Antiviral Immunity Flashcards
How do viruses replicate? (2)
Viruses must infect cells in
the host and hijack the host’s
biosynthetic machinery to replicate
What are cytokines? (2)
A group of low molecular weight, extracellular polypeptides/glycoproteins
expressed by different (immune) cells, which are responsible for promoting and regulating the immune response
What are the different cytokines and what are their actions? (10)
Interferons (IFN) - Antiviral proteins
Chemokines - Direct cell migration, adhesion and activation
Interleukin family - Variety of actions depending on the IL member and cell type
Tumour necrosis factor family - Regulate inflammation and immune response
Transforming growth factor beta family - Regulation of immune cells
Type 1 IFNs are produced by what? (2)
Infected cells and Dendritic
cells
What do IFNs do? (3)
Increase the expression of Interferon stimulated genes which
Induce MHC I expression for
communication and activation of the adaptive immune response
Induce NK cell activation and ultimately T cell activation
How do NK cells kill infected cells? (2)
Recognise lack of MHC class 1 molecules
Inject toxic enzymes and cytotoxic molecules and cause apoptosis of the infected cell
Antibodies are important defences against what kind of viruses? (1)
Extracellular
What are the three different antiviral activities of antibodies? (3)
Opsonise
Neutralise viruses
Activate the complement pathway
How do CD4+ T cells help B cells to become activated? (5)
B cells detect soluble, free antigens via their B cell receptor
Detection of antigen initiates B cell activation
Antigen is processed and bound to MHCII molecules for presentation to CD4+ T cells
A CD4+ T cell with a TCR that recognises the MHCII-peptide will bind, triggering activation and secretion of cytokines
These cytokines cause B cell differentiation into an antibody producing Plasma cell
What is neutralisation by antibodies? (3)
Antibodies bind to proteins on the surface of viruses
This prevents the virus from binding
to the receptors on host cells, entering the host cells and
uncoating
What is opsonisation by antibodies? (3)
Fc receptors bind to Fc region of antibody-antigen complexes ie viruses bound by antibodies (IgG)
Phagocytosis of immunoglobulin-bound virus can lead to the destruction of the virus
What is activation of complement by antibodies? (3)
Complement mediated neutralisation
Complement mediated virolysis
Complement mediated phagocytosis
What are the 3 different antigen presenting cells? (3)
Macrophages
Dendritic cells
B cells
What are toll-like receptors important for? (3)
Key inducers of pro-inflammatory responses in innate immunity
Mediate responses to pathogen-associated molecular patterns
(PAMPS)
Different types of TLRs recognise different types of PAMPs
How does TLR signalling induces transcription of IFN and pro-inflammatory cytokines? (3)
TLR7/8/9 signal through MyD88 to
NFKB to induce pro-inflammatory cytokines
In pDC a non-canonical pathway uses
IRF7 to induce IFN alpha transcription
TLR3 signals through TRIF to NFKB
and to IRF3 to induce pro-
inflammatory cytokines and IFNs
What are RNA helicases sensors of? (3)
Detect RNA via helicase domain and transmit signals through amino terminal CARD domains
RIG-I and Mda5 mediate non redundant detection of viruses
Recognition of viral RNA results in multimerisation and downstream signalling
How does RLR signalling induces pro-inflammatory cytokine and IFN expression? (2)
RLR switches on NFKB - makes pro inflammatory cytokines
RLR switches on IRF3 - makes interferons
How is viral DNA detected by cGAS? (6)
GMP–AMP synthase cGAS recognises dsDNA from DNA viruses and dsDNA that is produced by retroviruses
DNA binding causes cGAS to make cyclic GMP–AMP (cGAMP), which activates stimulator of interferon (IFN) genes (STING) on the endoplasmic reticulum in both the
infected and in neighbouring cells
cGAMP binding causes STING to form dimers and to undergo Lys63-linked ubiquitylation mediated by TRIM32 and TRIM56
STING then moves to the Golgi, interacts with TBK-1 and phosphorylation triggers activation
of IRF-3
How can cytokine production be dampened down? (1)
Suppressing expression of TLR9
Describe type I IFN signalling via the JAK-STAT pathway (7)
Interferons are cytokines and serve as signalling messenger moelcules to other cells
Bind to cell surface receptors to do this
In presence of interferon - monomers dimerise to form heterodimer
These receptor molecules are catalytically inactive
Cytosolic protein tyrosine kinases attached to tails of receptors (JAK1 and TYK2) are switched on by conformational changes brought about by dimerisation of receptors
catalytic activity - phosphorylate tyrosine
They have 2 substrates which are TF - STAT1 and STAT2 proteins
When they are phosphorylated by protein kinases they heterodimerise and bind to IRF-9 to form a protein complex called ISGF3
This reveals a nuclear localisation signals and translocate from cytoplasm into nucleus where tF work
bind to promoters of interferon stimulated genes
Summary:
Interferons released from cell - bind to cell with receptors - induce signalling - switch TF on - go to nucleus and bind to key promoters and drive transcription of a whole range of genes that are essential for antiviral response
Describe the viral inhibition of JAK-STAT pathway (1)
Viral proteins get rid of STAT proteins so they cannot be phosphorylated
IFITM proteins (ISG) have antiviral activity against what type of viruses? (2)
Have antiviral activity against enveloped viruses
Restrict virus infusion events early in infection
How has SARS-CoV2 evolved to avoid
restriction by IFITM proteins (3)
SARS-CoV2 has evolved a novel insertion in the spike protein that allows cleavage by TMPRSS2 at the cell surface and endosomal avoidance
Protein Kinase R (PKR) (5)
Interferon stimulated gene involved in translated
Activated by binding to dsRNA and then it dimerises
* Phosphorylates eIF2alpha which leads to blocking of translation, inhibition of protein synthesis and apoptosis
How is activation of Protein Kinase R (PKR) affected by viruses (3)
Viral proteins bind double stranded RNA which switches off PKR
Viral proteins prevent dimerisation of kinase so kinase not switches
Viral proteins substrate mimics - PKR phosphorylates wrong thing
Mechanism of K3L inhibition of PKR (2)
K3L has a sequence similar to eIF2alpha
Mops up all of PKR - cannot phosphorylate
How does Viperin restrict replication of viruses (3)
Virus inhibitory protein ER associated interferon inducible
Localises to the ER and thought to perturb several RNA viruses
Localises to lipid droplets to disrupt HCV replication
Induces a chain terminator through catalyzing the conversation of CTP into an analogue called ddhCTP - can’t replicate
What is tetherin? (4)
Cell surface expressed
Expression stimulated by interferon treatment
Blocks enveloped virus release
− HIV, also MLV and Ebola
Antagonised by Vpu which degrades tetherin
