Gastroenteritis Viruses:

Rotaviruses,
Astroviruses,
Caliciviruses and others

Major viruses causing acute gastroenteritis/diarrhea

FAMILY GENUS TYPE SPECIES

Reoviridae Rotavirus Rotavirus A

Astroviridae Astrovirus Human octavirus 1

Caliciviridae Norovirus Norwalk virus
Adenoviridae Mastadenovirus Adenovirus serotypes 40/41

In addition, not sufficiently charaterized small round viruses

which can not be grown in cell cultures can also cause diarrhea.

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 REOVIRUSES/ROTAVIRUSES
Respiratory Enteric Orphan (REO) viruses: infect the
human respiratory and intestinal tracts, usually without disease
symptoms. Cell receptors include sialic acid and integrins. There
are 2 subfamilies and 15 genera. Reoviruses have demonstrated
oncolytic activities and reovirus-based therapies for cancer are
being developed (continuous replication of reovirus in cancer cells
with mutations in the Ras pathway, but not in normal cells, leads
to cancer cell death).
The virus: dsRNA genome with 10-12 segments.
Non-enveloped icosahedral capsid with double protein shell,
and particles have the appearance of a wheel with spikes.
Stable in the environment (resistant to hand-washing agents)
but susceptible to disinfection with 95% ethanol, lysol ,
formalin, and pH<2.

Rotavirus structure
Outer capsid: VP4 (P serotype)+VP7 (G serotype)
Inner capsid: VP6 (subgroup or species antigen)

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ROTAVIRUSES: major reoviruses pathogenic to Man
RotavirusWorldwide distribution and all children get
exposed to Rotaviruses by the age of 4-5 years.
Genome consists of 11 segments (segment 9 encodes 2 proteins)
coding for 6 structural proteins (VP1-4 and VP6-7) and 6
nonstructural proteins (NSP1-NSP6).
NSP1 blocks interferon response. NSP3 is responsible for
shutdown of cellular protein synthesis and NSP4 is the viral
enterotoxin inducing diarrhea.
Structural proteins: VP1 is the RNA Polymerase. VP2 forms the
core layer of the RNA. VP4 is on the virion surface (forming spikes),
is the cell attachment protein, and is cleaved by trypsin to VP5 and
VP8 enabling the virus to become infectious. VP6 is the inner capsid
protein used in identifying virus species. VP7 is the outer capsid
glycoprotein which together with VP4 determine the main serotype
groups (P or G) of roatvirus

Groups
ROTAVIRUSES
Based on antigenicity and electrophoretic mobility of RNA
segments, rotaviruses are divided into 8 groups AH.
Humans are mostly infected by groups A, B, and C. Group A is
the main human pathogen (90% of all rotavirus infections).
Groups E and H infect pigs whereas D, F, and G infect mainly
birds.
Group B (adult diarrhea rotavirus) causes outbreaks due to
sewage water contamination of drinkng water.
Group C infects children occasionally.
Serotypes and subgroups of group A Rotavirus
29 different serotypes are known; 15 based on Abs to VP4 (P
for protease-sensitive type); 14 based on Abs to VP7 (G for
glycoprotein type) and 5 of them, G1-G4 and G9,
predominantly affect humans.
Group A viruses have 2 subgroups defined by differences in
the antigenicity of VP6 (subgroup I and II).

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Rotavirus replication cycle: only triple-layered particles are
infectious to enterocytes in small intestine.
Vp2+VP6

Entry is mostly
by viropexis,

ROTAVIRUSES-Pathogenesis
Rotaviruses infect mature enterocytes lining the middle and upper
ends of intestinal villi. Site of infection is duodenum and jejunum.
Villous atrophy is seen due to death of mature enterocytes
(responsible for digestive and absorptive functions) and
infiltration of lamina propria with leukocytes. Subsequently, there
is repopulation of villous tips with immature secretory cells (crypt
hyperplasia) releasing chlorine ions into the intestinal lumen and
contributing to lactose intolerance. Restoration of functional
mucosa may take 3-8 weeks
Pathophysiologic effects include a decrease in absorptive surfaces
of small intestine and decreased production of enzymes
(disaccharidases and lactase) transient malabsorption state
with defective handling of fats and sugars (milk intolerance due
to lactase deficiency).

