Chapter 4. Medical Important RNA Virus

Chapter 4
Medical important RNA virus
08/16/2022 Medical Virology by Alker A. 1

Dr.T.V.Rao 4
MD
4.1. Orthomyxoviridae
Influenza Virus
Historically Speaking
• Influenza can be traced as far back
as 400 BC
• In Hippocrates‟ Of the Epidemics,
he describes a cough outbreak that
occurred in 412 BC in modern- day
Turkey at the turn of the autumn
season
Dr.T.V.Rao 6
MD
Epidemiology
1918 Spanish Flu a great Memorable Event
• Mortality was greater than the 4-year “Black Death” Bubonic Plague
• Mortality rate was 2.5%, other epidemics had been 0.1%
• Unusually, most deaths associated with young, healthy adults
• Researchers isolated a wide selection of
bacteria – virus for influenza unknown
• Years later, H1NI strain found responsible for infection
• However, bacteria responsible for the severe secondary
complications of pneumonia causing death

Epidemiology
Circulating Seasonal Influenza A Sub-Types from Pandemics of the 20th
Century
1918/19 1957/58 1968/69

40-100 million deaths ~2 million deaths ~1 million deaths
H3N2 Seasonal Flu

H2N2
H1N1 Seasonal Flu H1N1 Seasonal Flu
1920 1940 1960 1980 2000
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4 pandemics since 1889, Medical
withVirology
11 to 39 years (average ~30 years)
by Alker A. 4
between each = ~3.3% annual risk of pandemic onset (but likely higher
Influenza Virus
• Virus are spherical in shape
• Size is 80 -120 nm
• Pleomorphism is common with variant forms
• - sense single stranded segmented genome (8)
• Helical symmetry

Viral structure
• The nucelocapsid is surrounded by an envelope with inner membrane
protein layer and outer lipid
• From the envelop there are projections of two types
1 Hem agglutinins
2 Neuraminidase

Prominent Characters of the Virus
Haemagglutination important character, when mixed with Fowl erythrocytes virus
absorbed onto mucoprotein receptors on the cell surface.
• Links other cells produce Haemagglutination
Elution Detachment of virus from cell surface resisting Haemagglutination is called

elution. Caused by enzyme neuraminidase
• Act on cell receptor splits off N Acetylneuraminiase

Dr.T.V.Rao 39
MD
Life cycle of the virus

Dr.T.V.Rao
MD
Transmission
• Aerosol
 100,000 to 1,000,000 virions per droplet
 18-72 Hrs incubation

• Shedding

WHO defines Influenza
• Influenza is a viral infection that affects mainly the nose,
throat, bronchi and, occasionally, lungs.
• Infection usually lasts for about a week, and is characterized
by sudden onset of high fever, aching muscles, headache and
severe malaise, non-productive cough, sore throat and
rhinitis.

Pathogenesis
 Infects the respiratory tract
 Even 3 or few viral particles can infect
 Neuraminidase facilitates infection reducing the viscosity of Mucous
 Ciliated cells are infected in the respiratory tract - site of viral infection
 When superficial layers are damaged exposes the basal layers and exposure of
the basal layer causes the bacterial infections.

Dr.T.V.Rao
MD
Symptoms
• Fever
•Headache
•Myalgia
•Cough
•Rhinitis
•Ocular symptoms

Dr.T.V.Rao
MD
Where do “new” HA and NA come from?

• Above 18 types HA and 11 types NA
 All circulate in birds
 Pigs
 Avian and human

Pandemics and Pandemic Threats of
the 20th Century
• 1918-19 “Spanish flu” H1N1 20-40 million deaths

• 1957 “Asian flu”
1-2 million deaths
• 1968 “Hong Kong flu” H2N2 700,000 deaths
• 1976 “Swine flu” episode H3N2 Mild Pandemic
• 1977 “Russian flu” H1N1 No pandemic
• 1997 “Bird flu” in HK H1N1
• 1999 “Bird flu” in HK H5N1
• 2003 “Bird flu” in Netherlands H9N2
H7N7
• 2004 “Bird flu” in SE Asia H5N1
Antigenic Variation
• Unique feature of this virus lies with antigenic variation.
• High in type A virus, less in type B virus, no in type C virus
• RNP and Matrix proteins are stable
• Haemagglutination and Neuraminidase are independent of the variations.
Influenza prominent Antigenic Changes
• Antigenic Shift major change, new subtype caused by exchange of gene
segments may result in pandemic
• Example of antigenic shift
 H2N2 virus circulated in 1957-1967
 H3N2 virus appeared in 1968 and completely replaced H2N2 virus
Influenza Antigenic Changes
• Antigenic Drift
 Minor change, same subtype
 Only type B undergoes antigenic drift
 Caused by point mutations in gene
 May result in epidemic
• Example of antigenic drift
 In 2002-2003, A/Panama/2007/99 (H3N2) virus was dominant
 A/Fujian/2002/411 (H3N2) appeared in late 2003 and caused widespread
illness in 2003-2004

Antigenic shift initiates
Pandemics

BIRD FLU
• Birds, just like people, get the flu.
• Bird flu viruses infect birds, including
chickens, other poultry and wild birds such
as ducks.
• Most bird flu viruses can only infect other
birds.
• However, bird flu can pose health risks to
people.

