ORGB 423 Lecture Notes - Lecture 2: Oral Rehydration Therapy, Giardia Lamblia, Astrovirus
MIMM466: Viral Pathogenesis
2018-01-08 LEC 2: Viral Diarrhea
Viral gastroenteritis
• Gastroenteritis: an acute infectious syndrome of the stomach lining and the intestine.
o Symptoms: diarrhea, vomiting, abdominal pain, nausea, fever and chills
o Causes: can be infection by:
§ Viruses: rotavirus, adenovirus, calicivirus, astrovirus
• Cause watery diarrhea
§ Bacteria: E. coli, salmonella, shigella and cholera
• Cause bloody or watery diarrhea (can breach intestinal wall)
§ Parasites: Giardia lamblia, Entamoeba histolytica and Cryptosporidium.
• Cause persisting diarrhea, hard to get rid of
o Transmission: highly contagious, oral-fecal route (contaminated water, food)
• Gastroenteritis is triggered either by the toxins secreted by microorganisms and lead to excessive loss of
water and electrolytes, or by direct invasion of the wall of the gut followed by inflammation
Toxin-induced diarrhea
E. coli
Cholera
• E coli stable toxin (Sta) binds to GCC receptor
protein, which enhances synthesis of cGMP (an
important second messenger)
• cGMP either directly activates chloride
channel (CFTR) or inhibit the sodium ion
channel through working on PKA kinase
o Result: More Cl pumped out, causing a
high level of chloride in the gut
• This causes the osmotic gradient to change and
water flows out of cells
• Toxin binding to GM1 receptor increases the
cAMP (not cGMP):
• Toxin gets internalized, and changes to the
active form (A1) in the ER
• It activates AC enzymes, which increases
cAMP
• This activates PKA which activates the Cl
channel and inhibits the Na channel
• Result: more Na and Cl in the gut, leasding to
water loss in cells
Annual Diarrheal Disease burden
• 2.3 billion have diarrheal illness, 1.3 million deaths annually
o 500,00 for children under 5 years of age, this number is second only to pneumonia
o 1 in 8 deaths of children due to diarrhea
o 90% occurs in Sub-saharan Africa and South Asia
• Mortality distribution: Rotavirus > typhoid = Shigella > ETEC > Cholera
Treatment
• Most diarrhea resolves without specific treatment
• Treatment goals are symptom reduction and prevention of dehydration
o Let GI tract settle by not eating for a few hours and get plenty of rest, gradually reintroduce food with
easy to digest options
o Drink small amounts of clear liquids, suck on ice
§ Children: use oral rehydration solution to replace fluids and electrolytes
o Avoid dairy, caffeine, alcohol until recovery is complete
• Prevention: wash hands
Acute gastroenteritis viruses
Rotavirus
Calcivirus
Adenovirus
Astrovirus
Leading cause among
children 3-15 months old,
also infects adults
Infects people of all ages,
most common cause,
Mainly infects children <2
years old, one of 49
gastrointestinal
adenoviruses
Primarily infects infants,
young children, the elderly
Rotavirus
General Information
• Belong to reoviridae, infects GI tracts
• History:
o Discovered by Ruth Bishop in 1973
o Name “rotavirus” suggested in 1974 by Thomas Flewett
o 1981, rotavirus grown in tissue culture
• Non-enveloped particles with icosahedral capsid (T=13), triple layered particle
o Has spiked surface
• Genome: 11 segments double-stranded RNA genome
o Each segment encodes only one gene
o Segments 9, 11 can produce 2 different versions of viral proteins
• Species A to H, rotavirus A causes > 90% of the infections
• Transmission: fecal-oral route
• Tissue tropism: infects small intestinal enterocytes
• Mainly infect infants and young children
o >500,000 children under 5 years of age die of rotavirus infection
o Mostly in developing countries
• Prevention & Treatment: vaccines and oral rehydration
segment
protein
location
function
1
VP1
Vertices of the core
RdRp
2
VP2
Inner shell of the
core
Stimulate RdRp
3
VP3
Vertices of the core
mRNA capping enzyme
4
VP4
Surface spike
Cell attachment
5
NSP1
Non-structural
Non-essential
6
VP6
Inner capsid
structural
7
NSP3
Non-structural
Shut-off cellular protein synthesis
8
NSP2
Non-structural
NTPase
9
VP7-1 VP7-2
Surface
structural
10
NSP4
Non-structural
enterotoxin
11
NSP5 and
NSP6
Non-structural
RNA binding
• VP = viral protein; structural protein found in viral particle
• NSP = non-structural protein; not in the viral particle, not directly involved in constructing virus
Serotypes of Rotavirus
• Serotypes are based on VP7 and VP4 (surface proteins) recognized by host immune system
o VP7: G types, VP4: P types
• 12 G types and 11 P types have been detected from infected children worldwide
• 5 GP combinations account for 95% of the disease cases:
o G1P[8], G2P[4], G3P[8], G4P[8],G9P[8].
Structure: 3 layers
• Outer layer: VP7 and VP4
• Intermediate: VP6