Infleunza Part2 Wk4 Flashcards
Transcription of virus mRNAs use fragment of cellular mRNA
Cellular mRNA transcription
- rapid addition of 5’ universal gap
Influenza virus polymerase complex is bound to every genome segment
PB2 protein binds the 5’-cap of cellular mRNA
PB1 & PA proteins work in concert as an endonuclease
= cleaves capped RNA (~10-15nt from the cap)
cap snatching
Influenza virus polymerase complex
PB1 binds to both
-mRNA fragment with 5’-cap
-3’-end of genomic vRNA
=polymerase function
PB1 protein transcribes (+)ssRNA using
-mRNA fragments (with 5’-cap) as a primer
-genomic vRNA as a template
On reaching 5’end of vRNA template
(=3’end of the new (+)RNA)
The PB1 polymerase produces a polyA tail by reiterative stuttering
=repeated transcription on a short polyUTP sequence in the vRNA
Results of transcription = capped, polyadenylated chimeric mRNAs
5’-region is a fragment of cellular mRNA
Remainder is (+)ssRNA copy of (-)vRNA
5’-cap & polyA tail promote
-exit from cell nucleus
-translation by cell ribosomes
Influenza A virus replication cycle - genome replication
Is also RNA transcription but doesnt involve cap-snatching
Free rNTPs bind to the 3’-end of each of the cRNAs
PB1 polymerase protein forms a phosphodiester bond
PB1 transcribes (-)ssRNA from this dinucleotide primer
No 5’-cap is added - this is cRNA, not mRNA
(+) sense cRNA intermediates associated with with NP and polymerase
A virus replication cycle - assembly & genome packaging
vRNAs & cRNAs associate with PB1, PB2, PA & NP in nucleus
Only vRNPs exit the nucleus - mediated through binding with M1 & NS2 proteins
M1 interacts with structual virus proteins at the plasma membrane
Plasma membrane & matrix layer wrap around vRNPs
Random / selective incorporation model
Influenza A replication cycle - budding release
Exit by budding - gains envelops
Neuraminidase cleaves bonds
Also prevents virion aggregation
HA on new virions binds neuraminidase acids
On other virions
Neuraminidase protein is a targets for antiviral drugs
Influenza virus pathogenesis
Acut, contagious infections of upper respiratory tract
-virus shed into respiratory lumen
-no systemic spread
-immune pathology
-self-limiting (strong immunity)
Fatalities rare
-elderly, young, immune-compromised
-viral / bacterial pneumonia
Influenza virus epidemics and pandemics
Seasonal recurrence of flu epidemics
-pandemic outbreaks also recorded through history
Influenza A virus genetic diversity, change + exchange
Advantageous mutations in human influenza/avian or swine influenza virus strains = new combinations of genome segments between human, avian & swine influenza virus strains.
Antigenic drift -selection due to immune pressure
Advantageous mutations occur over time, driving immune resistance
Protein antibody response. outcome
HA neutralising block infection, protective
NA non-neutralising. ADCC, curtail infection
M2, NP non- neutralising ADCC curtail infection, protective
Antigenic drink - cause of 1918 pandemic and 2013 outbreak
1918 H1N1 - avian virus HA mutations = expanded binding to a-2,6 AND a-2,3 galactose-sialic acid
2013 H7N9 - HA and PB2 mutations allow binding & efficient replication in human cells
Antigenic shift- reassortment of genome fragments
Influenza A viruses infect humans, mammals + birds
-miltiple virus types can infect individual hosts
-mixing of human, avian and swine virus genomes occurs
Significant intermediate (mixing) hosts = pigs, domestic birds, waterfowl
Antigenic shift - reassortment of genome fragments
-2 or more virus subtypes infect single cell
-both/all virus genomes replicate in same nucleus
= assembly of virions
-mixed packaging of genome segments from each original virus
= reassortment / antigenic shift
Novel combinations of virus genomes = reassortants
H/N combinations significant
Antigenic shift = cause of 1957 pandemic
Antigenic drift of avian H1N1 virus
Humanised over several decades
1957 pandemic = reassortment with avian H2N2 virus
New HA, NA, PB1
Antigenic shift = cause of 1968 pandemic
1957 H2N2 virus = reassortment with avian
H2 virus
(New HA, PB1)
(Same NA2)
Antigenic shift = cause of 2009 “swine flu” outbreak
First reassortment
=triple reassortment between avian, swine H1N1 & the 1968 H3N2 Hong Kong viruses
Second reassortment
Between “new” swine H3N2 (triple reassortment) with classical swine H1N1
Third assortment
Reassortment with the “new” swine H1N2 & another H1N1 swine virus