Immunity in Influenza
• After infection immunity lasts 1 to 2 years
• Immunity lasts short duration due antigenic

variants infecting at intervals.
• Antibodies produced locally are effective IgA

immunoglobulin.
• Anti Hemagglutinins and Antinerumanidase are

effective in prevention of infection.

Laboratory Diagnosis
i. Isolation of Virus
 In the first 2 -3 days from gargle samples
 Specimens inoculated into eggs, and Monkey kidney cells.
 Eggs are inoculated into Amniotic and Allantoic cavity Grows at 370 C in 3 days
 The virus causes Haemagglutination of Guinea pig and Fowl erythrocytes at 370
C
 Type A and B agglutinate guinea pig and fowl red cells
 Type C Hem agglutinates only Fowl cells
 Cytopathic effects on Monkey Kidney and Continuous cell lines

Laboratory Diagnosis…
ii. Serology
 Compliment fixation test
 Haemagglutination Inhibition testing
 Testing on paired sera
 Detection of Haemagglutination Inhibition testing
 Radial Immunodiffusion
 Immuno florescenc surface of Nasopharyngeal
cells
iii. Molecular method
 RNA detection by RT – PCR

Treatment
Tamiflu (oseltamivir) – inhibits the neuraminidase (Injectable

Peramivir has
and thus prevents the spread of the virus in the been
body approved
Tamiflu!
(oral)
Ralenza
(inhaled)
(Older
drugs)
08/16/2022 (Viral resistance to these is more
Medical Virology by Alker A. 24
Prevention
• Inactivated split/subunit vaccines are available against influenza A and B.
• The vaccine is normally trivalent, consisting of one A H3N2 strain, one A H1N1
strain, and one B strain.
• The strains used are reviewed by the WHO each year.
• The vaccine should be given to debilitated and elderly individuals who are at risk of
severe influenza infection.
• Oseltamivir can be used as an prophylaxis for those who are allergic to the vaccine or
during the period before the vaccine takes effect.
4.2.Paramyxovirus
Para influenza,Mumps,Measles
The Paramyxovirus include the most important agents of respiratory infections of infants and children
Parainfluenza viruses
Respiratory syncytial virus (RSV) and
As well as causative agents of two of the most contagious diseases of Child hood
 Mumps &
 Measles.
The WHO estimates that acute respiratory infections and pneumonia are responsible every
year world wide for the deaths of 4 million young children younger than 5 years of age.
• Paramyxovirus are respiratory pathogens of these age group.

i) Parainfluenza Virus
• ssRNA virus,linear,nonsegmented,negative sense, noninfectious enveloped,
pleomorphic morphology
• 5 serotypes: 1, 2, 3, 4a and 4b
• possess a neuraminidase and hemagglutinin.
• No common group antigen
• Closely related to Mumps virus
• Their mode of spread and pathogenesis is similar to that of the influenza
viruses.
• They differ from the influenza viruses
– RNA synthesis occurs in the cytoplasm rather than the nucleus.
– Not significant antigenic shift or drift does occur.
• In addition, the antigenic makeup of the four serotypes is relatively stable, and
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• Each serotype is considered
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ParaInfluenza Disease
• The para-influenza viruses are important because of the serious diseases they can
cause in infants and young children.
• Para-influenza 1 and 3 are particularly common in this regard.
• Overall, the group is thought to be responsible for 15 to 20% of all non-bacterial respiratory
diseases requiring hospitalization in infancy and childhood.
• Immunity to reinfection is transient; although repeated infections can occur in older
children and adults, they are usually milder than the illnesses of infancy and early
childhood.
Clinical Manifestation
• The onset of illness may be abrupt, as in acute spasmodic croup, but usually begins as a mild URI
with variable progression over 1 to 3 days to involvement of the middle or lower respiratory tract.
• Duration of acute illness can vary from 4 to 21 days but is usually 7 to 10 days.
Parainfluenza 1: is the major cause of acute croup (laryngotracheitis) in infants and young children.
• It also causes less severe diseases such as mild upper respiratory illness (URI), pharyngitis, and
tracheobronchitis in individuals of all ages.
• Outbreaks of infection tend to occur most frequently during the fall months.

Parainfluenza 2 : Croup is primary disease
 Parainfluenza 2 is of slightly less significance than Parainfluenza 1 or 3.
 It has been associated with croup, primarily in children, with mild URI, and occasionally
with acute lower respiratory disease.
 As with Parainfluenza 1, outbreaks usually occur during the fall months.
Parainfluenza 3: is a major cause of severe lower respiratory disease in infants and young
children.
 It often causes bronchitis, pneumonia, and croup in children less than 1 year of age.
 In older children and adults, it may cause URI or tracheobronchitis.
 Infections are common and can occur in any season; it is estimated that nearly one half of all
children have been exposed to this virus by 1 year of age.

