of features are conserved in all
Picornaviruses::
Picornaviruses
` Genomic RNA is infectious (~1x106
(~1x106--fold less
infectious than intact particles, although
infectivity is increased if the RNA is introduced
into cells by transfection) - CHARACTERá TáC iF
(+) EN E RNA VáRU E !!!
` There is a long (600-
(600-1200 base) untranslated
region at the 5' end (important in translation
translation,,
virulence and possibly encapsidation
` and a shorter 3' untranslated region (50-
(50-100
bases) - important in (-)strand synthesis.
` The genome RNA has positive polarity;
polarity; i.e., on entering
the cell, it functions as the viral mRNA.
mRNA.

` The single strand of positive-

positive-sense RNA (messenger RNA
sense) can act as a messenger RNA once it enters the
cytoplasm and uncoating has occurred.

` The genome RNA is unusual because it has a protein

on the 5' end that serves as a primer for transcription by
polymerase.(VPg)
RNA polymerase.(VPg)
` The open reading frame then extends to
near the 3' end.
` After the open reading frame of 7000
bases, there is a short sequence before
the poly A tract.
` The poly A tract of polio RNA is encoded
in the genome, unlike the situation with
cellular mRNAs where it is added post-
post-
transcriptionally.
` There is another way in which picornavirus
RNA differs from a typical mRNA.
` The latter have a methylated cap structure
at the 5' end, whereas picornaviruses have
a viral protein called VPG
VPG..
` The large 5' leader sequence has
considerable secondary structure that
comes about by intramolecular base
pairing and one of these structures is the
internal ribosome entry site (áRE ) which
allows this RNA to bind to cytoplasmic
ribosomes.
. The 5' UTR contains a 'clover-
'clover-leaf' secondary structure known
as the |!|" # .
. The rest of the genome encodes a single 'polyprotein' of
between 2100-
2100-2400 aa's.
. Both ends of the genome are modified
modified,,
. the 5' end by a covalently attached small, basic protein VPg
(~23 aa's), VPg is a protein attached to the 5' end of RNA during
RNA synthesis in a wide variety of viruses including Picornaviridae
such as Foot
Foot--and-
and-mouth disease and poliovirus .
.VPg stands for "viral protein genome-
genome-linked".
. the 3' end by polyadenylation
`   !
` The capsid is an arrangement of 60 protomers in a tightly packed
ácosahedral structure.
Each protomer consists of 4 polypeptides known as VP (viral
protein)1, 2, 3 and 4.
` VP2 and VP4 polypeptides originate from one protomer known as
VP0 that is cleaved to give the different capsid components.

` The ácosahedral is said to have a triangulation number of 3, this

means that in the icosahedral structure each of the 60 triangles that
make up the capsid are split into 3 little triangles with a subunit on
the corner. There are 60 identical subunits (vertices) which contain
five protomers.
protomers.

` Each protomer is made up of one copy of four proteins,

proteins, named
VP1, VP2, VP3 and VP4.

` These proteins are made as a single polypeptide (polyprotein) which

is cleaved by cellular proteases
ácosahedron
  subunits around 5- 5-fold axes are
r

r;;
| and | are
$ and
% respectively;
&' subunits (seen only internally) are
(

(.. The VP4 subunits are formed by
autocatalytic cleavage of
) (into
% and
(

()) upon binding of a "
" "" with
* |
+
VP1: is in blue
VP2: is in green
VP3: is in red
VP4: is in yellow (only visible on the inside of the particle)

Rhinovirus14,colorcodedby protein, as solved by X-

X-ray crystallography
A computer generated image of a picornavirus capsid.
capsid. This image is based on
the real atomic co-
co-ordinates of rhinovirus 16 and shows a view inside the
capsid.
  subunits around 5- 5-fold axes are
r

r;;
| and | are
$ and
% respectively;
&' subunits (seen only internally) are
(
(..
The VP4 subunits are formed by autocatalytic cleavage of
) (into
% and

()) upon binding of a "

( " "" with * |
+

` Depending on the type and degree of
dehydration the viral particle is around 27-
27-
30 nm in diameter.
` The viral genome is around 2500 nm in
length so we can therefore conclude that
it must be tightly packaged within the
capsid along with substances such as
sodium ions in order to cancel out the
negative charges on the RNA caused by
the phosphate groups.
` To view an electron micrograph of
negatively--stained picornavirus particles,
negatively
 Transmission electron micrograph of poliovirus
type 1. CDC/Dr. Joseph J. Esposito jje1@cdc.gov
` |
` The viral particle binds to cell surface receptors.
` This causes a conformational change in the viral
capsid proteins, and myristic acids are released.
` These acids form a pore in the cell membrane
through which RNA is injected.
` ince inside the cell, the RNA uncoats and the
(+) strand RNA genome is replicated through a
double--stranded RNA intermediate that is
double
formed using viral RDRP (RNA
(RNA--Dependent RNA
polymerase).
` Translation by host cell ribosomes is not initiated
by a 5' G cap as usual, but rather is initiated by
an áRE (ánternal Ribosome Entry ite).
` The viral lifecycle is very rapid with the whole
process of replication being completed on
average within 8 hours.
` However as little as 30 minutes after initial
infection, cell protein synthesis declines to
almost zero output ƛ essentially the
macromolecular synthesis of cell proteins is
Ơshut offơ.
offơ.
` iver the next 1ƛ2 hours there is a loss of
margination of chromatin and homogeneity in
the nucleus, before the viral proteins start to be
synthesized and a vacuole appears in the
cytoplasm close to the nucleus that gradually
starts to spread as the time after infection
reaches around 3 hours.
hours.
` After this time the cell plasma membrane
becomes permeable, at 4ƛ6 hours the virus
particles assemble
assemble,, and can sometimes be seen
in the cytoplasm.
` At around 8 hours the cell is effectively dead
and lyses to release the viral particles.
` The mechanisms and factors involved in the
replication of positive stranded RNA viruses are
still unclear
` Using poliovirus as a model, we show that a
long--range interaction between
long
ribonucleoprotein (RNP) complexes formed at
the ends of the viral genome is necessary for
RNA replication.
` ánitiation of negative strand RNA synthesis
requires a 3' poly(A) tail.
tail.
` trikingly, it also requires a cloverleaf-
cloverleaf-like RNA
(áRE ) structure located at the other end of the
genome.
` An RNP complex formed around the 5'
cloverleaf RNA structure interacts with the
poly(A) binding protein bound to the 3' poly(A)
tail, thus linking the ends of the viral RNA and
effectively circularizing it.
it.
` Formation of this circular RNP complex is
required for initiation of negative strand RNA
synthesis.
` RNA circularization may be a general replication
mechanism for positive stranded RNA viruses.
Replication of a positive strand RNA virus
`|
|

