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4. paramyxoviruse virus

The paramyxoviruses include the most important agents of respiratory infections of infants and

young children as well as the causative agents of two of the most common contagious diseases of

childhood (mumps and measles).

Characters

Large enveloped viruses (150-300 nm)

Negative sense linear non-segmented RNA

Contain 2 types of glycoprotein spikes which are responsible for the attachment and fusion of the

virus to the host cell:

Haemagglutinin-neuraminidase spikes (HN}

Fusion spikes (F)(Figure 2-33)

Classification

1.Parainfluenza viruses 1, 2, 3 and 4.

2.Mumps virus

3.Measles

4.Respiratory syncytial virus

Figure (2-33) Structure of paramyxovirus

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Four types of Parainfluenza viruses :

TYPE 1,2,& 3 are particularly considered major pathogens of severe respiratory tract disease in

infants & young children

Type 4 does not cause severe disease even on primary infection.

Respiratory syncytial virus

 It lacks haemagglutinin & neuraminidase activity, but has F spikes. RSV is transmitted via

droplet infection.

 Viral replication occurs in the epithelial cells of the nasopharynx.

 Viraemia has not been detected.

 RSV is the most important cause of lower respiratory tract infections in infants and young

children.

Measles

Measles is a highly contagious disease caused by the paramyxovirus. 90% of the people exposed to

the virus contract the disease. The symptoms are a fever, cough, runny nose, rash, and red

eyes(Figure 2-34) . Again, there is no specific treatment for the disease, but it has become much less

common with the increased use of the MMR vaccine.

Structure:

like other Paramyxoviruses but lacks the neuraminidase activity.

Complications

1. Post infection encephalitis: (rare) usually fatal.

2. Lower respiratory tract infection.

3. SSPE Subacute Sclerosing Panencephalitis:

(Occurs years after measles infection and very rare )

Figure (2-34) Child infected with Measles (Rubella)

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Transmission

 Measles transmission is primarily person to person via large respiratory droplets. Airborne

transmission via aerosolized droplet has been documented in closed areas (e.g., office

examination room) for up to 2 hours after a person with measles occupied the area.

 Measles is highly communicable, with >90% among susceptible persons. Measles may be

transmitted from 4 days prior to 4 days after rash onset. Maximum communicability occurs

from onset of symptoms through the first 3-4 days of rash.

Virulence factors

Portal of entry:

• Respiratory mucus membrane.

• It first infects the respiratory mucosa, spreads through the lymphatics and bloodstream, and

can then infect the conjunctiva, respiratory tract, urinary tract, GI tract, endothelial cells, and

the central nervous system.

Attachment:

Hemagglutinin

Hemagglutinin in an integral membrane protein found on the surface of the measles virus.

Hemagglutinin binds to CD46, a glycoprotein found on the surface of most cells.

(CD46 protects host cells from autoimmune destruction by binding to C3b and C4b and cleaving

them).

Destruction of tissue:

a serious febrile illness. The maculopapular rash, which starts at the hairline and spreads over the

whole body, is caused by immune T-cells targeted to the infected endothelial cells of the small blood

vessels. T-cell deficient individuals do not have the rash, but do have uncontrolled disease which

usually results in death.

 The damage, as well as the control of the disease, is most probably caused by the immune

system.

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Koplik's spots

Koplik's spots :

Found in the mouth, these spots look like tiny grains of white sand, each surrounded by a red ring.

They are found especially on the inside of the cheek (the buccal mucosa) opposite the 1st and 2nd

upper molars.

Measles Laboratory Diagnosis

• Isolation of measles virus from a clinical specimen (e.g., nasopharynx, urine)

• Significant rise in measles IgG by any standard serologic assay (e.g., EIA, HA)

• Positive serologic test for measles IgM antibody

Mumps virus :

- Is acute infectious disease causing enlargement of one or both of the parotid glands.

- Other organs may be involved as the pancreas, testes, ovaries and even the CNS.

- Mumps has become less common since the MMR vaccine became more widespread.

Pathogenesis

1. Transmission by droplet infection

2. Then to the blood stream.

3. Then to the salivary glands and other organs.

4. Incubation period 18-21 days

Rubella

Rubella virus is single-stranded RNA of positive polarity which is enclosed by an icosahedral capsid

with lipid bi-layer envelope.