Parainfluenza 4: mild upper respiratory illness only.
• Parainfluenza 4 is the least common of the group.
• It is generally associated with mild upper respiratory illness only
.
Main Clinical Manifestations

• Croup (laryngotraheobroncitis) most common manifestation of
parainfluenza virus infection.
• However other viruses may induce croup e.g. influenza and RSV.
• Other conditions that may be caused by parainfluenza viruses
include Bronchiolitis, Pneumonia, Flu-like tracheobronchitis, and
Corza-like illnesses.

• Detection of Antigen - a rapid diagnosis can be made by the detection of para-
influenza antigen from nasopharyngeal aspirates and throat washings.
Immunofluorescence or immunoenzyme assays can also be used for rapid detection of
antigen in respiratory epithelial cells.
• RT-PCR - a number of RT-PCR assays had been developed, including multiplex assays
for the detection of other respiratory viruses at the same time.
• Virus Isolation - virus may be readily isolated from nasopharyngeal aspirates and
throat swabs usually in monkey kidney cell cultures.
• Serology - a retrospective diagnosis may be made by serology. On serology using hem-
agglutination inhibition, complement fixation, or neutralization assays on paired sera
to detect a rising antibody titer.
Management: No specific antiviral chemotherapy and vaccine available. Severe

cases08/16/2022
of croup should be admitted to hospital
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ii) Mumps
• Mumps is an acute contagious disease characterized by non supportive enlargement
of one or both salivary glands.
• Mumps mostly causes childhood diseases, but in adults complication including
meningitis and Orchitis.
• More than one-third of infection are asymptomatic.
• Mumps virus is a Paramyxovirus and only one antigenic type is known.
• Single-stranded, negative-sense RNA with envelope.
• There are two glycoproteins on the surface of the envelope
 One mediates neuraminidase and hemagglutination activity
 The other is responsible for lipid membrane fusion to the host cell.

Mumps Infection
• Before an effective vaccine against mumps was developed, the disease was a
common childhood illness, commonly expressed as parotitis.
• It is also capable of causing
o Aseptic meningitis,
o Encephalitis, and (in adults)
o Acute orchitis.

Epidemiology
• The highest frequency of mumps infection is observed in the 5- to 15-year age group.
• Infection is rarely seen in the first year of life.
• Although about 85% of susceptible household contacts acquire infection, approximately
30 to 40% of these contacts do not develop clinical disease.
• The disease is communicable from approximately 7 days before until 9 days after onset of
illness
• However, virus has been recovered in urine for up to 14 days following onset.
• The highest incidence of infection is usually during the late winter and spring months,
but it can occur during any season.

Pathogenesis
• After initial entry into the respiratory tract, the virus replicates locally.
• Replication is followed by viremic dissemination to target tissues such as the salivary glands and central
nervous system (CNS).
• It is also possible that before development of immune responses, a secondary phase of viremia may result
from virus replication in target tissues (e.g, initial parotid involvement with later spread to other organs).
• Viruria is common, probably as a result of direct spread from the blood into the urine, as well as active
viral replication in the kidney.
• The tissue response is that of cell necrosis and inflammation, with predominantly mononuclear cell
infiltration.
• In the salivary glands, swelling and desquamation of necrotic epithelial lining cells, accompanied by
interstitial inflammation and edema, may be seen within dilated ducts.
Immune response
• As in most viral infections, the early antibody response is predominantly with IgM, which
is replaced gradually over several weeks by specific IgG antibody.
• The latter persists for a lifetime but can often be detected only by specific neutralization
assays.
• Immunity is associated with the presence of neutralizing antibody.
• The role of cellular immune responses is not clear, but they may contribute both to the
pathogenesis of the acute disease and to recovery from infection.
• After primary infection, immunity to reinfection is virtually always permanent.

• After an incubation period of 12 to 29 days (average, 16 to 18 days), the typical case is
characterized by
Fever and swelling with tenderness of the salivary glands,
The parotid glands.
• Swelling may be unilateral or bilateral and persists for 7 to 10 days.
• Several complications can occur, usually within 1 to 3 weeks of onset of illness.
• All appear to be a direct result of virus spread to other sites and illustrate the extensive
tissue tropism of mumps.

Clinical Manifestation…
Complications, which can occur without parotitis, include infection of the following:
• 1. Meninges: Approximately 10% of all infected patients develop meningitis.
 It is usually mild, but can be confused with bacterial meningitis.
 In about one third of these cases, associated or preceding evidence of parotitis is absent.
• 2. Encephalitis is occasionally severe.
• 3. Spinal cord and peripheral nerves: Transverse myelitis and polyneuritis are rare.
• 4. Pancreas: Pancreatitis is suggested by abdominal pain and vomiting.

Clinical Manifestation…
• 5. Testes: Orchitis is estimated to occur in 10 to 20% of infected men. Although

subsequent sterility is a concern, it appears that this outcome is quite rare.
• 6. Ovaries: Oophoritis is an unusual, usually benign inflammation of the
ovarian glands.
• Other rare and transient complications include myocarditis, nephritis, arthritis,
thyroiditis, thrombocytopenic purpura, mastitis, and pneumonia. Most
complications usually resolve without sequelae within 2 to 3 weeks.
• However, occasional permanent effects have been noted, particularly in cases of
severe CNS infection, in which sensor neural hearing loss and other impairment
can occur.