` This is quite simple compared to some
other RNA viruses.
` ince picornaviruses spend all of their time
in the cytoplasm, they must encode a
polymerase (replicase) that is made from
the sense strand of the infecting virus.
` The polymerase copies the sense strand to
anti--sense which is then copied back to
anti
the sense strand that is packaged into the
virus (previous figure).
` RNA replication seems to occur on the
cytoplasmic surface of membrane vesicles
to which the RNA polymerase binds.
` These appear to come from the
endoplasmic reticulum,
reticulum, as do vesicles in
the uninfected cells that transport
secreted and membrane proteins to the
Golgi body.
body.
` However, when the cell is infected by the
picornavirus, the vesicles do not fuse with
the cis face of the Golgi body as the
transport vesicles do (figure 2).
 Fig.2 When the cell is infected by a picornavirus,
the endoplasmic reticulum to Golgi body transport
vesicles do not fuse with the cis face of the Golgi
body
` These vesicles have specific targeting proteins
on their cytoplasmic surfaces (called CiP
proteins) and it is possible that they are involved
in the response to the viral infection.
` át should be remembered that picornaviruses do
not have a lipid envelope and do not have a
surface glycoprotein.
` Therefore, the production of virus is not
inhibited by compromising Golgi Body function,
function,
as would be the case with an enveloped virus.
virus.
` We do not know why there is this membrane
association of RNA replication of picornaviruses
but it may concentrate various substrates in the
vicinity of the polymerase (remember that in
bacteria, DNA replication is membrane-
membrane-
associated).
` The RNA of picornaviruses is polyadenylated at
the 3ƞ end,
end, as are cellular messenger RNAs but
this polyadenylation occurs in a different way.
way.
` án host cell mRNA synthesis, the poly A
sequence is not coded in the DNA copy of the
gene but is added by an enzyme called poly A
polymerase using ATP as a substrate.
` án the case of picornavirus RNA, however, the
poly A sequence in the sense strand is copied to
a poly U sequence at the 5ƞ end of the negative
strand.
` This is copied back to 3ƞ poly A,
A, again by the
replicase.
 |" *
` Different picornaviruses have different
receptors, among which are some
intercellular cell surface adhesion
molecules (áCAMs
(áCAMs).).
` The expression of these molecules
determine tissue tropism.
` Coxsackievirus (a type of enterovirus) and
most rhinoviruses bind to áCAM-
áCAM-1, an
adhesion glycoprotein expressed on the
surfaces of a variety of cells (epithelial,
endothelial, fibroblasts).
` Polio virus binds to another cell surface
glycoprotein known as CD155 (the
poliovirus receptor).
` When the virus binds to its receptor, the
VP4 protein is released from the protomer.
This allows the escape of the viral RNA
from the nucleocapsid when the virus is
internalized into the endocytic pathway.
` án the endosome, the nucleocapsid
disassembles in the acid environment.
Protein synthesis is detectable with 15
minutes of infection.
Virus: # erotypes: Receptor: Description:
Human 91 áCAM-1
áCAM- ámmunoglobulin--like
ámmunoglobulin
Rhinovirus (ántracellular molecule; 5
Adhesion Molecule
domains
1)
Human 10 LDLR (Low
Rhinovirus Density
Lipoprotein
receptor)
Poliovirus 3 CD155 ámmunoglobulin-like
ámmunoglobulin-
molecule; 3
domains
Coxsackie A 3 áCAM--1
áCAM

Echo 2 VLA-
VLA-2 (very late ántegrin--like
ántegrin
activation
molecule
antigen)
Echo 6 DAF (Decay
Accelerating
???
Factor)
EMCV 1 VCAM
VCAM--1 (Vascular
Cell Adhesion
???
Molecule)
Uncoating:

` After adherence to the receptor, the virus can be eluted again, but if
this happens, the particle undergos conformational changes due to
the loss of VP4 and infectivity is lost - this is also the first stage in
uncoating:
`
|
, ||

` An RNA virus needs to make an RNA that can serve as a
messenger RNA for protein synthesis in a host cell.
` án the case of the positive strand RNA viruses (whose
genome, by definition, is the same sense as mRNA), the
genomic RNA can serve as the message (figure 2).
` The virus capsid serves as the delivery vehicle to the
cytoplasm.
` ince the genome is RNA and copied by an RNA
polymerase, there is no need for a typical promoter
(TATA box, CAT box etc) upstream of the protein
encoding genes (as found in DNA viruses or
retroviruses);
` moreover, positive strand viruses do not need to make
new proteins before making mRNA as their RNA can
serve directly as a message.
  *

