Influenza Virus/fusion Flashcards
what are the characteristics of influenza virus?
- orthomyxoviridae
- membrane envelope
- RNA genome with 8 segments
- 4 types: A, B, C and D
- helical capsid
describe the nomenclature of influenza
Virustype (A-D)/geographical origin/strain number/ year of isolation (HxNx)
HxNx= virus subtype
e.g. A/bejing/32/92 (H3N2)
how is the genome organized in the capsid
- helical symmetry
- -RNA wrapping around NP
- NP is a monomer
- helix with loop region on one end and a Polymerase complex (PB1, PB2 and PA) on the other end
- helix has minor and major groove
describe the capsid structure of influenza
- lipid bilayer
- hemagglutinin
Neuraminidase
What determines host species specificity in influenza?
type of linkage in sialic acid
bird: a2-3
pig: a2-6 and a2-3
human: a2-6
what is the difference between seasonal vs pandemic influenza infection?
seasonal vs pandemic:
- drift vs shift
- new variant of old acquaintant vs new through zoonosis/reasortment
- partial immunity possible vs immunity unlikely
- usually normal immune response vs often overreaction of immune system
- every year vs unpredictable and more fatal
what is the cause of death in influenza infection?
inflammatory response and organ failure
describe the gene organization of hemagglutinin
N-terminus - signal peptide - HA1 - cleavage site - fusogenic region - HA2 - Tranmembrane region - COOH
describe the biogenesis of hemagglutinin. How do viruses obtain HA?
- synthesized on ER ribosomes
- con translationally insetted into the ER membrane
- HA is cleaved into two strains (HA1 and HA2)
- HA1 and HA2 held together by S-S
- trimers (H1-H2)3 form on rough ER
- trimers transported from golgi to PM
- functional part of molecule HA1 outside, HA2 tails anchored in the membrane
- progeny virus particles bud from PM and carry NA and HA
what does the receptor binding domain (RBD) of HA look like in influenza?
- monomeric subunit: long, fibrous stem like region
- part of HA1 and all of HA2 form the stem
- globular region formed by HA1
- jelly roll fold
describe the built up of HA trimers
3 long HA2 helices form coiled-coil –> pack against each other via hydrophobic contacts and salt bridges
- head domains form trimer contacts
How does HA induce membrane fusion?
two important conformational changes in HA due to pH change
from low to high pH:
- loop region B changes into helix
- alpha helical region at the middle of C-D changes into a loop
- only Cregion forms a coiled coil
in the low pH structure, A-B_C is a coild coil
why is a low pH important for HA mediated membrane fusion?
high pH trimer is metastable and the fusogenic peptide is 100 °A away from receptor binding site
–> in low pH the fusion peptide is move closer to the receptor binding site. The low pH form is stable
What kind of mechanism is involved in viral membrane fusion (influenza) and how does it work?
spring loaded mechanism
- low pH is fusogenic conformation
- interactions between HA1 and HA2 weakened
–> loop regions of HA2 “spring” into helical conformation
- extending trimeric coiled coil and propelling fusion peptide at the top of the structure
–> interaction with target membrane
Name Natural fusion inhibitors
- catechin
- elderberry
- curcumin
- andrographolide
describe the structure of Neuraminidase
- beta propeller structure: 6 consecutive, anti parallel beta sheets
- propellar blades connected by long loops
- 4, 5,6,7 or 8 bladed propeller
- NA form tetramers as quartäry structure
How does NA cleave sialic acid? What is the function of the cleavage?
cleave off sialic acid (exo + endo) from glycoproteins to:
1. prevent aggregation of virus
2. enable viruses to be released from the infected host cell
Name NA inhibitors
Tamiflu and Relenza
What is the M2 protein of Influenza? Where does it sit?
sits in envelope and is a proton channel
Name M2 (influenza) inhibitors
Amantadin and Rimantadin