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 How do Rotaviruses cause diarrhea?
Virus Enterotoxin (NSP4) induces age- and calcium ion-
dependent chlorine secretion and disrupts SGLT1-mediated
water reabsorption leading to water outflow
Stimulation of the enteric nervous system (ENS)increased
net secretion over net absorption
Release of vasoactive agents from infected epithelium leads
to villous ischemia and functional damage to enterocytes
Increased intestinal motility, possibly by stimulating ENS

Transmission of Rotavirus
Fecal-oral route due to poor hygiene (billions of particles/gram
of feces); contaminated water supplies; contaminated food;
fomites

Clinical features
Incubation period is 1-3 days. Contagious period is
before onset and up to few days after end of diarrhea.
Illness is manifested by:
Vomiting, abdominal cramps, and low grade fever
followed by watery stools that usually do not contain
mucus, blood, or pus
Fever can be of high grade in 30% of patients
Diarrhea lasts 3-9 days (longer in malnourished or
immunocompromised hosts)
Necrotizing enterocolitis and haemorrhagic
gastroenteritis are seen in neonates
Dehydration is the main contributor to mortality in
young children
Secondary malabsorption of lactose and fat, and chronic
diarrhea is seen in some cases

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 Diagnosis ROTAVIRUSES
Virus or Ag detection in stools by ELISA or by latex
agglutination (commercial kits are available). This detects only
group A rotavirus serotypes.
EM or RT-PCR can also detect non-group A viruses.
Treatment
No antivirals; management of symptoms/hospitalization
Supportive treatment is needed: rehydration (oral /i.v. fluids
and electrolytes replacement); Administration of probiotics
(Lactobacillus or Saccharomyces) were found to reduce
duration of diarrhea; antimotility drug Immodium; antiemetic
drug Zofran; Zn supplements.
Immune response and correlates of protection
After primary infection, a serotype-specific Ab response is
elicited and gives partial protection against subsequent
infections, even by other serotypes. sIgA in intestinal tract is
necessary for recovery.
Breast milk sIgA and mucin glycoproteins (bind rotavirus and
inhibit replication) confer protection in young infants.

ROTAVIRUSES
Prevention of spread
Hand-washing with good technique (Lysol)
Disinfection of surfaces, toilets, toys
Improved hygiene and adequate disposal of enteric excretions
Breast feeding helps to provide immunity in newborn
Vaccine (excellent protection)
An oral live attenuated vaccine Rotashield , made of 4
serotypes G1-G4, was licensed in 1998 for infants and was later
withdrawn due to occurrence of intussusception (blockage of
intestine) 3-20 days after first dose (15 cases /1.5 million doses).
Replaced by Rotateq in 2006: a live reassrotant oral vaccine
(5 strains G1-G4 plus 1 expressing bovine VP4) given as liquid
suspension in a series of 3 doses: 6-12 weeks, 16-22 weeks and
26-32 weeks. Very high efficacy and safety. Used in the USA
Rotarix, made of 1 live attenuated strain (G1-P8), is given
orally in 2 doses at 6 weeks of age and then at 20-24 weeks.
Used in south America and some European countries.

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 ROTAVIRUS-Epidemiology
Worldwide distribution with up to 2 million hospitaizations
and 450 000 deaths/year (200 000 in children <5 years)
Outbreaks are common among infants/young children (1-24
months) or among the elderly. Reinfection can occur at all ages
but older children and adults are generally more immune.
Infection at < 6 months and > 5 years gives a certain degree of
protection against diarrhoea whereas older infants and young
children (6 months-5 years) tend to be more symptomatic.
In temperate 1st world
populations, rotavirus is
main cause of winter
gastroenteritis whereas in
tropical and developing
countries, disease occurs
all year round with peaks
in summer

VIRAL GASTROENTERITIS-Astroviridae
Astroviruses (star-shaped viruses)
Described in relation to an outbreak of gastroenteritis in 1975
and was identified by EM. It can now be propagated in a
continuous line of colon carcinoma improved diagnosis
(+) sense ssRNA genome, non-enveloped, icosahedral capsid.
Seven human serotypes are known with serotype 1 being most
frequently observed (serotypes 2-4 are common and serotypes
5-7 are infrequent). Site of infection is the small intestine.
Astroviruses cause diarrhea, headache, nausea, low-grade
fever, and vomiting (less common). Symptoms are often milder
than those observed with rotaviruses. May cause encephalitis
in immunodeficient patients (X-linked agammaglobulinemia)
and disseminated lethal infection in immunocompromised
pediatric patients (SCID receiving allogeneic BM transplants)

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 Astroviruses
Worldwide distribution, mainly in children < 7 years of age.
Accounts for 2-8 % of cases of diarrhea in children.
Transmission from person to person by faecal-oral route
Outbreaks, due to fecal contamination of sea food or water,
occur in schools and nursing homes for the elderly.
Astroviruses are acid-stable, heat-resistant for short periods,
and resistant to a range of detergents and lipid solvents
Diagnosis by ELISA which can detect all 7 serotypes. Recently,
type-specific RT-PCR has become available.
Treatment is symptomatic; no antiviral drugs; no vaccine
Prevention during outbreaks consists of measures to interrupt
person-to-person spread by good hygiene, disinfection, and
surveillance of food sources.