Cell Culture:
• Mumps virus can be readily isolated early in the illness from the saliva, pharynx, and other affected sites, such as
the cerebrospinal fluid (CSF).
• The urine is also an excellent source for virus isolation.
• Mumps virus grows well in primary monolayer cell cultures derived from monkey kidney, producing syncytial giant
cells and viral hemagglutinin.
Serology:
• Rapid diagnosis can be made by direct detection of viral antigen in pharyngeal cells or urine sediment.
• The usual serologic tests are enzyme immunoassay (EIA) and Indirect immunofluorescence to detect IgM- and IgG,
complement fixation, hemagglutination inhibition, and neutralization.
RT-PCR: RT-PCR is very sensitive technique that can be useful to detect Mumps virus infection.
Prevention by MMR vaccine
• No specific therapy is available. Since 1967, a live attenuated vaccine that is safe and highly effective
has been available.
• The vaccine is produced by serial propagation of virus in chick embryo cell cultures.
• It is commonly combined with measles and rubella vaccines (MMR) and given as a single injection at 12
to 15 months of age.
• A second dose of MMR is recommended at 4 to 6 years of age; those who have missed the second dose
should receive it no later than 11 to 12 years of age
• A single dose causes sero-conversion in more than 95% of recipients.
• Duration of immunity, especially if the two-dose regimen is followed, appears to be more than 25 years
and may be lifelong.
iii) Respiratory Syncytial Virus (RSV)
 Negative ssrna eveloped virus.
 Belong to the genus pneumovirus of the paramyxovirus family.
 Considerable strain variation exists, may be classified into subgroups a and b by monoclonal
sera.
 Both subgroups circulate in the community at any one time.
 Causes formation of syncytia (fused cells)
 Spread by hand contact and respiratory secretions
 Causes a sizable epidemic each year.

Clinical Manifestations
• Most common cause of
 Severe lower respiratory tract disease in infants,
 Responsible for 50-90% of bronchiolitis and
 5-40% of bronchopneumonia
• Other manifestations include croup (10% of all cases).
• In older children and adults, the symptoms are much milder:
• It may cause a corza-like illness or bronchitis.
• It also causes rhinitis, tonsillitis, laryngitis, bronchitis, and pneumonia vary in degree of severity

Infants at Risk of Severe Infection
1. Infants with congenital heart disease - infants who were hospitalized within the first
few days of life with congenital disease are particularly at risk.
2. Infants with underlying pulmonary disease - infants with underlying pulmonary
disease, especially bronchopulmonary dysplasia, are at risk of developing prolonged
infection with RSV.
3. Immunocompromized infants - children who are immunosuppressed or have a
congenital immunodeficiency disease may develop lower respiratory tract disease at any
age.

• Detection of Antigen - a rapid diagnosis can be made by the detection of RSV antigen
from nasopharyngeal aspirates. A rapid diagnosis is important because of the availability
of therapy
• RT-PCR - a number of RT-PCR assays had been developed, including multiplex assays
for the detection of other respiratory viruses at the same time.
• Virus Isolation - virus may be readily isolated from nasopharyngeal aspirates. However,
this will take several days.
• Serology - a retrospective diagnosis may be made by serology. CFT most widely used.

Treatment and Prevention
• Aerosolised ribavirin can be used for infants with severe infection, and for those at risk of
severe disease.
• There is no vaccine available.
• RSV immunoglobulin can be used to protect infants at risk of severe RSV disease.

iv) Measles
• Measles is an acute highly infectious disease characterized by fever,
respiratory symptoms and maculopapular rash
• Complication are common and may be quiet serious.
• The introduction of an effective live virus vaccine has dramatically reduced the
incidence of this diseases in USA.
• But Measles is still a leading cause of death of young children in many
countries.

Measles…
 Paramyxovirus family, genus Morbillivirus.
 Linear, negative-sense single-stranded RNA, which encodes at least six virion structural proteins
 Three are in the envelope, comprising a matrix (M) protein that plays a key role in viral assembly
and two types of glycoprotein projections (peplomers).
 One of the projections is a hemagglutinin (H),
 Mediates adsorption to cell surfaces;
 The Other (F) Mediates

 Cell fusion,
 Hemolysis, and
 Viral entry into the cell.
 No neuraminidase activity is present.

 Single serotype restricted to human infection is recognized
 The receptor for measles virus is CD46 (membrane cofactor protein), a regulator of complement
activation.
Pathogenesis
• Humans are the natural host for measles.
• The virus gain access to the body via respiratory tract and it multiplies in RT locally
• The infection then spread to the regional lymphoid tissue, where further multiplication occur
• Primary viremia disseminates the virus, which then replicates in the reticulo-endothelial
system
• Secondary viremia seeds the epithelial surface of the body, including skin, RT and
conjunctiva, where local replication occurs.
• Measles can replicate in certain lymphocytes which aids dissemination throughout the body.

