Influenza

Question 1

Influenza Structure

Answer 1

• RNA virus
• genome consists of 8 negative RNA segments
• enveloped virus, with haemagglutinin and neuraminidase spikes
• 3 types: A, B, and C
• Type A undergoes antigenic shift and drift.
• Type B undergoes antigenic drift only
• type C is relatively stable
  
  • C does not cause serious human disease.
• Hemagglutinin: viral attachment and membrane fusion
• Neuraminidase: Viral release and disaggregation
• M2: membrane ion channel
  
  • acidification of interior of the viral particles in endosomes;
  • viral disassembly
• M1: membrane matrix proteins

Question 2

Influenza Biological Characteristics:

Answer 2

• Short incubation period (1-4 days).
• Large numbers of virions shed.
• Many symptomatic people in circulation.
• Population at large lacks immunity to new strains arising by antigenic shift

Question 3

Influenza Life Cycle

Answer 3

• Binds sialic acid on glycoprotein moiety on glycoproteins and glycolipids
• pH-dependent particle dissembly & envelop fusion
• Transcription and replication occurs in nucleus
• Steal 5’ capped termini of cellular mRNAs as primer for viral mRNA transcription
• Budding from plasma membrane
• Frequent genetic reassortment

Question 4

Symptoms and Pathogenesis: Primary Infection with influenza virus

Answer 4

1. Short incubation period
2. Local virus replication in respiratory epithelium
3. Damages to epithelium and ciliated columnal epithelial cells render the airway susceptible to bacterial infection.
4. No viremia
5. Macrophage and lymphocyte infiltration
6. Interferon and cytokines cause fever, aches, edema
7. Direct virus damage and immune response kill infected cells
8. Stimulation of antibodies and virus‑specific T cells
9. Clearance of virus from tissues
10. Immunity to re-infection mediated by IgA in respiratory tract.

Question 5

Symptoms and Pathogenesis: Secondary infections Influenza

Answer 5

• (re-infections) with influenza virus
  1. May have no symptoms, limited local virus replication if IgA levels are high enough to protect from that strain of virus.
  2. Partially immune person may get mild symptoms, but shed enough virus to infect others. Antigenic variants may be selected in these patients.

Question 6

Complications of Influenza

Answer 6

• Secondary bacterial pneumonia (more common): following improvement, fever reappears, cough, purulent sputum
• S. pneumoniae, S. aureus, H. influenzae
• Viral pneumonia (rare): relentless progression of illness, dyspnea, hypoxia, cyanosis, severe inflammatory reaction in alveoli, edema ->ARDS
• Myositis and cardiac involvement
• Neurologic symptoms:
  
  • Guillain-Barre syndrom
  • Encephalopathy
  • Encephalitis
  • Reye’s syndrome

Question 7

Influenza Mechanism of antigenic variation:

Answer 7

• Antigenic shift occurs as a result of the segmented genome of flu virus and the reassortment of the viral genomes in the large animal reservoirs of the virus.
• Antigenic drift occurs as a consequence of the mutations introduced by the viral RNA dependent RNA polymerase during replication.

Question 8

Influenza Pandemics

Answer 8

H1N1 “Spanish Influenza” 20-40 million deaths 1918
H2N2 “Asian Flu” 1-2 million deaths 1957
H3N2 “Hong Kong Flu” 700,000 deaths 1968
H1N1 Re-emergence No pandemic 1977
H5N1 Avian Flu hundred deaths
H1N1 Swine Flu hundred deaths 2009

Question 9

Influenza Diagnosis

Answer 9

• Virus isolation from clinical specimens.
• Samples obtained from respiratory secretion
• Throat swab, nasal wash, throat wash, nasopharyngeal aspirate.
• Virus grown in fertilized eggs or in cell cultures (Madin-Darby canine kidney cell line or primary monkey kidney cells)
• Detect virus replication by cytopathic effects, immunofluorescence, hemagglutination or hemadsorption
• Determine serotype by hemagglutination‑inhibition (HAI) test, neutralization, complement fixation.
• Rapid diagnosis by RT-PCR‑based tests.
• Naming of influenza virus isolates
• Type, place, date, species, HN antigenicity
• A, Hong Kong, 1/68, Man, H3 N2

Question 10

Influenza Vaccine

Answer 10

Trivalent Inactivated Vaccine (TIV): 2 type A, 1 influenza B
-Intra-muscular injection
-chemically inactivated
-induce serum antibodies
-6-month and older (healthy and high-risk)
-side effect: soreness at site of injection
Live Attenuated Influenza Vaccine (LAIV)
-2 influenza type A, 1 influenza B LAIV, nasal-spray flu vaccine (Flumist)
-cold-adapted, temperature-sensitive,
-Mutations in PA, PB1, PB2
-induce mucosal immunity
-5-49-yr old (healthy)
-side effect: runny nose

Question 11

Influenza Treatment

Answer 11

Amantadine, Rimantadine
-blocks the ion channel activity of the M2 protein, prevents H+ entry into viral interior thereby inhibits viral dissembly.
also inhibits maturation of HA during virus assembly.
-Reduces disease severity if given early.
-Only for type A influenza

Functions of M2 in virus life cycle:

• Lowers the pH in viral particle to facilitate dissociation of the ribonucleoprotein complexes from the M1 protein.
• facilitates HA maturation and egress by equilibrating the pH of Golgi and cytoplasm during viral assembly.

NEURAMINIDASE INHIBITORS:

• RELENZA AND TAMIFLU
• RELENZA (ZANAMIVIR FOR INHALATION)
• TAMIFLU (OSELTAMIVIR, ORAL USE)
• PROPERTIES: INHIBIT BOTH INFLUENZA A & B VIRUSES