` The picornavirus RNA binds to ribosomes and

makes a single polypeptide,
polypeptide, therefore the virus
has just one gene.
` This polyprotein has regions that have
proteolytic activity (they are cysteine proteases)
that cleave the polyprotein to three precursor
proteins (P1, P2, P3).
` P1 is cleaved to a VP0, VP1 and Vp3 plus a
leader peptide of unknown function.
` VP0 gives rise to VP2 and VP4.
` P2 and P3 do not give rise to viral structural
proteins.
` ine of the proteins that comes from P3 is
the VPG that is found at the 5' end of the
viral RNA while other proteins from this
precursor are the viral replicase and
enzymes that modify the behavior of the
host cell.
` P2 is also cleaved to give other cell-
cell-
modifying proteins. Details of some of the
cleavages are still vague.
` ince the various viral proteins have been made
in the infected cell, the replicase (also call a
transcriptase or protein 3Dpol) copies the viral
plus sense RNA to negative sense RNA.
` ither viral proteins are also involved in this
process.
` As new positive strand RNAs are made, they can
also be translated into more viral protein.
` There may be as many as half a million copies of
viral RNA per cell.
` ome of the proteolytic events outlined above
take place as the nucleocapsid is assembled.
` This is especially the case with the VP0 cleavage
to VP2 and VP4.
` P1 protein is the precursor that gives rise to the
four structural proteins of the nucleocapsid.
` Five copies of P1 first associate to form a
pentamer. Endoproteolysis then occurs to form
VP0, VP1 and VP3.
` Twelve of these pentamers than associate to
form an empty capsid (procapsid).
` The order of formation of the individual viral
proteins is important in the assembly of the
virus.
` The viral RNA now associates with the capsid
and at the same time, VP0 is cleaved.
` Release is by lysis of the host cell.
To replicate the viral genome, RNA-
RNA-dependent RNA polymerase enzymes copy
the (+) RNA genome producing ss (- (-) RNA. RNA-
RNA-dependent RNA polymerase
enzymes then copy the (- (-) RNA strands producing ss (+) RNA viral genome.
To produce viral mRNA molecules. RNA-RNA-dependent RNA polymerase enzymes
copy the (-
(-) RNA strand into (+) viral mRNA. The (+) viral mRNA can then be

transtated into viral proteins by host cell ribosomes.

 Fá
URE 1:1: The picornavirus binds to a receptor on the
cell surface (A).
` RNA is translated into one primary translation product
(B)
` which is then cleaved (C).
` The positive strand genomic RNA also associates with an
RNA polymerase that is bound to the cytoplasmic surface
of vesicles, probably from the endoplasmic reticulum,
and is copied to negative stand RNA. VPg is at the 5'
end of the negative strand (the
(the poly U end)
end) (D).
` The negative strand is copied to genomic positive strand
RNA (E)
` which associates with the procapsid to form a 150
virus (
)
` that is released on cell lysis

enomic structure of poliovirus type 1 (Mahoney) [PV1(M)] The PV genome consists of a
single--stranded, positive-
single positive-sense polarity RNA molecule, which encodes a single
polyprotein. The 5' non-
non-translated region (NTR) harbors two functional domains, the
cloverleaf and the internal ribosome entry site (áRE ),and
iscovalentlylinkedtotheviralprotein VPg. The 3'NTR

is polyadenylated.
Vp
is at the 5' end of the viral genomic sense
(+ve) RNA but is lost before translation
` At the same time as viral protein synthesis is
occurring, host cell protein synthesis is shut off.
` The host cell mRNAs however remain fully
functional when assayed in an experimental
system, so selective degradation of cell mRNAs
is not the reason for protein synthesis inhibition.
inhibition.
` 1- ine way host cell protein synthesis occurs is
via the cleavage of initiation factor eáF
eáF--4, one of
the cap binding proteins of the host cell's
ribosomes so that cellular mRNAs cannot bind to
the ribosomes.
` Association with cap-
cap-binding proteins is a
prerequisite for the translation of most cellular
RNAs.
` Thus, only uncapped messages such as that of
translated.
the picornavirus are translated.
` Note that most viruses express capped RNAs
similar to normal mRNA and so this mechanism
of shutting down host protein synthesis is not
available to them.
` 2- The viral proteins also change the
permeability of the host cell, altering the ionic
composition of the cell and inhibiting cell mRNA
association with ribosomes.
` 3- Moreover, the large number of copies of viral
RNA simply out-
out-compete the cell's mRNAs.
` Picornaviruses also have a protease
activity that can cut one of the proteins of
the initiation complex, eáF4
(figure 3),
and this seriously affects the cellƞs ability
to translates normal capped messages but
does not affect translation from the áRE ;
thus the virus can suppress host cell
translation while leaving the translation of
its own RNA unaffected.
Fig.3 Picornaviruses also have a protease activity
that can cut one of the proteins of the initiation
complex, eáF4

 án the picornavirus RNA there is a region of
secondary structure called an internal ribosome
entry site (áRE )
` The fact that there is only one áRE
means that there is only one primary
translation product;
` that is there can only be one large protein
made.. This protein will eventually be cut
made
up to make several proteins in the mature
virus and thus we call this primary product
a polycistronic protein since it is encoded
by more than one gene (cistron).
` The proteases that cut up the original
polyprotein are encoded in the virus
genome and the proteolytic process is
ordered as shown in figure 4.
 Fig.4 The proteases that cut up the original
polyprotein are encoded in the virus genome and
the proteolytic process is ordered
` A single RNA can code for more than one
protein in eukaryotes but this is done by splicing
out parts of the original transcript to make
another mRNA that serves as a monocistronic
message.
` plicing enzymes that carry out this process are
found in the nucleus (since this is where mRNAs
are made).
` ince RNA viruses are normally cytoplasmic,
they cannot take advantage of splicing enzymes.
` Thus, RNA viruses that have only one mRNA
ought only to be able to make one large protein
- but they have developed a number of tricks to
overcome this (figure 5) and do, indeed, make
more than one protein.
` ome can take advantage of the
alternative splicing enzymes of the host
cells (and therefore must have a nuclear
stage).
` ithers make a single large protein which
has a protease activity; this cuts up the
large precursor to a series of smaller
proteins.
` ithers, such as the picornaviruses, have
found ways to make a single mRNA
function in a polycistronic fashion even
though they are in a eukaryotic cell.
Fig.5
` The kinetics of Picornavirus replication are
rapid, the cycle being completed in from
5-10 (typically 8) hours.
`
enomic RNA is translated directly by
polysomes, but ~30 min after infection,
cellular protein synthesis declines sharply,
almost to zero, this is called r-r -
the primary cause of c.p.e(cytopathogenic
effect):
Time after ánfection: Event:
harp decrease in cellular macromolecular synthesis;
~1--2h
~1 margination of chromatin (loss of homogeneous appearance
of nucleus)

tart of viral protein synthesis; vaculoation of cytoplasm,

~2.5--3h
~2.5
beginning close to nucleus & spreading outwards

Permeabilization of plasma membrane

~3-4h
~3-
~4--6h
~4 Virus assembly in cytoplasm (crystals sometimes visible)

