Anti-viral Immunity Flashcards
How do host cells stop viral replication. List at least 5 mechanisms.
PRRs: TLR, RLR, NLRs
Transcription Factors: IRFs and NFkB
Restrict viral replication and assembly
Viral Restriction Factors: Tetherin, APOBEC, TRIM5alpha
What PRRs bind to:
ssRNA?
dsRNA?
DNA?
TLR7, RIG-I, MDA5
TLR3, RIG-I, MDA5
TLR9, AIM2, NLRs
Define interferon.
Cytokines that drive antiviral and anti-tumour responses by interfering with viral replication in host cells. Activate immune cells and upregulate Ag presentation and initiate cell pathways. Promote symptoms like fever during infection.
What are Type I IFNs?
Type II IFNs?
Type III IFNs?
Innate IFNbeta (1st wave) and IFNalpha (2nd wave). IFNgamma (macrophages/ adaptive T cells) Innate IFNlambda: IL-29 (first) and IL-28 (2nd)
Describe ISGs.
Interferon stimulated genes are stimulated by transcription factors associated with IFN signalling like IRFs and NFkB.
Describe first wave IFN signaling.
Mediated by PRRs. Initiates anti-viral response INSIDE host cell. Produces IFNs, and ISGs.
Describe second wave IFN signalling.
Is a positive amplification loop which propagates anti-viral responses through cells of infected tissue. Autocrine/paracrine effects. Produces more IFNs and ISGs.
Define viral restriction factors.
Proteins and enzymes that limit virus replication in hosts. There are multiple mechanisms and strategies directly for replication. Part of host cell’s intrinsic anti-viral immunity measures.
How are restriction factors express and induced?
They are expressed at basal levels an induced by IFN signalling cascades which can be amplified.
What is Trex1?
A viral restriction factor that degrades cytoplasmic DNA.
Do humans have Trex1? What does it do?
Humans have a mutant version that mounts chronic anti-viral responses in the presence of ERV DNA.
What is essential for limiting retroviral replication?
Innate immune signalling
Induction of host restriction factors with RT viruses is dependent on what?
IFN response
What kind of protease does HIV have?
Aspartic protease
What happens in HIV positive people when given HIV protease inhibitors?
Caused decline in opportunistic infections.
What does the HIV protease have an effect on?
RIG-I signalling pathway.
How can a virus evade IRF3
Inhibit phosphorylation, dimerization, or nuclear translocation
Degrate/Sequester IRF3
Inhibit interaction with transcriptional co-activators of target genes
What does the Ebola protein VP35 do? How does this work?
Inhibits phosphorylation of IRF3 which prevents dimerization and nuclear translocation
Name some viruses which can inhibit IRF3 activation.
Ebola, SARS coronavirus, PLpro, Dengue, etc.
What is SFTS virus? How is SFTS virus transmitted?
SFTS bunyavirus is an emerging pathogen. By ticks
What does SFTS cause in humans?
high fever, loss of WBCs and platelets, possibly multiorgan failure
How does SFTS virus evade the immune system? What other viruses do this?
It sequesters the IRF3.
RSV NS, Porcine epidemic diarrhea virus NS, HSV ICPO, Arenavirus NP, etc.
How does Rotavirus NSP1 evade the immune system? What other viruses do this?
Degrades IRF3 via the proteosome.
HTLV-1 via SOCS1, and BoHV ICPO
What viruses inhibit the transcriptional activity of host IRF3?
HHV8, EBV, vaccinia etc.
What is PKR? What does PKR do?
Protein kinase RNA-activated.
Recognizes dsRNA in the cytoplasm, shuts of protein synthesis (by phosphorylating eiF2alpha), and activates NFkB (by degradation of IkBbeta).
How can viruses evade PKR?
Decoy dsRNA, PKR degradation, hiding virus dsRNA, blocking PKR dimerization, PKR dephosphorylation
Name some viruses able to block PKR.
Influenza A (via non structural 1A protein) Adenovirus EBV (via EBER) HIV (via TAR and Tat) Poliovirus (via 2A pro) Vaccinia Reovirus HCV HSV
Which cells are crucial in limiting HTLV-1 replication? How?
Stromal cells (epithelial and fibroblast in particular) via secretion of type I IFNs
What does HTLV-1 infect?
Primary pDCs.
What is the Tax protein? What is its function?
What protein does the opposite and where does it come from?
Tax is a protein in HTLV-1 which promotes NFkB signalling while impairing IRF3 signalling.
HBZ inhibits NFkB p65 DNA binding and promotes degradation while also inhibiting IRF signalling. Also HTLV-1?
What does SOCS1 do in the cell?
What does it do with HTLV-1 present?
It affects multiple different pathways!
It degrades IRF3 and does not allow it to enter the nucleus.
HTLV-1, like HIV, is associated with several ___ ___
Opportunistic infections
Describe the innate immune system.
Rapid, intense, redundant, limited and fixed specificity to intact antigen, no memory.
Describe the adaptive immune system.
Requires time, requires Ag presentation, Dependent on T cells, Specific to intact and processed antigen, memory responses.
Describe how B cells recognize pathogens.
B cells use BcRs also called Immunoglobulin (Ig) which detect macromolecules like proteins, lipids, polysaccharides, and chemicals.
