BmedSc 2504

Lecture 25

References
Viral Gastroenteritis
BMED2804 - U4L13 - 25/4/05
Prescott, Harley & Klein ‘Microbiology’
Professor Peter Reeves Ditto, 6th ed. – Ch 18 and Ch 38 pp868-869 pp

School of Molecular and Microbial Biosciences White and Fenner ‘ Medical Virology edn 4 p138, 524 (rotaviruses),
p407 (Caliciviruses).
Rm 502,
Ph: 9351 2536
Email: reeves@angis.usyd.edu.au

1 2

Nature of virus infections (this will be covered in detail in

Viral infections of the human intestine
semester 2)
There are many viruses found in the intestine but most
All virus infections involve:
infections with significant impact on the intestine itself are:
Adsorption of virus to a cell receptor
Rotavirus
Adenovirus
Entry of the virus particle (virion) into the cell
Calicivirus incl Norwalk virus
Astroviruses
Replication of the virus nucleic acid
Others such as poliovirus and some hepatitis viruses move on
Assembly of complete virus particles (virions)
to a systemic infection and are not considered here.
Release of virus

3 4

Nature of virus infections - 2

(this will be covered in detail in semester 2) Examples of virus infection are
given in Prescott, from
Viruses are not organisms, and can only function as part of a cell. adsorption of virion to release
However on infection virus determined activities often come to of new virions. Each involves
dominate. the steps identified in slide 3

In general viruses lack toxins, with rota virus discussed below being the Prescott Figure l8.7 Simplified
major exception. Life Cycle of Influenza Virus.

Viruses are the agents for many major diseases, but the effects on the Abbreviations: PB 1, RNA
host seem to be entirely due to the effects of killing or weakening host polymerase; NP,' nucleocapsid
cells, the symptoms depending on the cells involved. However this view protein; HA, hemagglutinin;
may change with further research. and NA, neuraminidase.

Because viruses are so closely associated with host cells, antiviral agents
are few and often not available for a given disease. However many
infections are self limiting due to immune response and vaccines can 5 be 6

developed.

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Lecture 25

Prescott Figure 18.5 Impact of virus infections on the intestine.

Generalized Life Cycle for
Herpes Simplex Virus Type 1.
A second example, this time of
a DNA virus
Those viruses that infect the intestine and cause diarrhea or
other symptoms are said to cause gastroenteritis. There is
often abdominal pain and diarrhoea and sometimes vomiting.
The infection involves invasions of epithelial cells, as viruses
have no effect until cell invasion as their virion structures do
not include toxins. This invasion may cause cell death or loss
of function, and this is thought to be the major cause of
symptoms, but the connection between cell invasion and the
symptoms is not well understood, although a lot is known
about viral replication etc.

We do not have the same understanding of the effect on gut

function as we do of many bacterial infections involving
7 toxins of known function. 8

Rotavirus Rotavirus structure

We look first at rotavirus. Like all viruses rotavirus has a defined virion structure with a
protein coat and nucleic acid ‘genome’
Rotavirus is the most important cause of human diarrhoea
throughout the world. Rotavirus have a double strand RNA genome consisting of
11 DS RNA molecules
Is equally prevalent in high and low hygiene countries,
indicating very effective transmission. The coat is icosohedral in shape with a “diameter” of about
7O nm
Rotavirus infect many other species with similar life cycle,
but are generally host specific. The coat has 3 “layers” to its structure but no membrane
envelope as found in many other viruses.
In humans rotavirus generally infects in first few years of
life, with peak for clinical illness at 12 months.
9 10

Rotavirus structure - 2

The major structural proteins (VPs) are visible in figure 8 from van
Regenmorten.

Virus Protein 2 (VP2) forms the inner core that bounds the 11 DS RNA
molecules.

The middle layer is comprised of VP6.

The outer layer comprises VP4 and VP7 which are exposed.