Pathogenesis…
• Multinucleated giant cells with intranuclear inclusions are seen in lymphoid tissues through
out the body (lymph nodes, tonsils, appendix).
• The events occur during incubation period, which lasts 8-15 days but may last up to 3 weeks in
adults
• Patients are contagious during the prodromal phase (2-4 days) and the first 2-5 days of rash,
when virus is present in tears, nasal and throat secretion, urine and blood.
• The characteristic maculopapular rash appears about day 14 just as circulating antibodies
become detectable, the viremia disappears and the fever falls
• The rash develops as a results of interaction of immune T cells with virus infected cells in the
small blood vessels and lasts about 1 week.
• Common synonyms for measles include rubeola, 5-day measles, and hard measles.
• Incubation period - 7 to 18 days.

• A typical illness usually begins 9 to 11 days after exposure like cough, corza, conjunctivitis, and fever.
• One to three days after onset, pinpoint gray–white spots surrounded by erythema (grains-of-salt appearance)
appear on mucous membranes. This sign, called Koplik’s spots

Complication of Measles
Lymphadenopathy is common, with particularly noticeable involvement of the cervical nodes.
• Death can result from overwhelming viral infection of the host, with extensive involvement
of the respiratory tract and other viscera.
Subcute Sclerosing Panencephalitis (SSPE): is a progressive neurologic disease of children,
which usually begins 2 to 10 years after a measles infection.
• It is characterized by insidious onset of personality change, poor school performance,
progressive intellectual deterioration, development of myoclonic jerks (periodic muscle
spasms), and motor dysfunctions such as spasticity, tremors, loss of coordination, and ocular
abnormalities, including blindness.
Encephalitis
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Laboratory diagnosis
• The typical measles infection can often be diagnosed on the basis of clinical findings, but
laboratory confirmation is necessary.
Cell Culture :
• Virus isolation from the oropharynx or urine is usually most productive in the first 5 days
of illness.
• Measles grows on a variety of cell cultures, producing multinucleated giant cells similar
to those observed in infected host tissues.
Immunofluorescence :
• If rapid diagnosis is desired, measles antigen may be identified in urinary sediment or
pharyngeal cells by direct fluorescent antibody methods.
Serologic diagnosis: involve complement fixation, hemagglutination inhibition, EIA, or
indirect fluorescent antibody methods.

Treatment of Measles
• No specific therapy is available other than supportive measures and close observation for the
development of complications such as bacterial super-infection.
• Intravenous ribavirin has been suggested for patients with severe measles pneumonia, but no
controlled studies have been performed.
Prevention of Measles
• Live, attenuated measles vaccine is available and highly immunogenic, most commonly
administered as MMR.
• To ensure effective immunization, the vaccine should be administered to infants at 12 to 15
months of age with a second dose at 4 to 6 or 11 to 12 years of age.

V. Rubella
 Rubella virus is classified as a member of the togavirus family.
 It is enveloped and contains single-stranded, positive-sense RNA.
 The virus can agglutinate some types of red blood cells.
 Rubella is commonly known as German measles or 3-day measles
 Infections by rubella virus are often mild, or even asymptomatic.
Pathogenesis
• The major concerns are the profound effects on developing fetuses, resulting in
multiple congenital malformations.
• Mostly affect childbearing women through arthritis and rash due to mediation of
cellular immune responses and virus–antibody complexes

The mild sore throat and conjunctivitis, often just a gritty feeling in the eyes.
Fever is rarely high and the rash appears on the second or third day.
It consists of fine macules; papules are unusual, petechiae rare.
The macules coalesce to a generalized ‘blush’ in 1 or 2 days, and this fades
without desquamation in 3–5 days.
Lymphadenopathy commonly affects the neck, and suboccipital nodes may
be large and painful.
Arthralgia is common in young adults. It affects the small joints of the hands
and feet and occasionally large joints.
Laboratory diagnosis and treatment same to measles

4.3. Picornaviruses
Enteroviruses

Picornaviruses
 Pico – small , RNA – ribonucleic acid
Icosahedral
Nonenveloped viruses
Small - diameter 20-30 nm
Genome – single-stranded linear RNA
Coxsackievirus virions
RNA has positive polarity
5’ end of RNA has a protein that serves as a primer for
transcription by RNA polymerase

Classification
Family Genus Species
Picornaviridae Enteroviruses Poliovirus, Enterovirus,
Coxsackie,Echovirus
Hepatoviruses Hepatitis A
Rhinovirus Human Rhinovirus
Cardiovirus Encephalomyocarditis virus
Aphtovirus Hand foot and mouth virus O
Parechovirus Human parechovirus
Erbovirus Equine rhinitis B virus
Kobuvirus Aichivirus
Teschovirus Porcine teschovirus