~6--10h
~6 Cell lysis; release of virus particles

, &

` the virus can be assembled as the various

proteins are cleaved from the polyprotein.
` The polyprotein is first cleaved to three proteins
(P1, P2, P3).
` P1 is then cleaved into three proteins (VP0, VP1,
VP3) that make up the subunit of the virus coat.
coat.
` This is done by virus
virus--specified proteases that
are part of the polyprotein and are catalytic as
part of the single primary translation product.
` VP0, VP1 and VP3 assemble into the 5
structural subunit (protomer).
` VP0is only cleaved to VP2 and VP4 when the
virus has assembled.
` Five of these protomers assemble into a 14 pentamer
and twelve pentamers form the procapsid.
` RNA is encapsulated into the procapsid to form a
provirion. At this stage VP0 is cleaved to VP2 and VP4
and the virion is a mature, infectious virus particle.
` The other two parts of the primary translation product
(P2 and P3) are cleaved to form a number of non- non-
structural proteins (i.e. proteins that are not found in the
mature virus particle but which are used during
replication in the infected cell).
` These include the replicase and proteins that alter host
cell metabolism.
` VPg, the protein that is found at the end of each of the
positive sense genomic RNA molecules is formed from
part of P3.
` |!
` Release(in most cases) on the virus from
the cytoplasm occurs when the cell lyses -
probably a 'preprogrammed' event which
occurs a set time after the cessation of
'housekeeping' macromolecular synthesis
at shutoff.
` ámportant features of viruses that commonly
infect the intestinal tract are summarized in
Table below.
` Enteroviruses replicate optimally at 37l37lC,
whereas rhinoviruses grow better at 33l 33lC, in
accordance with the lower temperature of the
nose.
` Enteroviruses are stable under acid conditions
(pH 3-
3-5), which enables them to survive
exposure to gastric acid,
` whereas rhinoviruses are acid-
acid-labile. This
explains why rhinovirus infections are restricted
to the nose and throat.
 +Features of viruses commonly ánfecting the intestinal tract. diarrhea
+Features
Virus Nucleic Acid Disease Number of Lifelong Vaccine Antiviral Therapy
erotypes

Available
ámmunity
To disease

Poliovirus RNA Poliomyelitis 3 Yes (type-

(type-specific)

-
Echoviruses RNA Meningitis, etc Many No - -

Coxsackieviruses RNA Meningitis, carditis, Many No - -

etc

Hepatitis A virus RNA Hepatitis 1 Yes + -

(enterovirus 72)

Rotavirus RNA Diarrhea everal1 No -2 -

Norwalk virus RNA Diarrhea Unknown No - -

(Norovirus)

Adenovirus DNA Diarrhea 41; of which2cause Unknown - -

diarrhea
` án the previous table: 1 the exact
number is uncertain for the number of
hepatitis A serotypes.
` 2 Rotavirus vaccine was released but was
withdrawn because of side effects .

`
  |
|

-&

` Enteroviruses are spread via the fecal-

fecal-oral route.
The ingested viruses infect cells of the oro-
oro-
pharyngeal mucosa and lymphoid tissue (tonsils)
where they are replicated and shed into the
alimentary tract..
` From here they may pass further down the
gastrointestinal tract. Because of the acid
stability of these viruses they can pass into the
intestine and set up further infections in the
intestinal mucosa.
` The virus also infects the lymphoid tissue
(Peyer's patches) underlying the intestinal
mucosa.
` Atthese sites, the virus replicates and are
shed into the feces often for months after
the primary infection.
` án the primary viremic phase, the virus
also enters the bloodstream at low levels.
The tissues that are then infected depend
on the expression of the correct receptors.
` For example, CD155
CD155,, the polio virus
receptor, is expressed in spinal cord
anterior horn cells, dorsal root ganglia,
skeletal muscle, motor neurons and some
cells of the lymphoid system.
` Expression of CD155 within embryonic
structures giving rise to spinal cord
anterior horn motor neurons may explain
the restrictive host cell tropism of polio
virus for this cellular compartment of the
system.
central nervous system.
` The Coxsackie virus receptor (which also
binds adenovirus) is a surface protein with
two immunoglobulin-
immunoglobulin-like domains is more
widely expressed.
` At this stage symptoms may occur and the
patient may experience fever and malaise.
` A secondary viremia may occur at this time.
` The spread of the virus from the gastro-
gastro-
intestinal tract and the secondary viremia that
occurs about 10 days after the initial infection
leads to a humoral and cell-
cell-mediated immune
importance).
response (the latter being of less importance).
` This rapidly limits the further replication of the
virus in all tissues except the
á tract because
the virus must pass through extracellular space
to infect another cell.
` án the
á tract replication may be sustained for
several weeks even though a high titer of
neutralizing antibody is achieved.
` The cells in which this replication occurs
are not known and it is unclear why
replication occurs in the presence of the
neutralizing antibody.
` Although each group of enteroviruses
share a receptor, the various serotypes of
a group are usually not blocked by group-
group-
specific antibodies even though it would
be expected that they would have a
common receptor binding site.site.
 Human diseases caused by enteroviruses
./
 ./     
      0

#   yes yes yes yes yes



,* yes yes yes yes yes

# yes yes yes yes no

" no yes yes yes yes

. 

  no yes yes yes yes

#

,#  no yes yes yes no

 no no yes yes no
 * 1  *

` Pathogenesis of enteroviruses. Cox =

Coxsackie virus A or B, Hep A = hepatitis
A virus, Echo = echovirus, Polio =
poliovirus
 

 & |
|

` Most patients infected with an enterovirus

remain asymptomatic but in small children
benign fevers caused by unidentified
enteroviruses are relatively common (non-
(non-
specific febrile illness).
` Many outbreaks of febrile illness
accompanied by rashes are also caused by
enteroviruses.
 
|
` Poliovirus caused about 21, 000 cases of
paralytic poliomyelitis in the United tates each
year in the 1940's - 50's prior to the introduction
of the alk (inactivated) and abin (attenuated)
vaccines.
` The height of the epidemic occurred in 1950
when there were 34,000 cases. Today, the
number of cases of paralytic polio in the U is
fewer than 10 and these are the result of the
attenuated ( abin) vaccine reverting to virulence
(see Vaccine section).
` iur first record of polio comes from an Egyptian
stele from the 18th dynasty (1580-
(1580-1350 BCE)
showing a victim of the disease with a withered
leg (figure 6).
` Egyptian stele from the 18th dynasty showing a
victim of polio with a withered leg figure .
` Fig.6
  
`  !
- ánfection is limited to the primates (receptor?)

