Antiviral immune responses, immune evasion Flashcards
(33 cards)
Can you give an overview of the different aspects of host defenses?
During what time are the different phases active?
Anatomical and chemical barriers:
Continuous. Physical barriers
- Mucus, saliva, stomach acid, tears, skin, scabs, defensins
Intrinsic:
Immediate.
- IFNs, autophagy, apoptosis, miRNAs, CRISPRs
Innate immunity:
Minutes/hours.
- NK cells, complement, APCs, neutrophils, cytokines
Acquired immunity:
Adaptive. Hours/days
- T & B cells
How can IFNs indirectly contribute to the antiviral state?
Binding of e.g., type I IFN to IFNAR -> signaling cascade -> gene expression of PRRs detecting viral molecules and modulate signaling pathways or of TFs that form amplification loop -> more IFN produced
Mention some ISGs that encode proteins with potential for direct antivital activity.
Name some of the proteins
- Catalyze cytoskeletal remodeling
- Induce apoptosis
- Regulate post-transcriptional remodeling (splicing, mRNA editing, RNA degradation, steps of translation)
- Regulate post-translational events
Examples:
ISG15
Mx1 (GTPase)
Ribonuclease L (RNaseL)
Protein kinase R (PKR)
What is the role of IFIT1 and how can viruses escape it?
IFIT1 = IFN-induced protein with tetratricopeptide repeats 1
It binds RNAs lacking 2’-O methylation.
May inhibit viral replication and initiation of translation.
Escape:
- Cap snatching (IAV)
- 5’ end-independent translation (picornavirus)
- Viral N-7 and 2’-O methylase (parmyxovirus, flavivirus, poxvirus,…)
- Host N-7 and 2’-O methylase (polyomavirus, herpesvirus, parvovirus, retrovirus)
- RNA structure (alphavirus)
What are sentinel cells? How do they contribute to the antiviral state?
Can be APCs such as macrophages and DCs, or other types such as mast cells and specialized T cells.
Tissue cells that are not part of the immune system can be referred to as sentinel cells, e.g., fibroblasts or epithelial cells.
Sense and monitor the presence of dangerous and injurious foreign material in all body tissues.
Example: DCs
- Virus binds to epithelial cells
- Replication and local spread of infection
What are sentinel cells? How do they contribute to the antiviral state?
Can be APCs such as macrophages and DCs, or other types such as mast cells and specialized T cells.
Tissue cells that are not part of the immune system can be referred to as sentinel cells, e.g., fibroblasts or epithelial cells.
Sense and monitor the presence of dangerous and injurious foreign material in all body tissues.
Example: DCs
- Virus binds to epithelial cells
- Replication and local spread of infection
- Release of cytokines, viral proteins/nucleic
acids from infected cells.
Immature DC -> mature DC
- Spread to lymphatics (activation of T cells via
MHC II and cytokines)
- Circulatory system: adaptive immunity takes
over (B/T cells, Ab)
What determines the killing function of NK cells? How can viruses modulate the killing?
The ratio of activating and inhibitory receptors.
More activating receptors -> killing
Viruses can upregulate the inhibitory receptors -> no killing
Describe the complement system and its three pathways briefly.
Can be activated directly by pathogens or indirectly by pathogen-bound antibody, leading to a cascade on the surface of pathogens and generates active components with various effector functions
-> enhance immune response.
Pathways:
- Classical - membrane attack
- Lectin - phagocytosis
- Alternative - inflammation
What are the four classical signs of inflammation? Why do they occur?
Redness, pain, heat, swelling.
Increased blood flow, increased capillary permeability, influx of phagocytotic cells, tissue damage
What are the three classes of cytokines and their main activities?
Proinflammatory - Promote leukocyte activation.
Antiinflammatory - Suppress PICs.
Chemokines - Recruit immune cells
How do neutrophils move in the blood to the site of action?
Rolling - activation - arest; adhesion - transendothelial migration.
Have chemokine- or chemoattractant receptor, CAM, and integrin on surface.