Figure(2-35) Koplik's spots

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• Rubella, or the German measles is the third most common disease caused by

paramyxovirus. disease

• Rubella virus is the pathogenic agent of the disease Rubella, and is the cause of congenital

rubella syndrome when infection occurs during the first weeks of pregnancy. Humans are

the only known host of this virus.

• Spread by contact with an infected person, through coughing and sneezing

Two clinical forms:

• Postnatal rubella – malaise, fever, sore throat, lymphadenopathy, rash, generally mild,

lasting about 3 days

• Congenital rubella – infection during 1st trimester most likely to induce miscarriage or

multiple defects such as cardiac abnormalities, ocular lesions, deafness, mental and physical

retardation

• Diagnosis based on serological testing

• No specific treatment available

• Attenuated viral vaccine MMR

Measles Vaccines

attenuated and killed vaccines

1965 Live further attenuated vaccine

1967 Killed vaccine withdrawn

1968 Live further attenuated vaccine

 )Edmonston-Enders strain(

1971 Licensure of combined measles-

 mumps-rubella vaccine

1989 Two dose schedule

- Composition Live virus

- Efficacy 95% (range, 90%-98%)

- Duration of

- Immunity Lifelong

- Schedule 2 doses

- Should be administered with mumps and rubella as MMR

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MMR Vaccine

• First dose of MMR at 12-15 months

• Second dose of MMR at 4-6 years

• Second dose may be given any time >4 weeks after the first dose

Rabies

• Rhabdovirus family; genus Lyssavirus

• Enveloped, bullet-shaped virions(Figure 2-36)

• Slow, progressive zoonotic disease

• Primary reservoirs are wild mammals; it can be spread by both wild and domestic mammals

by bites, scratches, and inhalation of droplets.

• Virus enters through bite, grows at trauma site for a week and multiplies, then enters nerve

endings and advances toward the ganglia, spinal cord and brain.(Figure 2-37)

• Infection cycle completed when virus replicates in the salivary glands (Figure 2-38)

• Clinical phases of rabies:

• Prodromal phase – fever, nausea, vomiting, headache, fatigue; some experience pain,

burning, tingling sensations at site of wound

• Furious phase – agitation, disorientation, seizures, twitching, hydrophobia

• Dumb phase – paralyzed, disoriented, stuporous

Figure (2-36) Enveloped bullet shaped Rubies virus

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• Progress to coma phase, resulting in death

Figure (2-37) Rote spread of virus

Figure(2-38) Rabies virus inoculation and replication in infected person

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Rabies Virus diagnosis

Laboratory diagnosis

1. PCR

2. Serology (IFA)

3. Animal control

Rabid or suspected rabid animals are killed and examined by histopathology for Negri bodies and

viral antigen

• Vaccination of pets is required by law in most states

Immunity and protection

- Vaccines

- First one developed by Pasteur by using spinal cords from infected dogs

- Today’s principal vaccine is the human diploid cell vaccine (HDCV) made in the WI-38

fibroblast cell line

- Virus is inactivated by βPL

- Post-exposure prophylaxis

- One dose of hyperimmune antiserum

- Five immunizations over 28 days

Recommended prophylaxis in exposed individuals not previously vaccinated against rabies

Wound site(s)

Human Rabies

Immune Globulin

(RIG)

Rabies Vaccine

Laboratory diagnosis

• Diseased dog: viral antigen and Negri body in brain tissue (Figure2-39).

• Patient: IF assay, PCR.

•

• Immediate thorough cleansing of all wounds with soap and

water.

• Tetanus prophylaxis

- IU/kg body weight

- should be infiltrated in wound(s)

- The remainder should be given IM

 at a site distant from vaccine

IM (1 mL) in the deltoid area on days 0, 3, 7, 14, and 28

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ORTHOMYXOVIRUSES (Figure 2-40)(Figure2-41)

pleomorphic

influenza types A,B,C (Figure 2-42)

febrile, respiratory illness with systemic symptoms

Figure(2-41)Orthomyxoviruses

Figure(2-40) Orthomyxoviruses structure

A B

Figure (2-39) (A,B) Negri body brain tissue

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Wild aquatic birds are the main reservoir of influenza A viruses. Virus transmission has been

reported from wield waterfowl to poultry, sea mammals, pigs, horses, and humans. Viruses are

also transmitted between pigs and humans, and from poultry to humans. Equine influenza

viruses have recently been transmitted to dogs. (From Fields Vriology (2007) 5th edition, Knipe,

Figure (2-42)Influenza virus nomenclature

Figure(2-43) Influenza A reservoir

,

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DM & Hawley, PM, eds, Wolters Kluwer/Lippincott Williams & Wilkins, Philadelphia Figure(2-

43).