Describe how T cells recognize pathogens
T cells use TcRs which recognize/detect MHC-peptide complexes.
Describe how antigen presenting cells recognize pathogens.
APCs recognize peptides via MHC molecules
How is endogenous Ag recognized? By what? To whom?
How is exogenous Ag recognized? By what? To whom?
MHC I - peptide presentation to CD8+ T cells
MHC II - peptide presentation to CD4+ T cells
Name the APCs
DCs, macrophages, monocytes, B cells, epithelial cells, and eosinophils.
How are T cells positively selected?
How are T cells negatively selected?
Weak recognition of the MHC.
Responding to self.
What is the TcR-CD3 complex?
A way for the T cell to recognize the MHC complex. TcR and CD3 are next to each other on the T cell and both need to be activated in order to react
Name the T cell counterpart to the DC sample. Describe whether it is activating or deactivating if applicable. MHC II MHC I CD80/CD86 CD40
MHC II - TCR+CD4
MHC I - TCR+CD8
CD80/86 w - CD28 (activating) / CTLA4 (deactivating)
CD40 w CD40L activating
Describe how DCs initiate T cell tolerance.
A resting DC presents low Ag and no costimulation with short contacts.
Describe how DCs initiate T cell effectors.
An active DC presents high Ag, high costimulation with cytokines present, with long contacts.
Describe how DCs initiate T cell memory.
An exhausted DC presents high Ag, high costimulation with short contacts.
DC instruction of T cells determines which three things in the T cell?
On/Off
flavour or T cell
Population size of T cells
Define cytokine
Low MW protein which regs type, intensity, and duration of immune response
Define chemokine
cytokine which mediates chemotaxis
DCs secrete which IL at rest?
Which ILs do DCs secrete to effect Th1 cells?
Which ILs do DCs secrete to effect Th2 cells?
IL6
HIGH IL12 and 18
LOW IL 12 and 18
Can Th1 cells affect Th2 cells? If so, how?
Th1 –> Th2 = IFNgamma
Th2–> Th2 = IL4/IL10
What are the functions of Th1 cells?
Killing microbes/infected cells and reacting with B cells
What are the functions of Th2 cells?
Responding to allergy, affecting mast cells, interacting with B cells
What are the four kinds of T cell subsets?
Describe further subsets or functions of these.
CD4+ helpers: Th1, Th2, Th17, Tregs
Tregs: FoxP3 and IL10 secreting
CD8+ cytotoxic: antiviral and anti-tumour
NKT: inflammatory, antiviral, and anti-tumour
How can a virus avoid detection by T cells?
Block MHC activity by... Block host proteosome activity Block Tap import of peptides into ER Block MHC maturation/peptide loading Prevent MHC presentation on APCs
How does EBV evade T cell response?
EBV uses protein EBNA1 to block proteasomal breakdown of peptides so they can’t be presented by MHC.
What is a virokine?
Virus encoded secreted proteins which mimics host cytokines. Usually in DNA viruses
What kinds of virokines are there? I.e. what do they mimic?
Cytokines, receptor/binding homologues, viral growth factors, and SERPINs
How can viruses alter cytokine signalling?
By mimicking host proteins.
Name a chemokine that is mimicked. Name the virus that does this and how.
vIL10 mimicks IL10 by EBV using BCRF1
What is Castleman’s disease? What is the presentation of symptoms for Castleman’s? How is it treated?
Disfunctional cytokine networks by HHV8 encoding vIL-6. This causes lymphoproliferative diseases.
Spotty bright red patches near lymph nodes.
Cured by anti-IL6 treatment.
Which polymerases have the highest mutation rate?
RdRp and RdDp because they are encoded by viruses and have no proof reading.
What is a viral quasi-species?
Viral genomes with point mutations in genes which leads to distinct viruses.
When can virus specific CTLs not recognize virus infected cells?
if the mutations in the genome occurred in the epitope of the amino acid sequence.
What is an escape mutant?
A virus who has had a point mutation in the epitope portion of the AA sequence of its genome causing it to be unable to be recognized by the CTLs.
Why are escape mutants important?
They allow viruses to stay one step ahead of the immune system response.
When can viral epitopes undergo mutations?
All the time unless in highly conserved region that is necessary for protein function
Escape mutants can cause a loss in viral fitness. How can they fix this?
Compensatory mutation.
Name a virus in which escape mutants are very common. Describe this.
HIV-1
The virus has much selective pressure through out the body and slightly different variants of the virus can be found in many areas.
What is the function of the protein p53?
p53 is an anti-oncoprotein that induces apoptosis when activated. It can kill virally infected cells before viruses can reproduce.
Name a way for a virus to trigger p53
SV40 and HPV activate phosphorylation which causes apoptosis.
Which viruses encode Bcl-2 family proteins. What do Bcl-2 proteins do?
Large DNA viruses, All gamma herpes, and adenoviruses. Bcl-2 blocks apoptosis (p53)
Name a virus associated with cancer. Describe which cancer it causes, which protein is uses, and the mechanism.
HTLV-1 caues Adult T cell leukemia via the Tax protein. It is involved in the regulation of the cell cycle, apoptosis, cell transcription, NFkB, etc.
What does NFkB dependent lack of apoptosis result in?
Uncontrolled proliferation and cell transformation to cancer.
