(V) 24: Viral Entry Flashcards
Concept of entry
- ATTACHMENT: recognition of host receptor
- mechanisms to RELEASE genome (ex. in cytoplasm)
Viruses and passive diffusion
Viruses are too LARGE to be passively transported through the host cell membrane
Random electrostatic interactions
They occur but will NOT initiate infectious cycle
- non-specific
How do viruses find the “right” receptor?
- specific interactions btwn a virus and its receptor will initiate the infectious cycle
- opened the door to the OBLIGATE INTRACELLULAR parasite
- RELEASE of genome “inside” the host
Susceptible cell
functional receptor for virus
Permissive cell
allows the virus to REPLICATE
resistant cell
no receptor
Co-receptor
second receptor (sometimes needed)
- specific to humans and animals
Very, very essential for many viruses
NOT in yeast and plants
Host cell receptors
they are functional receptors in humans (NOT just there for the virus)
they are all SURFACE MEMBRANE PROTEINS
in some cases, the same receptor can recognize more than a single virus and vice versa
Host cell receptors and SARS-CoV2
Angiotensin-converting enzyme 2 receptor (ACE2) is used by SARS-CoV2
- has a role in controlling b.p. and CV system
Modes of attachment depends on…
outer shell of the virus
Non-enveloped viruses: outside of shell is hard protein
Enveloped viruses: outer surface is a membrane
Picornaviridae general structure
non-enveloped virus w/ icosahedral symmetry
ss (+) RNA = “ready” to go
Viral proteins: 60 VP1 (membrane insertion), 60 VP2, 60 VP3
- 60 faces of 3 proteins each
Ex. Poliovirus
- naked virion: release their genomes at plasma memb
- injects RNA directly across plasma memb. after conformational change in capsid proteins
Host cell entry for non-enveloped virus
Naked virion: viruses can RELEASE their genomes at the plasma memb
Ex.
Poliovirus INJECT RNA DIRECTLY across plasma membrane after conformational change in capsid proteins
- hydrophobic N-termini of VP1 insert into membrane
- creation of a channel
Poliovirus Receptor (PVR): can interact w/ VP1 (conformational change to create PORE on susceptible cell) = (+) ssRNA is injected in plasma memb.
VP4 is buried
Host cell entry for enveloped viruses
Influenza virus
(-) RNA and HAS an ENVELOPE
Hemagglutinin = viral envelope glycoprotein
- binds cell host receptors (sialic acid)
Sialic acid (sugar) = host cell receptor
How is specificity of viruses determined?
Sugar linkages determine specificity
- orientations determine stereochemistry + specificity of sialic acid’s interactions w/ hemagglutinin
2-3 and 2-6 linkages are possible
- human influenza prefers 2-6 linkages
- avian influenza prefers 2-3 linkages
Human influenza viruses and linkages
Human influenza viruses preferentially prefer 2-6 linkages
Avian influenza viruses and linkages
Avian influenza viruses prefer 2-3 linkages
Avian influenza viruses and humans
- sialic acid receptors w/ 2-6 linkages in upper AND lower tract = bind human influenza virus
- sialic acid receptors w/ 2-3 linkages in LOWER tract = bind avian influenza virus
Very deep breath of many virions is needed to travel all the way to lungs to find susceptible cells for avian flu
SARS-Cov2 and receptors
SARS-Cov2 has evolved (ex. Omicrom) to interact w/ upper respiratory tract receptors
- opposed to original virus that interacted w/ lower tract
How do viruses enter the cell?
Via common cellular mechanisms - endocytosis
- phagocytosis
- pinocytosis
- receptor-mediated endocytosis (MOST viruses)
- transport vesicles “move” along tracks that are powered by molecular motors
- ACTIVE TRANSPORT applies to virus trafficking inside the cell
Release of virus
a TRIGGER releases virus or genomic contents in the cytoplasm
Locations of genomic “release”
- release can occur at the CELL SURFACE
- release can occur at an EARLY ENDOSOME
- release can occur at a LATE ENDOSOME
pH is different btwn locations = becomes more acidic as you go further way from plasma membrane
Reoviruses
- NON-enveloped example for entry
- onion virus = many layers
- attachment
- receptor-mediated endocytosis
- disassembly (cysteine proteases)
- cathespin = molecular scissors (HUMAN = host enzyme) - membrane penetration
Early endosome = pH causes loss of capsid
Late endosome = pH causes holes in late endosome
Cathepsin
MOLECULAR SCISSORS
HUMAN host enzyme/protein
- more active in acidic environment
Paramyxoviridae
Measles = HAS an envelope (lipid)
- fusion events are regulated by viral proteins
- viral fusion proteins will “behave” differently depending on specific pH
- different viral fusion proteins respond differently to different pH
- CO-RECEPTOR is needed (often interacts w/ fusion receptor)
Influenza virus membrane fusion
When acidity increases, viral protein stretches (conformation changes) to mediate fusion event
- brings host membrane closer to viral envelope
- co-receptor like interaction
Requirement for TWO host receptors
Ex. HIV (ENVELOPE virus)
- Host receptor: CD4/CCR5
- viral protein: gp120
- gp41: viral fusion protein
PROXIMITY of viral and cellular membranes = fusion
Ebola Uptake
Niemann-Pick C1 (NPC1) cholesterol transporter: essential for Ebola virus infection in LATE ENDOSOMES
- already working receptor in humans