Caliciviruses
Described in 1968 following an outbreak in Ohio
Non-enveloped, (+) sense ssRNA, NS, and icosahedral capsid.
The family Caliciviridae has 2 genera: Norovirus (round
particles) and Sapovirus (star-shaped particles). Infectivity
persists after exposure to acid, ether, and heat (60 C for 30
minutes). These viruses have not been propagated in culture.
Norovirus genus has one species, Norwalk virus, with 5
genogroups each containing several genotypes, serotypes and
strains. Genogroups I, II, and IV (to a lesser extent) commonly
infect humans.
Norwalk viruses are named after the place where they were
first isolated: Norwalk, Hawaii, Snow Mountain, Mexico,
Lordsdale, Wilkinson, Toronto, Otofuke, and Sapporo.
Worldwide distribution, outrbreaks in infants and school-aged
children. Viral excretion in stool can continue beyond the
cessation of symptoms and Noroviruses are common cause of
gastroenteritis in older children and adults (unlike rotaviruses)

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 NOROVIRUSES
Virus genome is translated into one polypeptide chain that is
cleaved into 6 nonstructural proteins and 2 capsid proteins: VP1,
a major capsid protein and VP2, a minor one with carbohydrate-
receptor binding regions.
Noroviruses affect around 270 million people and cause 200,000
deaths every year, mostly in developing countries, affecting the
very young, elderly, and immunosuppressed subjects.
Transmission by fecal-oral route, person-to-person contact, and
by aerosols (breathing air near area of vomiting, even if cleaned
up). Outbreaks have been associated with consumption of
contaminated water, uncooked shellfish and other food (salads).
Noroviruses can survive on several surfaces used for food
preparation 7 days after contamination. On contaminated
carpets, noroviruses can survive for 12 days. Can be inactivated
by sufficient heating or by chlorine-based disinfectants.

Norwalk virus
Winter vomiting disease 1968, Norwalk
OH. Causes 90% of nonbacterial explosive
epidemics in camps, cruise ships, and
nursing homes due to ingestion of raw
shellfish and salads.
Adults and children are affected; site of
infection is the jejunum; relatively
short incubation period (< 24 hr-48 hr).
Vomiting is prominent with diarrhea,
anorexia, and abdominal pain for 1-3 days;
symptoms are less severe than with rotavirus
gastroenteritis.
Complications are rare (lethargy, myalgia,
fever, and dehydration) and mostly seen in
the very young, in the elderly and in
immunocompromised subjects.

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Noroviruses
Interaction of Noroviruses with human histo-blood group
antigens (HBGA) expressed in epithelial tissues plays an
important role in infection. Individuals with mutation in fucosyl
transferase II (FUT-II) do not express the ABH antigens in gut
epithelial cells and are not infected with most Noroviruses.
Moreover, people with different ABH phenotypes are susceptible
to Norovirus infections in a genotype-specific manner. Global
epidemics are caused by strains of genogroup II/genotype 4 since
these can bind to more HBGA antigens than other genogroups.

Diagnosis by EIA and RT-PCR (can detect 10 virus particles).

No anti-viral treament available and management is by fluid and
electrolyte replacement. Prevention is by good hygienic measures.
With the use of vaccines against Rotaviruses, Noroviruses have
become the main cause of acute gastroenteritis in children.

Adenoviruses
A limited number of strains of adenovirus have been
usually related to childhood diarrhea
Adenovirus serotypes implicated in gastroenteritis are
40, 41, 31, and 52
Incubation period is 8-10 days; site of infection is the
small intestine
Diarrhoea lasts 5-12 days, prolonged diarrhea often
seen with serotype 40
Diagnosis by latex agglutination, ELISA, EM
Diagnosis of 40/41 strains is now done by PCR

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 Gastrointestinal viruses that are not regularly associated
with acute diarrhoeal disease
Enteroviruses: some echoviruses and coxsackie virus A1 have
been documented in outbreaks of diarrhoea (not consistently)
Coronaviruses: associated with cases of neonatal diarrhea and
of more severe necrotizing enterocolitis
HIV: evidence for primary HIV infection in gut-associated
lymphoid tissues and in enterocytes enteropathy with
chronic diarrhoea in AIDS patients
Cytomegalovirus and herpes simplex virus: co-infection
observed in gut of HIV-infected patients leading to chronic
colitis
Picobirnaviruses: recent family of Birnaviridae; bisegmented
RNA viruses with icosahedral structure. Associated with cases
of diarrhoea specially in AIDS patients.

Cytomegalovirus colitis

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