Hemagglutinin

• Required for virus binding to cell surface sialyloglygolipids and sialyloglygoproteins.

• Responsible for virus penetration.

• Antibodies to HA neutralize virus.

• Trimer in envelope.

• Cleavage to HA1 and HA2 required for infectivity.

• Fiviteen HA subtypes

1. Lowest homology is 25% (H1 and H3)

2. Highest homology is 80% (H2 and H5)

3. Less than 10% variation within subtype(Figure 2-44).

Neuraminidase

- Removes sialic acid from any glycoconjugate.

- Aids virus spread

Figure(2-44) structural and non-structural coding by influenza virus genome

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- May remove “decoy” receptors on irrelevant cells during infection

- Prevents virus clustering at cell surface upon release

- High concentration of anti-NA antibody are necessary for virus neutralization(Figure 2-45).

Different species harbor different strains of the flu virus:

Table(2-3)and figure(2-46)

• Human flu (Table2-3)

• Bird flu

• Swine flu

• ………………

Figure(2-45)Influenza replication

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Influenza A virus: HA subtypes

Figure(2-46) NA subtypes in different animal species

Table(2-3) Influenza A virus : HA subtypes

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Binds to cell surface carbohydrate - sialic acid

Ubiquitous receptor

Can be present as part of glycoprotein or glycolipid

Specific requirement for  2-3 and  2-6 linkages gives different tropism for avian vs. human cells

(pigs have both)Figure(2-48)

Figure (2-47) Influenza A virus , receptor of AH

Binds to cell surface carbohydrate - sialic acid

Ubiquitous receptor

Can be present as part of glycoprotein or glycolipid

Specific requirement for  2-3 and  2-6 linkages gives

different tropism for avian vs. human cells (pigs have both)

Figure(2-48) Influenza A virus: attachment

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• On the surface of influenza virus reside two major proteins; Haemagglutinin (HA) and

Neuraminidase (NA). Sixteen subtypes of HA (H1 to H16) and nine subtypes of NA (N1 to

N9) are recognized in aquatic birds.

• Death mostly occurs as a consequence of primary viral pneumonia or of secondary

respiratory bacterial infections, especially in patients with underlying pulmonary or

cardiopulmonary diseases which causes death in different outbreak time( Figure2-50).

Figure(2-49) Type A influenza cannot be eradicated

Figure(2-50) Eras of human Influenza A virus

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Viruses undergo genetic change by several mechanisms

• Genetic drift where individual bases in the DNA or RNA mutate to other bases.

• Antigenic shift is where there is a major change in the genome of the virus. This occurs as a

result of recombination(Figure2-51).

Seasonal flu/ Pandemic flu

• Epidemic (seasonal) influenza which occurs annually and is attributable to minor changes in

genes that encode proteins on the surface of circulating influenza viruses. These are known

as interpandemic epidemics.

• Pandemic influenza which occurs when more significant changes in the influenza A virus

arises when human virus strains acquire genes from influenza viruses of other animal

species. When this happens, everyone in the world is susceptible to the new virus, and a

worldwide epidemic or pandemic can result.

Reassortment of Gene Segments

• Influenza has 8 separate gene segments that encode 10 different proteins

• When a host cell is infected with two different influenza viruses, the progeny virus can be a

mixture of both “parent” viruses

Figure(2-51)Antigenic variation of influenza virus envelope proteins

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• Reassortment provides for increased biological variation that increases the ability of the virus

to adapt to new hosts (figure 2-51) which result a pandemic influenza (Figure 2-53)

Figure(2-52)genetic mutation of influenza A-Antigenic drift B-Antigenic shift

A

B

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Avian Influenza

• Avian influenza is an infectious disease of birds caused by type A strains of the influenza

virus.

