Enteric Viruses

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Enteric Viruses - General Background

Structure of Intestinal Epithelium

The intestinal epithelium is made up of small tower-like projections called villi. The space between these tower-like projections is called a crypt. There are many cells types in the intestinal epithelium:

Enterocyte: Cell that make up the majority of the intestinal epithelium.

Goblet Cell: Responsible for mucus production in the intestinal epithelium.

Enteroendocrine Cell: Responsible for hormone production in the intestinal epithelium.

Crypt Stem Cell: Cell from which mature intestinal epithelial cells are derived.

Paneth Cell: Highly secretory cell which is most recognisable for its antimicrobial properties, secreting α-defensins, angiogenin-4, lysozyme and secretory phospholipase A2.

Positive Sense Virus: Positive sense viruses have RNA like mRNA which can be immediately translated by the host cell

Negative Sense Virus: RNA is complementary to the mRNA and thus must be converted into mRNA (positive sense RNA) by an RNA polymerase before being translated by the host cell.

Types of Viruses in the Gut:

Double Stranded Segmented RNA Viruses:

Rotaviruses

Single Stranded Positive Sense RNA Viruses:

Enteroviruses

Caliciviruses

Orthohepeviruses

Astroviruses

Double Stranded DNA Viruses:

Adenoviruses

Single Stranded DNA Viruses

Parvoviruses

Double Stranded Circular DNA Viruses

Polyomaviruses

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Rotavirus

General:

Double stranded positive sense genus of the Reoviridae family

Highly prevalent in young children (under 2 y/o)

Of 3 million infants that die per year, rotaviruses are the main infective agent

Infection in adults is usually asymptomatic

As few as 10 virus particles can cause disease

Mechanism of Action:

Incubation period of 1-2 days before 4-7 days of disease

Enterocytes at the tip of the villi become infected causing breakdown and blunting, leaving behind immature/dysfunctional cells with a reduced absorptive ability

Lower absorption of sugar, salts and water leads to the accumulation of fluid within the intestinal lumen, culminating in diarrhoea and dehydration

Crypt stem cells repopulate the villi following infection (days 6-7 of the infection, generally)

The NSP4 (non-structural protein 4) viral enterotoxin mobilises intracellular calcium from the endoplasmic reticulum and was the first viral enterotoxin ever discovered. There are two form of the protein:

Integral Membrane Protein - facilitates the formation of the Rotavirus virion

Secreted Protein - the enterotoxin form

The NSP4 causes an increase in cytosolic calcium levels thus increasing the permeability of the cell membranes by disrupting tight junctions and opening Cl- channels, thus increasing the fluid transfer across the membrane (water into intestinal lumen)

NSP4 also acts as a viroporin, increasingly cell permeability to allow the replicated viruses to escape the host cell and infect other host cells.

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Norovirus

General:

Single stranded segmented positive sense genus of the caliciviridae family

The genus Norovirus has one species, which is called Norwalk virus

They are responsible for at least 95% of viral outbreaks and over 50% of all outbreaks worldwide

Transmission: Contaminated food or water, but also through person-to-person contact and exposure to fomites (clothing, utensils, etc).

Causes epidemic gastroenteritis (cruise ships,military barracks, hospitals, etc) as it is highly transmissable and thus hard to control outbreaks

Very stable in the environment and can survive some disinfectants

Only takes a small number of viral particles (as few as 20) to cause disease

Commonly found in shellfish

Incubation period of 1-2 days before a 1-2 day disease period

Infection is most common in older children and adults

Resistance:

Some people confer natural immunity to norovirus via a nonsense mutation (G428A) in the FUT2 gene, conferring immunity to the msot prominent norovirus serotype GII. 4.

Pathogenesis:

Causes blunting of the villi and shortening of the microvilli in the proximal intestine, leading to malabsorption and delayed gastric emptying (bringing about explosive diarrhoea)

Small changes to enterocytes occur but overall these cells remain intact, although some studies suggest that noroviruses may in fact bring about apoptosis of these cells.

