ICL 1.19: Antivirals II Flashcards
what determines if if you get sick or not when a virus infects a cell?
virus infects cells, which trigger rapid innate antiviral responses and many viruses have mechanisms to antagonize the host responses
the final outcome is determined by the strength of these interactions
so when a virus enters a cell, we have a rapid innate anti-viral response that starts within minutes – viral proteins and nucleic acids can be sensed by the host immune system and they trigger and innate response!
after the virus is done with primary replication, it can antagonize the host immune response and it’s kind of like tug-o-war
this is why certain people can kill the virus and others don’t; it just depends on the strength of this interaction and whether the virus or your immune system wins
what is our first line of antiviral defense?
the interferon system!
what are the components of the interferon system?
- virus
- cellular sensors = TLRs, RLRs, cGAS/STING
- transcription factors = IRFs, NFkB
- interferons = IFNβ
- ISGs/viral restriction factors = IFITs, PKR
- viral replication
how does the interferon system work?
first the virus infects the cell and starts to replicate so we have viral RNA and proteins
host cell cellular sensors like TLR, RLR, cGAS/STING can sense these proteins and RNA as foreign
then there’s a complex series of reactions that go on in the cells very quickly and the cellular sensors activate transcription factors IRF and NFkB
these two transcription factors are not usually active, only when there’s a viral infection present! if they were active all the time there would be autoimmune disease
IRF and NFkB go from the cytoplasm to the nucleus and sit on the promoters of IFNβ gene so that IFNβ is produced
IFNβ either stays in the cell or goes to other cells and protects them both by promoting ISGs/viral restriction factors like IFITs and PKR
IFITs and PKR inhibit viral replication!
what are the cellular sensors in the interferon system?
TLRs
RLRs
cGAS/STING
what are the transcription factors in the interferon system?
IRFs
NFkB
which interferon is used in the interferon system?
IFNβ
what are the ISGs/viral restriction factors in the interferon system?
IFITs
PKR
what is part 1 and part 2 of the interferon system?
part 1 = virus detection and IFN synthesis
part 2 = execution of ISG action and viral antagonism
what are the different kinds of cellular sensors in the interferon system?
there are cellular sensors that recognize both viral RNA and DNA
there are also endosomal and cytoplasmic cellular senors
ex. TLR, RIG-I, MDA5
what are TLRs?
they are transmembrane proteins expressed on host cell surface or endosomal membrane
they sense viral and bacterial nucleic acids and/or proteins
there are 13 TLRs and they each detect specific microbial components
once they detect a PAMP in the endosome or cell surface, they activate rapid downstream signaling to trigger the synthesis of antiviral, antimicrobial and inflammatory genes
where are TLRs located?
viral TLRs are located inside the endosomal membrane
bacterial TLRs are on the cell surface
what are RLRs?
they are cellular sensors that detect cytoplasmic viral RNA
there are 3 members: RIG-I, MDA5, LGP2
once they detect PAMPs in the cytoplasm, they activate rapid downstream signaling to trigger the synthesis of antiviral, antimicrobial and inflammatory genes
what are cGAS/STING?
they are cellular sensors that detect cytoplasmic viral DNA
once they detect PAMPs in the cytoplasm, they activate rapid downstream signaling to trigger the synthesis of antiviral, antimicrobial and inflammatory genes
what are interferons?
small (20 kDa), soluble, cellular glycoproteins made by a wide variety of animal cells in response to viral infection (or various non-viral stimuli) that
lead to a state of antiviral resistance in homologous cells
they are species-specific, not virus specific
they are a family of cytokines that share the property of inhibiting viral replication
what are the 3 classes of interferons?
- type 1 = IFN- α/β
- type 2 = IFN-γ
- type 3 = IFNλ
what are type I IFNs? by which cells are they produced?
IFN- α/β
type I is produced by basically all cells!
what are type II IFNs? by which cells are they produced?
IFNγ
produced by NK cells in innate response, and by TH1 cells in adaptive response
what are type III IFNs? by which cells are they produced?
IFN-λ
IL-10R and IL-28R are its receptors; stimulates same genes as type I IFN
but type III receptors are not expressed in the brain and only in certain tissues, unlike type I receptors
a female patient presents with symptoms of the common cold after the respiratory epithelial cells were infected with rhinovirus. Due to the presence of the virus, her respiratory epithelial cells begin producing INF. Which is LEAST likely to be an outcome of the IFN response?
A. decreased viral replication within the cell
B. a rhinovirus specific cell mediated immune response
C. upregulation of NK cell ligands on the infected cell
D. activation of NK cells
E. interferon binding to nearby uninfected epithelial cells
B
a rhinovirus specific cell mediated immune response
what happens when you block IFN production in immunocompromised patients?
they die
how does IFN function?
- IFN binds to IFNAR receptor
- IFNAR activates JAK
- JAK phosphorylates STAT
- phosphorylatedSTAT-1/2 dimerizes and binds IRF9
- Dimerized STAT translocates to nucleus-binds to interferon stimulated response element (ISRE) in the nucleus
- Activates transcription of interferon stimulated genes (ISGs)
- ISGs encode antiviral proteins that protect cells from many different kinds of viruses
which genes do IFNs turn on?
PKR
P56
ADAR
TRIM protein
these are all proteins that we normally don’t want to be turned on because they shut everything down in cells
they cause cell growth inhibition, altered mRNA translation, apoptosis, viral protein degradation, mRNA degradation, etc.
what does ISG stand for?
interferon stimulated gene