• These viruses occur naturally among wild aquatic birds worldwide and can infect domestic

poultry and other bird and animal species. The disease, which was first identified in Italy

more than 100 years ago.

• Fifteen subtypes of influenza virus are known to infect birds, thus providing an extensive

reservoir of influenza viruses potentially circulating in bird populations.

• H5N1; the strain of avian flu known as has been behind outbreaks of deadly avian flu.

• Migratory water birds, especially wild ducks. They may do not show clinical disease. The

virus colonizes the intestinal tract and is spread in the feces . They act as a reservoir for the

infection of other species .

• Pigs can be infected by bird influenza (as well as by the form of influenza that affects

humans) and can pass on the flu to humans.

Figure(2-53) Generation of pandemic influenza virus strains

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Swine Flu

- Influenza in swine was first recognized as an epizootic disease in 1918.

- Swine influenza virus was first isolated from humans in 1974. Serologic evidence of

infections with a swine influenza virus in humans has also been obtained. Viruses of swine

may be a potential source of epidemic disease for humans.

Avian Influenza

- Avian influenza transmitted by birds usually through feces or saliva.

- Avian influenza is not usually passed on to humans, although it has been contracted by

people who have handled infected birds or touched surfaces contaminated by the birds.

Swine Flu

• Swine influenza (swine flu) is a respiratory disease of pigs caused by type A influenza virus

that regularly cause outbreaks of influenza in pigs.

• Like human influenza viruses, there are different subtypes and strains of swine influenza

viruses. The main swine influenza viruses circulating in U.S. pigs in recent years are: H1N1

influenza virus, H3N2 virus, H1N2 virus.

Figure(2-54) Influenza virus: the immune response

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Influenza Prevention

 Vaccination before the start of influenza season

• Northern Hemisphere: October-November

• Southern Hemisphere: April-May

 Antiviral treatment

• Therapeutic

• Prophylactic

Vaccination

 Trivalent: two current A strains and one current B strain.

 For 2010 season (Figure 2-55)

• A/California/7/2009 (H1N1)–like virus

• A/Perth/16/2009 (H3N2)–like virus

• B/Brisbane/60/2008–like virus

 Formalin fixed “wild type” virus approved for parenterally administered vaccination.

 Live attenuated vaccine (“Flumist”)

 Temperature sensitive recombinant bearing relevant HA and NA genes.

 Must anticipate shift and drift in order to identify appropriate vaccine strain.

Figure(2-55) General steps for influenza vaccine production

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5.Hepatitis B Virus

Hepatitis (Liver-Attacking) Viruses

Hepatitis A – fecal/oral, contaminated food, vaccine available

Hepatitis B – blood, semen, vertical (mother-child), vaccine available

Hepatitis C – blood (IV drug use, transfusion, organ donation, unsterile injecting equipment, sexual

intercourse)

Hepatitis D – survives only in cells co-infected with hepatitis B

Hepatitis E* – contaminated food or water, fecal/oral(Table 2-3)

*causes short-term disease and is not a chronic carrier state

Table (2-3)Characteristics of hepatitis viruses

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Hepatitis B

- Hepatitis B is caused by infection with the Hepatitis B virus (HBV), the prototype member of

the hepadnavirus family

- It has a circular DNA genome of 3.2 kb (Figure 2-56)

- Currently, eight genotypes (A−H) are identified by a divergence of >8% in the entire genom

(Figure 2-57)

Hepatitis B Characteristics

• A Hepadnaviridae – partially double-stranded DNA virus

• HBsAg – stimulates protective antibodies, a marker for current infection

• HBcAg – localized within liver cells, identifies acute infection, anti-HBcAg persists for life

and is a marker of past infection

• HBeAG – a marker of active replication and infectivity

Hepatitis B Virus :

- Hepadnaviridae family (DNA)

- Numerous antigenic components

- Humans are only known hosts

- May retain infectivity for more than 7 days at room temperature

Figure(2-56)Hepatitis B

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Hepatitis B virus infection :

- More than 350 million chronically infected worldwide

- Established cause of chronic hepatitis and cirrhosis

- Human carcinogen – cause of up to 80% of hepatocellular carcinomas

- More than 600,000 deaths worldwide in 2002

-

Epidemiology

• Worldwide, HBV is the primary cause of liver cancer

1. For males, it is the third leading cause of cancer mortality

2. For females, it is the sixth leading cause of cancer mortality

Epidemiology

• The incubation period from the time of exposure to onset of symptoms is 6 weeks to 6

months.