Bind E-selectin via CAM in endothhelium when rolling, and Ig-superfamily CAM via integrin (on neutrophil) when adhering to epithelium (stronger connection)
Mention three viral countermeasures against cytokines
- Interrupt cytokine production
- Interfere with cytokine action (homologs, soluble cytokine receptors to neutralize them)
- Interfere with cytokine effector function (cytokine signaling pathway)
What are the differences between cytophatic and non-cytophatic viruses? Examples?
Cytophatic - cause inflammation because they promote cell- and tissue damage. Activate innate response.
- Adenoviruses, herpesviruses, poxviruses
Non-cytopathic - no cell damage or apoptosis. Low/ineffective innate response. No effective activation of adaptive response.
Persistent infections: rarely or ineffectively cleared.
Give examples of viral countermeasures for intrinsic/innate defenses
All viruses must encode at least one regulator.
Sensing
IFN production
IFN signal transduction
Cytokines
Chemokines
NK cells
DCs
Complement
Give examples of how Ab can neutralize viruses
- Block attachment
- Block endocytosis
- Block uncoating
- Aggregation -> no effective uptake
- After replication has started
Give an example of how non-neutralizing Ab can protect against disease
Do not prevent cellular infection.
Can lead to cellular uptake into endosomes -> lysosomes -> virus degradation
Neutrophils can secrete DNA (w/histones) to capture viruses. IgA-stimulated NETosis (Neutrophil Extracellular Trap).
Give an example of how non-neutralizing Ab can protect against disease
Do not prevent cellular infection.
Can lead to cellular uptake into endosomes -> lysosomes -> virus degradation
Neutrophils can secrete DNA (w/histones) to capture viruses. IgA-stimulated NETosis (Neutrophil Extracellular Trap).
How can viruses counteract the MHC I pathway?
- MHC I synthesis
- TAP synthesis and function
- MHC I transport
- Retain in ER
- Dislocate to cytoplasm
- Increase MHC I endocytosis
How can a CTL lead to lysis of a virus-infected cell?
Two mechanisms:
1. Release of cytoplasmic contents (perforin)
2. Apoptosis (granzyme B cleaves pro-caspase to caspase)
Mention four mechanisms by which Ab’s can eliminate viruses
- Neutralizing Ab’s: prevent infection
- Opsonization: mark virus for phagocytosis
- Complement fixation and formation of the membrane attack complex -> phagocytosis or lysis
- Antibody-dependent cell-mediated cytotoxicity (ADCC): NK-induced apoptosis
What determines the outcome (on infecition) of a heterotypic infection?
Heterotypic infection = many serotypes. Mixture of neutralizing and non-neutralizing Ab’s are produced. Some Abs produced during primary infection are/will be cross-reactive.
Outcome depends on the quantity of the specific Abs.
May be antibody-dependent enhancement of disease.
Example: Dengue virus
Which types of RNA do TLRs and RIG-I-like receptors (PRRs) recognize and where?
TLRs:
In the host: only mRNAs are present in the cytoplasm. These are 5’ (guanosine) capped. Bind non-capped RNAs in the endosome or on the cell surface.
RIG-I-like:
Recognize cytoplasmic RNAs that are not cellular products.
Results are the same: IFNs + cytokines produced
How can a cell sense DNA viruses?
“Foreign DNA” receptors in cytosol and nucleus.
Viruses may leak DNA as they pass through the cytosol.
Recognition in endosome: TLR9.
In cytoplasm: cGAS
In nucleus: IFI16
How does SARS-CoV-2 evade the immune system?
- Modify its RNA (5’ capping)
- Formation of double-membrane vesicles (DMVs) to evade immune responses
- Degrade/displace signaling components
- Inhibit translocation of IRF and STAT
- Suppresses IFN responses
- Inhibits IFN-synthesis and IFN-mediated
signaling
- Inhibits IFN-synthesis and IFN-mediated
Impaired/delayed IFN induction -> uncontrolled (early) virus replication -> cytokine storm