Crypt cell hyperplasia also occurs, thus adding more mucous to the intestinal contents and causing the watery aspect of diarrhoea

Also causes inflammation within the lamina propria of the proximal intestine.

Vomiting is a symptom of norovirus - not yet known why although there are various hypotheses:

It has been hypothesized that the viral toxin of norovirus stimulates sensory entrochromaffin cells to release serotonin which activate's the brain's vomiting centre via the vagus nerve (CNX).

Also hypothesized is that Paneth cells directly control vomiting via the enteric nervous system.

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Poliovirus

General:

Poliovirus is a single-stranded, positive-sense RNA enterovirus (genus) of the picornaviridae family.

There are three poliovirus serotypes (P1, P2, and P3).

Incubation period is approximately 7-10 days

Poliovirus can cause serious damage e.g. if it spreads to the CNS it can result in paralysis

Transmission of poliovirus is faecal-oral

Disease it causes is poliomyelitis

Death of the motor neurons in the spinal cord, thus bringing about paralysis

Replication:

Poliovirus typically replicates in the oropharyngeal tonsils and the Peyer's patches (small masses of lymphatic tissue) of the ileum.

This causes viraemia which can then causes infection of the anterior horns of the spinal cord, which house the motor neurons of the spinal cord

Following this, infection of the meninges (leading to meningitis) or the brain (leading to encephalitis and paralysis in <1% of cases) can occur

Epidemiology:

Mainly still affects areas of Afghanistan and Pakistan (especially the mountainous regions)

Vaccination:

Salk Vaccine:

Introduced in 1955 containing poliovirus strains from each of the three serotypes that have all been inactivated using formalin.

Intramuscular administration

Generally given in 5 doses as part of the NHS vaccination schedule (4 between 8 weeks and 3 yrs 4 months and a booster at age 14)

Sabin Vaccine:

Introduced in 1961, containing low-virulence live attenuated strains of each of the three serotypes.

Monovalent (one serotype only)and bivalent vaccines of this type are also available for certain areas with high incidence of one poliovirus serotype.

Oral administration

More generally used for mass immunisation campaigns in low-income countries

Three doses generally for immunity but in some areas up to seven can be given

Vaccine Derived Polio Virus (VDPV) occurs in areas of low vaccine coverage, as the OPV strain(s) acquire the virulence and transmissibility of the wild type strain by genetic drift thus leading to outbreaks of infection.

These VDPVs are mainly found in African countries and are now a larger problem than the wild type strain itself (e.g. war in DRC meant that healthcare workers couldn't get into the country to give the vaccine, thus leading to a large outbreak)

Most cases of VDPVs are due to the P2 serotype of poliovirus

In OPV Type III, a single point mutation at nucleotide 472 causing a uracil to become a cytosine is associated with the development of VAPP.

Global Polio Eradication Initiative (GPEI):

Uses oral Polio vaccine combined with one dose of intramuscular polio vaccine (to reduce VDPVs)

GPEI Polio Endgame Strategy 2019-2023 aims to eradicate the condition entirely by the end of 2023

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Other Enteric Viruses

Hepatitis E:

Water-bourne single stranded RNA virus of Hepeviridae family which causes a typically self-limiting hepatitis.

Faecal-oral transmission

Different serotypes:

Resource-poor areas tend to be affected by genotypes 1 and 2

Areas with good sanitation standards are typically affected by genotype 3

HEV is the leading cause of enterically transmitted hepatitis globally

Parvoviruses:

Small icosahedral viruses with a Single Stranded DNA genome of ~5 kb

Infects animals and birds

Several cause serious disease e.g. canine parovirus and feline panleukopenia

The former causes severe gastroenteritis

They have very smaller genomes, only 8 kilo bases which encodes only 3 proteins

Adenoviruses

Double stranded DNA viruses

Replicate in upper resp tract or gut

Spread is either resp or orofaecal

Mainly subgroup F (types 40 and 41) which cause gastroenteritis

Army barracks tend to be primarily affected, no one really knows why