VP4 forms a spike which is cleaved by proteases to give VP5* and Prescott Figure 38.20. Rotavirus.
VP8*.
Electron micrograph of rotaviruses in a human gastroenteritis stool
VP4 is involved in attachment but the cleavage does not seem to be filtrate (X 90,000). Note the spoke-like appearance of the icosahedral
needed for attachment itself. 11 capsids that surround double-stranded RNA within each virion. 12

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Lecture 25

Rotavirus symptoms and spread

Clinical illness has a rapid onset and symptoms include

vomiting, diarrhoea and dehydration, but rarely fatal if
treated by oral rehydration. Nonetheless is major cause of
infant death in some countries.

However infections often lack symptoms, but infection is

inferred from the near universal presence of antibodies from
about 3 years of age.

Virus particles can be 1010 per ml. and transmission is faecal

Left, Cutaway view of mature particle of rotavirus illustrating the triple-
oral route. However the rate of transmission is so high that in
layered capsid structure.
all countries most people get infected in early childhood,
Right, Cutaway view of the transcriptionally-competent double layered
suggesting that it may also be spread by aerosols – perhaps
particle at 19 A.
From Fig 8 of van Regenmortel et al. (2000) “Virus taxonomy”
from the throat – but no good data.
13 14

Rotavirus NSP4

Some viral proteins are not part of the virion structure, and are referred
to as non-structural proteins (NSPs).

NSPs function within the infected cell. Some are enzymes concerned
with replication of DS RNA for example

Of interest to us is NSP4, which is a toxin and the first virus toxin to be

described. Indeed to my knowledge the only viral toxin described thus
far. It plays a role in causing diarrhoea but unlike the Cholera and coli
toxins we discussed earlier, is produced inside the host cell and also has
Effect of rotavirus on mucosal epithelia a role in virion assembly.

E and G (right) are respectively rabbit ileal mucosa and jejunal-ileal NSP4 can induce diarrhoea in mice after intraperitoneal injection but
mucosa from rabbits infected with rabbit rotavirus. details of mode of action not understood.
D and F (left) are equivalent sections from uninfected rabbits 15 16
From Ciaret et al (1998) Virology 251:343

Rotavirus vaccine
Rotavirus vaccine - 2
There is a long recognized need for a rotavirus vaccine but they have
only recently been developed after many years of work.
The tetravalent RotaShield vaccine had passed all of its trials, being
effective and no side effects detected.
The first to be released (1998) was a RotaShield, a reassortment virus
based on a rhesus monkey rotavirus with human VP7 genes.
However once in full scale use an unexpected side effect appeared.
The VP7 gene from three of the four human serotypes was incorporated
A small proportion of vaccinees suffered intussusception, a rare event in
into the rhesus rotavirus, making three single-gene human-rhesus
which there is an infolding of one part of the intestine into another. This
reassortants.
causes serious blockage and must be treated if it does not reverse.
The VP7 gene present in the native rhesus rotavirus strain provides
Because of this the vaccine was withdrawn in 1999, and new vaccines
immunity to the fourth human serotype.
are now being introduced.
Using a combination of the native rhesus rotavirus and the three
The phenomenon is an indication of the effect of rotavirus damage on
reassortant strains, the tetravalent RotaShield aimed to protect against
the intestine, although in this case not a typical human virus.
all four significant human rotavirus serotypes. 17 18

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Lecture 25

Caliciviruses in gastroenteritis
Caliciviruses in gastroenteritis - 2
Rotavirus was discovered, in Australia, only in 1973, and likewise
Caliciviruses were only recognised as a cause of human diarrhoea in
Calicivirus including Norwalk virus and Norwalk-like (Norovirus)
1972, whereas Vibrio cholerae and Shigella dysenteriae were identified
infections can occur in children or adults and thus differ from the usual
over 100 years ago.
rotavirus infection.
The discovery related to an outbreak in Norwalk Ohio and this particular
It is often an infection of institutions such as aged care facilities or
calicivirus virus is known as Norwalk virus and similar viruses are
spread by food handlers and associated with restaurants.
known as Norwalk- like viruses (or Noroviruses).
It does not have the high efficiency of transmission found in rotavirus
Caliciviruses are a significant cause of gastroenteritis but as little detail
so only found in ‘favorable’ situations
is known of the of pathogenesis let us just note that again it is the tips of
the villi that are affected White and Fenner).

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The microbial flora of the alimentary 4