19 Virus: Influenza Flashcards
Influenza
Genome
Segments
Proteins
-ssRNA
8 segments
10 proteins (splicing 2x)
HA, NA, M1 matrix, M2 ion channel, nucelocapsid, PA, PB1, PB2
NEP, NS1
What is cap snatching?
Influenza replicates in nucleus, mRNA of influenza uses caps from host mRNAs
NS1 proteins inferfere with proteins that process 3’ end of mRNA, few cellular mRNAs surive and immune response prevented through same mRNA structure compared to host?
Types
What’s different?
Typing
A,B similar disease and have HA and NA
C mild upper RT infections, only has HEF protein
A cause disease in humans and animals (wild aquatic birds) zoonotic, can cause pandemics
B only humans
C humans and pigs
all worldwide
Typing
mostly Influenza A, based on HA/NA subtypes
Antigenic shift and drift
Antigenic shift
Different viruses strains mix in intermediate host that have bost receptors
reassortment leads to new strain like H5N1
Antigenic drift
Point mutations leading to new subtypes that can infect other species
Nomenclature
Type
Species
region
strain
Year
subtypes
Influenza Virus receptors
Sialic acid
via HA that binds sialic acid (alpha2,3 or 2,6 linked to galactose)
NA removes terminal sugar from sialic acid and blocks influenza infection during viral exit
HPAI vs LPAI
Which receptor dominant for which species?
HPAI
spreads slowly and often fatal
infects lower RT, lung
LPAI
spreads fast and rarely fatal
infects upper RT
Which receptor dominant for which species?
Avian: alpha 2,3
Human alpha 2,6, alpha 2,3 only few in lower RT
Ferret: similar to humans
HA
activation and mechanism
role in pathogenesis
HA0 is cleaved in HA1 and HA2 via host proteases for activation
HA1 binds sialic acid
HA2 with Tm domain and fusion peptide
HA leads to attachement and fusion:
after endocytosis: pH leads to conformational change to trigger membrane fusion and uncoating
nucleus
production of +ssRNA (genome and mRNA)
translation
packaging/Assembly
Budding
NA cleaves sugar from sialic acid to inhibit infexction of same, neighbour cells (spread)
role
host protease cleave HA:
seasonal flu: trypsin like proteases on RT epithelium, self limiting to RT
Highly pathoegnic strains cleaved via ubiquitinous protease like Furin
Antivirals and targets
Amantadine
Hydrogen transport across M2 channels to disrupt viral uncoating
Oseltamivir/Familflu/Relenza
Neuraminidase inhibitor
Nucelozin
RNP formation
Adhesion
Fludase
mRNA synthesis
Ribavirin
Influenza Pandemic
which strains?
most severe pandemic?
age groups?
other pandemics?
Why did the Russian flu also affect more young adults?
Whats special about 2009 outbreak?
only type A
mutation in bird
1918: H1N1: 20-50M deaths
first America, then pandemic, also Spain (not censored), thats why Spanish Flu
Young, old, immunocompromised (war)
Herd immunity after half a year
Asian/Hong Kong
Genetic reassortment in swine
Russian Flu
because older groups were protected from earlier outbreaks
2009
Swine flu, quadruple reassortment (human-bird-2xswine)
mild disease
Why was the Spanish flu so pathogenic and how did scientist find out?
Influenza Reverse Genetics
Sequence original flu:
Permaforst in Alaska to find virus in dead inubits, infect cell culture / ferrets etc. but there was no live viruses
Lung sections from WW1, sequenced the virus
Recreative virus from genomic infomration:
Make plasmids that produce viral RNA and mRNAs
Pathogenicity
avian origin, 10aa changed
could replicate without trypsin
wide dissemination and replication
hemorrhagic pneumonia
overacxtivation of immune system
Avian Influenza Outbreaks
Why H5N1 severe pandemic potential?
H5N1 or H5N8
H5N1
so far no human to human transmission, if that happens:
no immunity, pandemic potential
mortality 60% (lower RT, ARDS, systemic)
Resistant to different antivirals, but Tamiflu and Relenza could work
Risk: Livestock birds, need to kill all infected birds and populations
Host barriers the virus needs to overcome?
Upper vs lower respiratory tract
receptors alpha 2,3 and alpha2,6
Temperature 40° avian
Immune modulation
Host factors like importins to shuttle proteins to nucleus (species specific)
Best modell to study Influenza
Ferret because of similar receptor pattern
Ferret modell showed that mutation in H5N1 makes ferret to ferret transmission possible
Gain of function always ethical questionable