- Three serologic types are present

- CD155, the polio virus receptor, is expressed 0

 2 **2/ 2

   #  # 3

- For unknown reasons, polio virus does not spread to

the cells of the central nervous system in all patients
` This virus causes poliomyelitis.
` The host range is limited to primates
primates,, i.e., humans
and nonhuman primates such as apes and monkeys.
` This limitation is due to the binding of the viral
capsid protein to a receptor found only on primate
cell membranes.
` However, note that purified viral RNA (without the
capsid protein) can enter and replicate in many
nonprimate cellsƜ
cellsƜthe RNA can bypass the cell
"infectious RNA."
membrane receptor; i.e., it is "infectious RNA."
` There are three serologic (antigenic) types based on
different antigenic determinants on the outer capsid
proteins.
` Because there is little cross-
cross-reaction,
reaction, protection from
disease requires the presence of antibody against
each of the three types.
Primary site of infection is #   
associated with the oropharynx and gut (
ALT).
Virus production at this site leads to a  ,
following which the virus may infect the  .
This is of interest because of this apparent 'dual tropismƝ
of the virus for two distinct cell types - lymphoid/ epithelial
cell in the gut and neurons in the CN - different receptors, etc
.
Replication of the virus in the CN occurs in the 'grey matter',
particularly motor neurons in the anterior horns
of the spinal cord and brain stem. Distinctive 'plaques'
produced in the grey matter are due to lytic replication
of the virus & probably inflammation caused
by an over-enthusiastic immune response.
 |#
` ánteraction of the virus with its receptor
` Enters the cell, uncoating
` The genome RNA functions as mRNA
` Translated into one very large polypeptide
` viral RNA polymerase synthesized the progeny
RNA genomes
` Replication (+ve ssRNA::-
ssRNA::-ve ssRNA:: +ve ssRNA)

` Assembly occurs at the cytoplasm

` Release occurs by lysis of the cells
Life cycle
` Poliovirus infects human cells by binding to an
immunoglobulin--like receptor, CD155
immunoglobulin CD155,, (also known as
the poliovirus receptor (PVR)) on the cell surface.
` ánteraction of poliovirus and CD155 facilitates an
irreversible conformational change of the viral particle
necessary for viral entry.
` The precise mechanism poliovirus uses to enter the host
cell has not been firmly established. Attached to the host
cell membrane,
membrane, entry of the viral nucleic acid was
thought to occur by one of two ways:
` via the formation of a pore in the plasma membrane
through which the RNA is then Ơinjectedơ into the host
cell cytoplasm
cytoplasm,,
` or that the virus is taken up by receptor
receptor--mediated
endocytosis..
endocytosis
` Recent experimental evidence supports the latter
hypothesis and suggests that poliovirus binds to
CD155 and is taken up via endocytosis.
` ámmediately after internalization of the particle, the
viral RNA is released.
` Translation of the viral RNA occurs by an áRE -
mediated mechanism.
` Poliovirus is a positive stranded RNA virus.
virus. Thus the
genome enclosed within the viral particle can be used
as messenger RNA and immediately translated by the
host cell.
` in entry the virus hijacks the cell's translation
machinery; causing inhibition of cellular protein
synthesis in favor of virusƛ
virusƛspecific protein production.
` Unlike the host cell's mRNAs the 5' end of
poliovirus RNA is extremely longƜ
longƜover 700
nucleotidesƜ
nucleotides Ɯand is highly structured.
` The polio virus RNA comprises 7741 bases with
a large 5' leader sequence of 743 bases that
does not code for viral protein (untranslated
region).

` This region of the viral genome is called internal

ribosome entry site (áRE ) and it directs
translation of the viral RNA.
`
enetic mutations in this region prevent viral
protein production.
` Poliovirus mRNA is translated as one long
polypeptide called noncapsid viral protein 00.
00.
` This polypeptide is then cleaved by a virus
virus--encoded
protease to form both the capsid proteins of the
progeny virions and several noncapsid proteins,
proteins,
including the RNA polymerase that synthesizes the
progeny RNA genomes,approximately
genomes,approximately 10 individual viral
proteins, including:
` 3Dpol,, an RNA dependent RNA polymerase whose
3Dpol
function is to copy and multiply the viral RNA genome.
` 2Apro and 3Cpro/3CDpro
3Cpro/3CDpro,, proteases which cleave the
viral polypeptide.
` VPg (3B), a small protein that binds viral RNA and is
necessary for synthesis of viral positive and negative
strand RNA.
` 2BC, 2B, 2C, 3AB, 3A, 3B proteins which comprise the
protein complex needed for virus replication.
` VP0, VP1, VP2, VP3, VP4 proteins of the viral capsid.
` Replication of the genome occurs by synthesis of
a complementary negative strand, which then
serves as the template for the positive strands.

` ome of these positive strands function as

mRNA to make more viral proteins, and the
remainder become progeny virion gene RNA.

` The assembly of new virus particles, (i.e. the

packaging of progeny genome into a capsid
which can survive outside the host cell) is poorly
understood. Assembly of the progeny virions
occurs by coating of the genome RNA with
capsid proteins.
` Fully assembled poliovirus leaves the
confines of its host cell 4 to 6 hours
following initiation of infection in cultured
mammalian cells.
` Virions accumulate in the cell cytoplasm
and are released upon death of the cell.
They do not bud from the cell membrane.