Mode of Transmission of Picorna Virus
• Picornaviruses are widely prevalent.
• Enteroviruses are transmitted by the
• Fecal-oral route,
• Via salivary and
• Respiratory droplets and
In some cases via conjunctival secretions and skin lesion exudates
• Cockroaches and flies may be vectors.
• Rhinoviruses are transmitted by
 Saliva,
 Respiratory discharge, and
 Contaminated inanimate objects.
• Immunity is serotype specific.
4.3.1 Enterovirus
• Poliovirus - first identified in 1909 by inoculation of specimens into monkeys. The virus
was first grown in cell culture in 1949 which became the basis for vaccines.
• Coxsackieviruses - In 1948, a new group of agents were identified by inoculation into
newborn mice from two children with paralytic disease. These agents were named
coxsackieviruses after the town in New York State. Coxsackieviruses A and B were
identified on the basis of the histopathological changes they produced in Newborn mice
and their capacity to grow in cell cultures.
• Echoviruses - were later identified which produced cytopathic changes in cell culture and
was nonpathogenic for newborn mice and subhuman primates.
• New enterovirus (68 - 71) types more recently discovered enterovirus.

A) Poliovirus
• A highly contagious virus that causes the medical condition polio
(poliomyelitis) is a human enterovirus and member of the family
of Picornaviridae.
• Humans are the only susceptible hosts.
• Polioviruses are distributed globally.
• Before the availability of immunization, almost 100% of the
population in developing countries before the age of 5.
• Poliovirus was originally targeted for eradication by 2000. As of
Poliovirus remain endemic in only 3 countries: Afghanistan, Pakistan
and Nigeria
Poliovirus classification
• Group: Group IV (+) ssRNA)
• Order: Picornavirales
• Family: Picornaviridae
• Genus: Enterovirus
• Species: Human enterovirus C
• Scientific name: Poliovirus
• There are three serotypes of poliovirus, VP1, VP2, and VP3; each with a slightly
different capsid protein.
• Capsid proteins define cellular receptor specificity and virus antigenicity.
• PV1 is the most common form encountered in nature, however all three forms are
extremely infectious.

Poliovirus Structure
 Protein capsid.
 RNA genome.
 Single-stranded positive-sense.
 RNA genome that is about 7500 nucleotides long.
 The viral particle is about 30 nano metres in diameter with
icosahedral symmetry.
 Non-enveloped .

Poliovirus Replication cycle
 The virus first multiplies in tonsil, the lymph nodes of the neck, Peyer’ s
paches, and the small intestine.
 The central nervous system may be invaded by way of the circulating blood.
 Large amounts of anti-body are necessary to prevent passage of the virus
along nerve fiber.
• Poliovirus can spread along axons of peripheral nerves to the central
nervous system, along the fibers of the lower motor neurons to the spinal
cord or the brain.
• Virus invades certain types of nerve cell, and may damage or completely
destroy these cells for its intracellular multiplication.

Pathogenesis
• The incubation period is usually 7 - 14 days.
• Following ingestion, the virus multiplies in the oropharyngeal and intestinal mucosa.
• The lymphatic system, in particular the tonsils and the Peyer's patches of the ileum
are invaded and the virus enters the blood resulting in a transient viraemia.
• In a minority of cases, the virus may involve the CNS following dissemination.
Transmission
• Fecal – oral route, hands and objects, food and water

There are 3 possible outcomes of infection:
– Subclinical infection (90 - 95%) - inapparent subclinical infection account for the vast majority of
poliovirus infections.
– Abortive infection (4 - 8%) - a minor influenza-like illness occurs, recovery occurs within a few days
and the diagnosis can only be made by the laboratory. The minor illness may be accompanied by aseptic
meningitis
– Major illness (1 - 2%) - the major illness may present 2 - 3 days following the minor illness or without
any preceding minor illness.
 Signs of aseptic meningitis are common.
 Involvement of the anterior horn cells lead to flaccid paralysis.
 Involvement of the medulla may lead to respiratory paralysis and death.

• Most infections asymptomatic, 95%
• Abortive polio (minor illness), 5%: fever, malaise, sore throat, myalgia, headache)
• Aseptic meningitis (non-paralytic polio), 1%
• Paralytic polio (major illness), 0.1%:
 Asymmetric flaccid paralysis / paresis.
 Lower, or upper extremities, thoracic, abdominal, bulbar.
 Involvement : spinal cord anterior horn cells, motor cortex, dorsal root ganglia neurologic sequela (2/3)
• Post-polio syndrome: progressive atrophy years later

• Virus Isolation
– Poliovirus can be readily isolated from throat swabs, faeces, and rectal swabs. It is rarely isolated from
the CSF
– Can be readily grown and identified in cell culture
– Requires molecular techniques to differentiate between the wild type and the vaccine type.
• RT-PCR - a rapid diagnosis of poliovirus infection may be made by the use of RT-PCR.
• Serology - Very rarely used for diagnosis since cell culture is efficient. Occasionally used for
immune status screening for immunocompromised individuals.

