Orthomyxovirus

three genera of influenza virus:

Influenzavirus A, Influenzavirus B and Influenzavirus C.
Each genus includes only one species,
Influenza A and C infect multiple species,
influenza B almost exclusively infects humans.[

Influenza A viruses are further classified, based on

the viral surface proteins hemagglutinin (HA or H) and
neuraminidase (NA or N).
16 H subtypes, 9 N subtypes of influenza A

Further variation exists; thus, specific influenza strain

isolates are identified by a standard nomenclature
specifying virus type, geographical location where first
isolated, sequential number of isolation, year of isolation,
and HA and NA subtype
The type A viruses are the most virulent human pathogens
among the three influenza types
and causes the most severe disease.
The serotypes that have been confirmed in humans,
by the number of known human pandemic deaths, are:
H1N1 caused "Spanish Flu".
H2N2 caused "Asian Flu".
H3N2 caused "Hong Kong Flu".
H5N1 is a pandemic threat in 2006-7 flu season.
H7N7 has unusual zoonotic potential.[10]
H1N2 is endemic in humans and pigs.
H9N2, H7N2, H7N3, H10N7.
Influenza B virus is almost exclusively a human pathogen
less common than influenza A.
The only other animal known – seal.
mutates at a rate 2-3 times lower than A
less genetically diverse
has only one influenza B serotype.
lack of antigenic diversity - immunity to influenza B acquired
at an early age.
mutates enough that lasting immunity is not possible
This reduced rate of antigenic change + limited host range
(inhibiting cross species antigenic shift), ensures that
Pandemics of influenza B do not occur
influenza C virus infects humans and pigs
can cause severe illness and local epidemics
less common than the other types
usually seems to cause mild disease in children
 Orthomyxoviridae
• Orthos – straight, Myxa – mucus
• (-)ve ss RNA virus
• 5 genera
– Influenza A – causes pandemics, infects
humans, mammals, birds
– Influenza B – infects humans, seals
– Influenza C – infects humans, pigs
– Thogotovirus – infects salmon,
invertebrates
– Isavirus – infects humans, pigs
 Morphology
• Enveloped
• Pleiomorphic (Spherical 50-120nm)
• Filamentous (20nm, 200-300nm long)
• 500 distinct spike-like surface projections
(10-14nm)
• Bilipid layer
• Surface glycoproteins – HA, NA
• 3 viral antigens
– Nucleoprotein – determines the virus type A, B,
C
– Hemagglutinin –H – 13 types
– Neuraminidase – N – 9 types
• 117 possible combinations, observed 71
• 3 combinations that have affected humans
adversely
• Genome
– ss (-) sense RNA – 7-8 segments
– 5’ & 3’ seq are highly conserved
– Packaged into a core
– 12000-15000 nt
• Replication
– Binds to cell thru HA glycoprotein onto sialic acid sugars on
epith cell in lung and throat
– Cell imports virus by endocytosis
– In endosome HA fuses viral envelope to membrane – viral RNA,
accessory mol, polymerase released into cytoplasm
– Viral proteins form complex and transported into nucleus
– Transcription begins - +ve strand mRNA
– Exported into cytoplasm and translated
– Secreted via Golgi to cell surface or back into nucleus
– Assembly occurs with neg strand and exported with help of NA
via budding
Segme Size Polypep Function
nt (nt) tide
1 2341 PB2 Transcriptase :cap binding
2 2341 PB1 Transcriptase : elongation
3 2233 PA Transcriptase : protease activity
4 1778 HA Hemagglutinin
5 1565 NP Nucleoprotein: RNA binding, part of
transcriptase complex,
nuclear/cytoplasmic transport
6 1413 NA Neuraminidase : release of virus
7 1027 M1 Matrix protein : major component of
M2 virus
Integral membrane protein : ion
8 890 NS1 channel
Non-structural : nucleus; effects on
cellular RNA transport, splicing,
translation, Anti-interferon protein
NS2 Non-structural : Nucleus+cytoplasm
– unknown fn
Every 10,000 nt single nt insertion error ( size of influenza virus)
Every newly syn virus – 1 mutation
8 segments – reassortment if more than 1 strain
New viral progeny – confer new behaviour
 Pathogenesis
• Transmission – aerosol, infected bird droppings, saliva,
nasal secretions, feces, blood, contact with body
fluids, contaminated surfaces
• Primary site – tracheobronchial mucosa – ciliated epith
cells of URT
• Neuraminidase – liquefies – viral spread
• Very infectious – 1 week at human body temp, 30
days at 4 C, indefinitely at very low temp
• Inactivated very easily by disinfectants, detergents
• Necrosis of these cells – symptoms
• Fever, chills, muscle aches, headache, prostration,
anorexia
• Normally self-limiting 3-7 days
• Death is rare – determined by host factors
• Damage to respiratory epithelium – predisposes to
secondary bacterial infections – accounts for most
deaths
 Prevention/Control
• Drugs – antivirals
– Amantadine, rimantadine
– Main target – M2 matrix protein
– Resistance only to HA
– Action ? – pH of endosome
– Amantadine – not licensed – side effects, poor efficiency
– Neuraminidase inhibitor
• Prospective target
• Synthetic sialic acid analogues
• Works against all strains of influenza A & B
• Tamiflu – oseltamivir phosphate – pill form
• Relenza – Zanamivir - inhaled
• Vaccines
 Prevention/Control
• Vaccines
– Isolated HA – good protection 60-80 %
– Produced in eggs using the required HA type –
purified and formalin inactivated
– Sub-cutaneous inoculation
– 2 doses if there is a new antigenic type – for
adequate protection
– Currently - ?
– Naked DNA vaccine
 Epidemiology
• Typical pattern – school children
bring the disease home – infect
family
• Epidemics – 3-6 weeks
• Highest attack rates – 5-19 yrs
• Every winter – recurring problem
– Susceptible population
– Major changes – antigenic drift
– Rearrangement of genome segments –
mutations in viral RNA
– Minor changes – antigenic drift – yearly