` The mechanism of viral release from the

cell is unclear, but each dying cell can
release up to 10,000 polio virions
virions..
 irigin and serotypes
` Poliovirus is structurally similar to other human
(coxsackieviruses and echoviruses
enteroviruses (coxsackieviruses echoviruses),), as
well as to human rhinoviruses
rhinoviruses,, which also use
immunoglobulin--like molecules to recognize and enter
immunoglobulin
host cells.
` Phylogenetic analysis of the RNA and protein sequences
of poliovirus suggests that PV may have evolved from a
C-cluster coxsackie A virus ancestor
ancestor,, that arose through
a mutation within the capsid.
` The distinct speciation of poliovirus probably occurred
as a result of change in cellular receptor specificity from
intercellular adhesion molecule-
molecule-1 (áCAM-
(áCAM-1), used by C- C-
cluster coxsackie A viruses, to CD155
CD155;; leading to a
change in pathogenicity, and allowing the virus to infect
nervous tissue. There are three serotypes of poliovirus,
PV1,, PV2 , and PV3
PV1 PV3;; each with a slightly different capsid
protein.
` Capsid proteins define cellular receptor specificity and
virus antigenicity.
antigenicity.
  4
  *#
` Poliovirus is spread via the fecal-
fecal-oral route

` Most disease results from type 1 polio virus

` Poliovirus caused about 21, 000 cases of paralytic

poliomyelitis in the United tates each year in the
1940's - 50's

` Today, the number of cases of paralytic polio in

the U is fewer than 10 and these are the result of
the attenuated ( abin) vaccine reverting to
virulence
` @
is the most common form encountered in
nature, however all three forms are extremely
infectious.. Wild polioviruses can be found in
infectious
approximately
0 countries.
` @
is highly localized to regions in ándia,
@akistan, Afghanistan, and Egypt, but following
outbreaks of poliomeyletis in 2003ƛ
2003ƛ2004 it
remains widespread in West and Central Africa.
` Wild poliovirus type 2 has probably been
eradicated; it was last detected in ictober
999
in Uttar @radesh,
@radesh, ándia.
` Wild @ 3 is found in parts of only five countries
(Nigeria, Niger, @akistan, ándia, and udan).
` pecific strains of each serotype are used to
prepare vaccines against polio.
polio.
` ánactive polio vaccine (áPV) is prepared by
formalin inactivation of three wild, virulent
reference strains, Mahoney or Brunenders (PV1),
MEF--1/Lansing (PV2), and aukett/Leon (PV3).
MEF
iral polio vaccine (iPV) contains live attenuated
(weakened) strains of the three serotypes of
poliovirus.
` Passaging the virus strains in monkey kidney
epithelial cells introduces mutations in the viral
áRE , and hinders (or attenuates) the ability of
the virus to infect nervous tissue.
 *4 #
` Replicate 1st in oropharynx &
á

` Then, spread via blood to the CN

` The virus replicates in the motor neurons located in the

anterior horn of the spinal cord

` Paralysis occurs due to the death of these cells

` ámmunity is lifelong type

type--specific

` án infected individuals, the immune response consists of

both intestinal ágA and humoral ág
to the specific
serotype.
`  #  
` Poliovirus uses two key mechanisms to evade
the immune system.
system.
` First, it is capable of surviving the highly acidic
conditions of the gastrointestinal tract,
tract, allowing
the virus to infect the host and spread
throughout the body via the lymphatic system.
system.
` econd, because it can replicate very quickly,
the virus overwhelms the host organs before an
immune response can be mounted.
` ándividuals who are exposed to poliovirus, either
through infection or by immunization with polio
vaccine,, develop immunity
vaccine immunity..
` án immune individuals, antibodies against
poliovirus are present in the tonsils and
gastrointestinal tract (specifically ágA antibodies)
and are able to block poliovirus replication
replication;;
` ág
and ágM antibodies against poliovirus can
prevent the spread of the virus to motor
system.
neurons of the central nervous system.
` ánfection with one serotype of poliovirus does
not provide immunity against the other
serotypes, however second attacks within the
same individual are extremely rare.
  *
`
#  !
- This occurs when the replication of the virus is restricted
to the
á tract
- Asymptomatic infection is quite common. Roughly 1% of
infections are clinically apparent
- áP is 10-
10-14 days

`
" #0 3!

- is febrile disease and occurs in the first week of infection
- occurs in about 5% of infected individuals
- general malaise which may be accompanied by vomiting,
a headache and sore throat.
- Most patients recover spontaneously.
spontaneously.
  *+
`  # #!
- This is similar to aseptic meningitis with fever, headache &
a stiff neck .This also usually resolves spontaneously.
spontaneously.

` #!
- flaccid paralysis is the predominant finding
- Respiratory paralysis can occurs due to brain stem
involvment

`  #  !

- iccurs many years after the acute illness
- involves further loss of function in affected muscles perhaps
as a result of further neuron loss.
 Human poliovirus
` Viral particles seen by
` transmission electron
` microscopy (TEM) at a
` magnification of
350,000x).
` This image is from
Dennis
` Kunkel's excellent
` Microscopy cience
and
` Photography
Through a
` Microscope web
site.
 "#*

` ásolation of the virus

` Detection a rise in antibody titer

` Clinical spicemens include: throat swabs, stool or spinal

fluid by inoculation of cell cultures.

` The virus causes a cytopathic effect (CPE) and can be

identified by neutralization of the CPE with specific

antisera.
  4

` No antiviral therapy

` Prevented by vaccination using:

1- killed vaccine ( alk vaccine,
vaccine,
áPV))
inactivated vaccine, áPV
2- live attenuated vaccine ( abin
vaccine,, oral vaccine, iPV
vaccine iPV))
(current version of áPV is called enhanced
polio vaccine ƢeáPVƠ
ƢeáPVƠ))
 ./ 
` There are many infections caused by
Coxsackie viruses, most of which are never
diagnosed precisely
` Algonquin indian name of village in N.Y. where first
isolated (Daldorf and ickles/suckling mice/1948).
Two groups, based on pathology in suckling mice:
` Coxsackie type A usually is associated with
surface rashes (exanthems) 24 serotypes
` Type B typically causes internal symptoms
(pleurodynia, myocarditis) 6 serotypes
Both can also cause paralytic disease or mild
respiratory tract infection.
 ./ 
` ,*!
Enteroviruses are the major cause of viral
meningitis
- Both Coxsackie virus A and B can cause aseptic
meningitis
- Viral meningitis typically involves a headache, stiff
neck, fever and general malaise
- Most patients recover from the disease unless
encephalitis occurs
- The disease is most prevalent in the summer and fall
 ./ 
` -*!