Poliovirus prevention
No specific antiviral therapy is available. However the disease may be prevented through vaccination. There
are two vaccines available.
• Intramuscular Poliovirus Vaccine (IPV) ‘salk’
– consists of formalin inactivated virus of all 3 poliovirus serotypes.
– Produces serum antibodies only: does not induce local immunity and thus will not prevent local infection of the
gut.
– However, it will prevent paralytic poliomyelitis since viraemia is essential for the pathogenesis of the disease.
• Oral Poliovirus Vaccine (OPV) ‘sabin’
– Consists of live attenuated virus of all 3 serotypes.
– Produces local immunity through the induction of an IgA response as well as systemic immunity.
– Rarely causes paralytic poliomyelitis, around 1 in 3 million doses.
– The normal response rate to OPV is close to 100%.
– OPV is used for the WHO poliovirus eradication campaign.

B) Coxsackieviruses
• Coxsackie viruses are distinguished from other entero viruses by their pathogenicity for
suckling rather than adult mice.
They are divided into 2 groups on the basis of the lesions observed in suckling mice.
 Group A viruses produce a diffuse myositis with acute inflammation and necrosis of
fibers of voluntary muscles.
 Group B viruses produce focal areas of degeneration in the brain, necrosis in the
skeletal muscles, and inflammatory changes in the dorsal fat pads, the pancreas and
occasionally the myocardium.
• Each of the 23 group A and 6 group B coxsackieviruses have a type specific antigen.
• In addition, all from group B and one from group A (A9) share a group Ag.
• Cross-reactivities have also been demonstrated between several group A viruses but no
common group antigen has been found.
Coxsackieviruses pathogenesis
• Coxsackie viruses are characterized by their pathogenicity for suckling mice.
• They are classified by antibody neutralization tests as
 Coxsackie virus group A (A1 to A24) produces
Myositis in skeletal muscles and
 Generalized paralysis.
 Coxsackie virus group B (B1 to B6) produces
Focal muscle lesions,
Necrosis of fat pads between the shoulders,
Focal lesions in the brain, and
Spinal cord and spastic paralysis

Pathogenesis …
• Autopsies of neonates with generalized coxsackie virus
 B infection show focal myocarditis and inflammation.

 Fatal myocarditis in adults is also associated with focal necrosis.
• Findings in order of decreasing incidence include

 Meningoencephalitis,
 Hepatitis, and
 Pancreatitis.
• Fatal cases of encephalomyelitis show involvement of the motor neurons in the brain stem and spinal cord.
• Coxsackievirus B affects both white and gray matter.

• Most coxsackieviruses infections are in apparent or mild.
Group A most commonly cause rashes and vesicular lesions
Group B cause Pleurodynia and viral pericarditis / myocarditis
Group A24 variant causes epidemic and pandemic outbreaks of acute
hemorrhagic conjunctivitis.
• Occasionally, coxsackie viruses are associated with paralytic and encephalitic
diseases.

C) Echoviruses
• The first echoviruses were accidentally discovered in human faeces, unassociated with
human disease during epidemiological studies of polioviruses.
• The viruses were named echoviruses (enteric, cytopathic, human, orphan viruses).
• These viruses were produced CPE in cell cultures, but did not induce detectable
pathological lesions in suckling mice.
• Altogether, There are 32 echoviruses (types 1-34; echovirus 10 and 28 were found to be
other viruses and thus the numbers are unused)
• There is no group echovirus Ag but heterotypic cross-reactions occur between a few
pairs.

• Echoviruses, like coxsackie viruses, are associated with various disorders including
o Respiratory illnesses,
o Febrile illnesses with or without rash,
o Boston exanthema,
o Aseptic meningitis,
o Paralytic diseases, and occasional conjunctivitis .
• Echovirus type 3 was responsible for epidemics of wandering myoclonus in China that most commonly affected young adults.
• The prominent features are
• Migratory pains and
• Tenderness in the trunk and
• Musculatures of the limbs and
• Severe sweating.
• Mortality is high (12 to 33 percent).

D) New Enteroviruses
• Newly identified picornaviruses that are not polioviruses are no longer
classified separated into the species coxsackie and echovirus because of the
ambiguities presented by overlapping host range variations.
• 4 new enteroviruses have been identified (68 - 72).
• Enterovirus 70 is the causative agent epidemics of acute haemorrhagic
conjunctivitis that swept through Africa, Asia, India and Europe from 1969 to
1974.
• The virus is occasionally neurovirulent.

Enterovirus…
Enterovirus 71 appears to be highly pathogenic and has been associated
with epidemics of a variety of acute diseases, including
 Aseptic meningitis,
 Encephalitis,
 Paralytic poliomyelitis-like disease and
 Hand-foot-mouth disease.
• Enterovirus 72 was originally assigned to hepatitis A virus, but
it had now been assigned to a new family called heptoviruses.

Diseases caused by enteroviruses
Viruses Disease Symptoms
Polioviruses Poliomyelitis Paralysis
Coxsackie-viruses A Herpangina Fever, sore throat and tender vesicles in the
(CAV) oropharynx
Hand-foot-and- mouth Vesicular rash on the hands and feet and
disease ulceration in the mouth
Coxsackie-viruses B Pleurodynia Fever and severe pleuritic-type chest pain

(CBV)
Myocarditis, pericarditis Fever, chest pain, and signs of congestive failure
Both CAV and CBV Aseptic meningitis, mild paresis and transient paralysis. Upper
respiratory infections and minor febrile illness with or without rash.