• HBV is found in highest concentrations in blood and in lower concentrations in other body

fluids (e.g., semen, vaginal secretions, and wound exudates).

Figure(2-57) Geographic distribution of Hepatitis virus

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• HBV infection can be self-limited or chronic.

• In adults, only approximately half of newly acquired HBV infections are symptomatic, and

approximately 1% of reported cases result in acute liver failure and death.

Diagnosis

• Hepatitis B is detected by looking for a number of different antigens and antibodies:

Hepatitis B surface antigen (HBsAg):

- A protein on the surface of HBV; it can be detected in high levels in serum during acute or

chronic HBV infection.

- The presence of HBsAg indicates that the person is infectious.

- The body normally produces antibodies to HBsAg as part of the normal immune response to

infection.

- HBsAg is the antigen used to make Hepatitis B vaccine.

Hepatitis B is detected by looking for a number of different antigens and antibodies:

Hepatitis B surface antibody (anti-HBs):

• The presence of anti-HBs is generally interpreted as indicating recovery and immunity from

HBV infection.

• Anti-HBs also develops in a person who has been successfully vaccinated against Hepatitis

B.

Total Hepatitis B core antibody (anti-HBc):

• Appears at the onset of symptoms in acute Hepatitis B and persists for life.

• The presence of anti-HBc indicates previous or ongoing infection with HBV in an undefined

time frame.

Hepatitis B is detected by looking for a number of different antigens and antibodies:

IgM antibody to Hepatitis B core antigen (IgM anti-HBc):

• Positivity indicates recent infection with HBV (≤6 months).

• Its presence indicates acute infection.

Hepatitis B e antigen (HBeAg):

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• A secreted product of the nucleocapsid gene of HBV that is found in serum during acute and

chronic Hepatitis B.

• Its presence indicates that the virus is replicating and the infected person has high levels of

HBV.

Hepatitis B is detected by looking for a number of different antigens and antibodies: (Table 2-4)

Hepatitis B e antibody (HBeAb or anti-HBe):

• Produced by the immune system temporarily during acute HBV infection or consistently

during or after a burst in viral replication.

• Spontaneous conversion from e antigen to e antibody (a change known as seroconversion) is

a predictor of long-term clearance of HBV in patients undergoing antiviral therapy and

indicates lower levels of HBV. (Figure 2-58)

Table (2-4) Hepatitis B

Typical interpretation of serologic test results for hepatitis B virus infection

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Figure(2-58)Immune response of hepatitis B virus A-Chronic hepatitis B , B-Acute of hepatitis B virus

A

B

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Hepatitis B complication :

- Fulminant hepatitis

- Hospitalization

- Cirrhosis

- Hepatocellular carcinoma

- Death

Chronic Hepatitis B virus infection :

- Chronic viremia(Figure 2-59)

- Responsible for most mortality

- Over risk 5% (Figure 2-60)

- Higher risk with early infection

Hepatitis B perinatal transmission :

 If mother positive for HBsAg and HBeAg

- 70%-90% of infected

- 90% of infected infants become chronically infected

 If positive for HBsAg only

Figure (2-59) Hepatitis B virus multiplication

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- 5% - 20% of infants infected

- 90% of infected infants become chronically infected

Global patterns of chronic HBV infection :

 High (> 8%) : 45% of global population

- Lifetime risk of infection >60%

- Early childhood infections common

 Intermediate (2%-7%):43% of global population

- Lifetime risk of infection 20%-60%

- Infections occur in all age groups

 Low(<20%):12% of global population

- Lifetime risk of infection <20%

- Most infections occur in adult risk groups

Adult at risk for HBV infection :

 Sexual exposure

- Sex partners of HBsAg-positive persons

- Sexual active persons not in a long – term , mutually monogamous relationship.

- Persons seeking evaluation or treatment for a sexually transmitted disease.

- Men who have sex with men.

adults at Risk for HBV Infection

Figure (2-60) Risk of chronic HBV carriage by age of infection