- Coxsackie virus A can cause a fever with painful

ulcers on the palate and tongue leading to
problems swallowing and vomiting

- Treatment of the symptoms is all that is required

as the disease subsides in a few days.
days.
 ./ 
`   :
- 2    :
(HFMD)
- This is an exanthem (rash) caused by Coxsackie type
A16
- ymptoms include fever and blisters on the hands,
palate and feet.
- it subsides in a few days

` ,# !
- Type A and B can cause myocarditis in neonates and
young children
- Fever, chest pains, arrhythmia and even cardiac
failure can result
- Mortality rates are high.
high.
` "#*
` The diagnosis is made either by isolating the
virus in cell culture or suckling mice or by
observing a rise in titer of neutralizing
antibodies.
` A rapid (2.5 hour) PCR
PCR--based test for
enteroviral RNA in the spinal fluid is useful for
making a prompt diagnosis of viral meningitis
because culture techniques typically take days to
obtain a result.
`  4
` There is neither antiviral drug therapy nor a
vaccine available against these viruses. No
passive immunization is recommended.
  
` ECHi = enteric cytopathic human orphan

` Cause aseptic meningitis, URT, febrile illness,

infantile diarrhea & hemorrhagic conjunctivitis

` Transmitted by fecal-
fecal-oral route

` Diagnosed by isolation in cell culture

` No vaccine or antiviral available

 The structure of echoviruses is similar to that of
other enteroviruses.
More than 30 serotypes have been isolated.
` án contrast to coxsackieviruses, they are not
pathogenic for mice.
` Unlike polioviruses, they do not cause disease in
monkeys.
` They are transmitted by the fecal-
fecal-oral route and
occur worldwide.
` Pathogenesis is similar to that of the other
enteroviruses.
` Along with coxsackieviruses, echoviruses
are one of the leading causes of aseptic
(viral) meningitis.
` The diagnosis is made by isolation of the
virus in cell culture.
` erologic tests are of little value, because
there are a large number of serotypes and
antigen.
no common antigen.
` There is no antiviral therapy or vaccine
available.
   
` Acute hemorrhagic conjunctivitis is
caused by Coxsackie A24 and Enterovirus
70. The disease resolves in a week or two

` Enterovirus 71 is one of the leading

causes of viral CN disease,
disease, including
meningitis, encephalitis, & paralysis

` Enterovirus 72 is hepatitis A virus

 È
5r !
ince 1969, 'new' Enteroviruses have been
assigned numbers, not names:

Type: állness:
68 Pneumonia

69 None (?)

70 Acute haemorrhagic conjunctivitis

(1969--1974 pandemic)
(1969
71 Meningitis

72 Hepatitis A virus (now a separate

genus: Hepatovirus)
 |- 
|
` Rhinoviruses are the main cause of the common
cold (but not the only one!).

` There are more than 100 serotypes

` They are sensitive to low pH and replicate well

at 33 lC

` ánfect the URT & spread directly via aerosols or

by fomites such as hands and other forms of
direct contact
 |- 
|

` There are nearly 62 million cases of the
common cold annually in the U

` 52.2 million of these cases affect Americans

under age 17

` There are nearly 22 million school

school--loss days
annually due to the common cold

` There are approximately 45 million bed days

annually associated with the common cold
  *
` áP is 2-4 days
` ymptoms include discharging or blocked
nasal passages often accompanied by
sneezes, and perhaps a sore throat
` The illness lasts about 1 week
` other viruses cause symptoms that are
similar to those of rhinoviruses
(parainfluenzaviruses, coronaviruses and enteroviruses)
` They replicate better at 33
33llC than at 37l
37lC,
which explains why they affect primarily
the nose and conjunctiva rather than the
lower respiratory tract.
` Because they are acidacid--labile,
labile, they are
killed by gastric acid when swallowed.
` This explains why they do not infect the
gastrointestinal tract, unlike the
enteroviruses.
` The host range is limited to humans and
chimpanzees
`  #|#
` Replication is similar to that of poliovirus.
The cell surface receptor for rhinoviruses
is áCAM-
áCAM-1, an adhesion protein located on
the surface of many types of cells
 *4 #
` The portal of entry is the upper respiratory
tract, and the infection is limited to that
region.
` Rhinoviruses rarely cause lower
respiratory tract disease, probably
because they grow poorly at 37l 37lC.
` ámmunity is serotype-
serotype-specific and is a
function of nasal secretory *
rather
than humoral antibody.
antibody.
` "#*

` Diagnosis can be made by isolation of the virus from

nasal secretions in cell culture, but this is rarely
attempted. erologic tests are not done.
`  4

` No specific antiviral therapy is available.

` Vaccines appear impractical because of the large
number of serotypes.
` Paper tissues impregnated with a combination of citric
acid (which inactivates rhinoviruses) and sodium lauryl
sulfate (a detergent that inactivates enveloped viruses
such as influenza virus and respiratory syncytial virus)
limit transmission when used to remove viruses from
fingers contaminated with respiratory secretions.
`
` High doses of vitamin C have little ability to
prevent rhinovirus-
rhinovirus-induced colds.
` Lozenges containing zinc gluconate are available
for the treatment of the common cold, but their
efficacy remains unproved.
` But rehydration and keeping the airways
unblocked is advisable
` Prescription of aspirin to relive fever ??
` ánterferon nasal sprays have little effect
` The best way to avoid spreading the virus is
interrupt the infection chain by hand washing
Human rhinovirus 1A
` 14, as solved by cryo-
Rhinovirus 14, cryo-electron microscopy
and image reconstruction
` Molecular surface of Rhinovirus 14,
14, radially depth cued,
as solved by X-
X-ray crystallography
` Rhinovirus 14,
14, radially depth cued with antigenic sites
highlighted, as solved by X-
X-ray crystallography

This image is based of the real atomic co-

co-ordinates of

rhinovirus 14. The

antigenic
sites on the surface of
this
particle are highlighted
in purple. Note how
the distribution of
the antigenic sites
on the capsid
` emphasises its
` icosahedral symmetry.
`
` Rhinovirus 14 complexed with neutralizing antibodies, as
solved by cryo-
cryo-electron microscopy and image
reconstruction
` Rhinovirus 14 complexed with the áCAM
áCAM--1 receptor, as
solved by cryo-
cryo-electron microscopy and image
reconstruction
` No effective prophylaxis or treatment.
` There is little or no cross-
cross-protection
between serotypes.
` Protection relies on levels of secreted Ab
in URT - may be relatively short-
short-lived (e.g.
a few years rather than life-
life-long).
, 
! What's New With
Common Colds? Complications and
Management..
Management
 % 

|
` # / 

`    *!