Laboratory Diagnosis (Enterovirus, Coxsackie virus &
Echo viruses )
• Virus Isolation
 Mainstay of diagnosis of enterovirus infection
 Coxsackie B and Echoviruses can be readily grown in cell culture from throat
swabs, faeces, and rectal swabs, and also from the CSF
 Coxsackie A viruses cannot be easily isolated in cell culture.
• RT-PCR - PCR assays are becoming increasingly used for the detection and
identification of enteroviruses. They are especially useful in the case of Coxsackie A
viruses and also for the diagnosis of menigitis.
• Serology
– Very rarely used for diagnosis since cell culture is efficient.
– Neutralization tests or EIAs are used but are very cumbersome and thus not
offered by most diagnostic laboratories
4.3.2. RhinoVirus
• Rhinovirus are the common cold viruses.

• They are the most commonly recovered agents from people with mild upper
respiratory illness.
• They are usually isolated from nasal secretions.
• The viruses- as well Corona virus, Adeno viruses, Enteroviruses,
Parainfluenza viruses and Influenza viruses- cause upper respiratory tract
infections, including the common cold syndrome.
• Rhinoviruses are responsible for half of asthma exacerbations.

RhinoVirus Pathogenesis & Pathology
• The natural hosts of rhinoviruses are humans and chimpanzees.
• Rhinoviruses are present in the nose and pharynx
• The virus enter through the upper respiratory tract.
• High titer of virus can be obtained from nasal secretion after 2-4 days of
viral exposure- are associated with the maximum illness.
• Thereafter virus titer fall but illness persists.
• In some instance virus may detectable for 3 weeks.
• Replication is limited to surface epithelium of the nasal mucosa.
• Biopsies have shown that histopathological changes are limited to the sub-
mucosa and surface epithelium.
Pathogenesis & Pathology…
• Pathologic findings in the common cold consist of inflammatory changes with hyperemia,
edema, and inflammation of the columnar epithelial cells lining the nasopharynx.
• Desquamation of these infected cells coincides with the peak of virus spread.
• Regeneration is completed within a few weeks.
• Rhinovirus rarely cause infection of lower respiratory tract although they are associated
with the majority of the acute asthma
Mode of transmission
• Contaminated hands to nasal and
• Conjunctival mucosa is a more important mode of virus transmission than are
respiratory droplets and aerosols.

RhinoVirus Clinical Manifestation
• Rhinovirus infections are among the most prevalent of acute respiratory
illnesses in humans.
• More than 90 percent of susceptible individuals infected with rhinoviruses
succumb to the infection.
• Although most rhinovirus infections manifest as
Mild common colds with rhinorrhea,
Nasal obstruction,
Fever,
Sore throat,
Coughs, and hoarseness lasting for a few days,
Serious lower respiratory tract illnesses in infants are common.
RhinoVirus Clinical Manifestation…
• Secondary bacterial infections with Streptococcus pneumoniae and Haemophilus
influenzae may result in
 Sinusitis
 Otitis media,
 Bronchitis or
 Pneumonitis especially in children.
• The incubation period is a few days.
• Viral shedding begins several days after infection peaks shortly after the onset of
symptoms, and may persist for a few weeks.
• In the adult population, rhinovirus disorders create significant economic losses in terms
of lost working hours.
Treatment and control
• No specific prevention and treatment methods are available.
• The potential Rhinovirus vaccines are unlikely because they are difficult to grow in
culture, the fleeting immunity and multiplicity of the serotypes causing cold
• Antiviral drugs are under experimental control and many compounds are failed in vitro
drug test.
• A five days course of intranasal interferon-alfa has been shown to be effective the spread
of rhinoviruses from an index case within a family.
• It was not effective as therapy of established infections.

Chapter 4. Medical Important RNA Virus

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Chapter 4. Medical Important RNA Virus

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Chapter 4

Medical important RNA virus

08/16/2022 Medical Virology by Alker A. 1

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1918/19 1957/58 1968/69

H3N2 Seasonal Flu

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Elution Detachment of virus from cell surface resisting Haemagglutination is called

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Life cycle of the virus

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 18-72 Hrs incubation

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Where do “new” HA and NA come from?

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• 1918-19 “Spanish flu” H1N1 20-40 million deaths

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• After infection immunity lasts 1 to 2 years

• Immunity lasts short duration due antigenic

• Antibodies produced locally are effective IgA

• Anti Hemagglutinins and Antinerumanidase are

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Tamiflu (oseltamivir) – inhibits the neuraminidase (Injectable

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Main Clinical Manifestations

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Management: No specific antiviral chemotherapy and vaccine available. Severe

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• 5. Testes: Orchitis is estimated to occur in 10 to 20% of infected men. Although

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 Severe lower respiratory tract disease in infants,

 Responsible for 50-90% of bronchiolitis and

• In older children and adults, the symptoms are much milder:

• It may cause a corza-like illness or bronchitis.

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• There is no vaccine available.

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 The Other (F) Mediates

 Viral entry into the cell.

 No neuraminidase activity is present.

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• Incubation period - 7 to 18 days.

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