r ** 
% * /
 

` 5 * #!

r 5/ 0 3
% - 
 5/ 0  3

`    

* 
`    "/
  "/ 02
r

3
` 6|
2 2
6|
2 2
 
` #
` |# " 
  
  4
  *#
`  0
0
 453

`   0* *3

`  "/ 22

 "/ 22
 

` 5  2

4 #*2
*
` There are many animal caliciviruses, but there
is no evidence that they cause human infection.
` ánfection is enhanced by several features of the
virus:
` low infectious dose,
` excretion of virus in the stool for several weeks
after recovery,
` and resistance to inactivation by chlorination and
to drying in the environment.
` át is thought to remain infectious for several
days on environmental surfaces such as door
handles.
 *4 #

`    

` '# '7"
'# '7"

` ,##  

`  #03

  *
`  
   *4 

` '5
'5 *  4
4" 
"  

 

`   '7"
  '7"

`  #

  4

` * # #"#

|

`    *

`   
   #8 

` #*

 

` This is the group of viruses responsible for

foot--and-
foot and-mouth disease (FMD) ƛ
` a major economic pest worldwide,
especially in .America and Australasia.
` Controlled largely by vaccination
(inactivated vaccine - occasional vaccine-
vaccine-
linked outbreaks)
` or slaughter of infected animals.
` They are physically quite distinct from
other Picornaviruses:
`
 " - below pH 7.0.
`
*# - 7 serotypes, (A; C; i;
AT1,2,3; Asia-
Asia-1),
` location of antigenic sites on capsid quite
different from Enteroviruses.
`   - Larger than other
Picornaviruses, ~ 8.5kb;
` 5' non-
non-translated region contains poly
poly--C
tract of ~100-
~100-170nt - function not known
(encapsidation?).
Foot--and-
Foot and-mouth disease virus i
` Molecular surface of Foot and Mouth Disease Virus,
radially depth cued, as solved by X-
X-ray crystallography
` The virus is found in breath, saliva, faeces,
urine, milk and semen of infected animals as
well as meat and by-by-products in which have
remained above pH 6.0.
` ánfection causes:
` Vesicles or blisters on the tongue, gums, cheek,
palate, lips, nostrils, muzzle, teats, udder, snout
and hooves.
` Pyrexia, anorexia, shivering, reduction in milk
production for 2-
2-3 days, grinding of the teeth,
drooling, lameness, stamping or kicking of the
feet.
` Death of young stock.
` Clinicallyindistinguishable from:
` Vesicular stomatitis (Rhabdovirus
(Rhabdovirus))
` wine vesicular disease (Enterovirus - very
similar to human coxsackievirus B5)
` Vesicular exanthema of swine (Calicivirus
(Calicivirus))
` Very similar to:
` Rinderpest (Paramyxovirus
(Paramyxovirus))
` ánfectious bovine rhinotracheitis
(Herpesvirus
Herpesvirus))
` Bluetongue (Reovirus
(Reovirus))
` Bovine viral diarrhoea (Flavivirus
(Flavivirus))
` Affects:
` Bovidae (cattle, zebus, domestic buffaloes, yaks), sheep,
goats, swine, all wild ruminants and pigs.
` Camelidae (camels, dromedaries, llamas, vicunas) have
low susceptibility.
` Horses may be carriers but do not become sick.

Virus is highly infectious and can persist in contaminated

fodder and the environment for up to 1 month,
month,
depending on the temperature and pH.
` FMD is one of the most contagious animal diseases.
Transmission occurs by:
` Direct or indirect contact (droplets)
` Animate vectors (humans, etc)
` ánanimate vectors (vehicles, implements)
` Airborne, especially temperate zones (up to 60 km
overland and 300 km by sea - e.g. 1967 UK outbreak
spread from France to ásle of Wight)
`     9
Yes - just:
Foot and mouth disease is a zoonosis, a disease
transmissible to humans, but it crosses the
species barrier with difficulty and with little
effect.
`
iven the high incidence of the disease in
animals, both in the past and in more recent
outbreaks worldwide, its occurrence in man is
rare so experience of the human infection is
limited.
` The last human case reported in Britain occurred
in 1966, during the last epidemic of foot and
mouth disease.
` The circumstances in which it does occur in
humans are not well defined, though all
reported cases have had close contact with
infected animals.
` There is one report from 1834 of three
veterinarians acquiring the disease from
deliberately drinking raw milk from infected
cows.
` There is no report of infection from pasteurised
milk, and the Food tandards Agency considers
that foot and mouth disease has no implications
for the human food chain.
` The type of virus most often isolated in humans
is type i followed by type C and rarely A.
` The incubation period in humans is 2-2-6 days.
` ymptoms have mostly been mild and self limiting,
mainly uncomfortable tingling blisters on the hands
but also fever, sore throat, and blisters on the feet
and in the mouth, including the tongue.
` Patients have usually recovered a week after the last
blister formation.
` Foot and mouth disease should not be confused with
the human disease hand, foot, and mouth disease.
This is an unrelated and usually mild viral infection,
principally of children, caused by different viruses,
principally coxsackie A virus. BMJ 322: 565-
565-566,
2001..The UK was finally declared oficially free from
2001
FMDV again in January 2002, 11 months after the
beginning of the outbreak.
outbreak.
  

` ine serotype.
` áncludes encephalomyocarditis virus (EMCV)
(model infection of mice), mengovirus,
` Maus--Elberfield virus,
Maus
` Columbia virus
` all considered to be strains of EMCV (really a
mouse virus, but can infect man, elephants,
squirrels...).
`
enome size ~7.8kb; 5' non-
non-translated region
contains poly-
poly-C tract of ~100-
~100-170nt (like
Apthoviruses).
Encephalomyocarditis virus

` Molecular surface of Mengovirus, radially depth cued, as

solved by X-
X-ray crystallography