Innate immunity against viruses and viral evasion strategies Flashcards
List the different sites of Microbe Entry
Conjunctiva
Respiratory Tract
Alimentary tract
Urinogenital tract
Anus
Arthropod
Capillary
Scratch, injury
Skin
Physical barriers - Skin, mucosal surfaces
Chemical barriers - acid pH, secreted factors, proteolytic enzymes, bile
What are the Intrinsic defences – “the hostile cell”
- Apoptosis
- Restriction factors/Intrinsic Immunity
- Epigenetic silencing
- RNA silencing
- Autophagy/Xenophagy
Microbicidal peptides have broad-spectrum
antiviral effects
Give examples of some
- during influenza virus infection mucins, gp-340 and pentraxins compete with the virus for its receptor, sialic acid, and cause aggregation of virus particles.
Respiratory secretions are also rich in the collectin surfactant proteins (SP)-A and SP-D. These molecules bind to carbohydrates on a range of pathogens, including influenza virus where they adhere to the hemagglutinin protein (HA) resulting in virus neutralization. Some strains of influenza virus fail to be recognized by collectins due to reduced levels of glycosylation of HA. An example of this was the H1N1 virus that caused the 1918 pandemic.
Other families of antimicrobial peptides include the defensins and the related cathelicidins. Alpha-defensin and the cathelicidin LL37 are produced by epithelial cells and neutrophils in reponse to infection. They have broad-spectrum direct antiviral activity, and also modulate the inflammatory response at sites of infection.
Type I interferons have critical antiviral
and immunostimulatory roles
Describe this
The activation of the IFN system is arguably the most important defence for containing the initial stages of virus infection. There are three major families of IFNs:
* type I (multiple subtypes of IFNa and one subtype of IFNb);
* type II (IFNg); and
* type III (IFNl1, IFNl2, and IFNl3, also known as
IL-29, IL-28a, and IL-28b).
Of these, it is the type I and type III IFNs that are induced directly following virus infection, whereas IFNg is produced by activated T cells and NK cells.
Type I IFNs can be produced by almost any cell type in the body if it becomes infected with a virus. There are also specialized interferon-producing cells, plasmacytoid DCs, which can
be triggered to produce high levels of type I IFN following exposure to virus without themselves becoming infected.
Type I IFN production is triggered following recognition of molecular patterns characteristic of viral but not host components (Fig. 13.1). Host pattern-recognition receptors involved in detecting the presence of virus infections
include:
- cytoplasmic pattern-recognition receptors expressed by almost all cells (e.g. the retinoic acid-inducible gene I (RIG-I)-like receptors, which recognize viral 50- triphosphorylated ssRNA and dsRNA, and cytoplasmic DNA sensors);
- members of the Toll-like family of receptors (TLRs), which are expressed on the cell membrane or within endosomes/lysosomes of immune system cells and certain non-immune cells located at common sites of pathogen entry, e.g. epithelial cells (TLR3, TLR7, and TLR9, which recognize viral dsRNA, viral ssRNA, and DNA containing CpG motifs, respectively).
Effector functions of Type I interferon
IFNs mediate their activity by up-regulating the expression of a large number of genes known as IFN-stimulated genes (ISGs), some of which encode proteins that mediate an antiviral response. These include the key dsRNAdependent enzymes protein kinase R (PKR) and 20,50- oligoadenylate synthetase.
* PKR disrupts virus infection by phosphorylating and inhibiting eukaryotic initiation factor (eIF)-2a, hence blocking the translation of viral mRNA and by initiating
apoptosis via Bcl-2 and caspase-dependent mechanisms, killing the cell before virus can be released.
* 2’,5’-oligoadenylate synthetase specifically activates a latent endonuclease (RNaseL) that targets the degradation of viral RNA.
IFNs also activate macrophages and NK cells and enhance their antiviral activity.
In addition, they help to promote the activation of adaptive responses. They act on APCs to stimulate increased expression of MHC class I and II, and components of the antigen processing machinery; and they also act directly on T and B cells to promote an antiviral response
Describe how virus induce apoptosis in host cells
Describe how virus can evade the induction of apoptosis in host cells
List the restriction factors and their functions
Particularly active against retroviruses
* APOBEC3G
- Highly potent ssDNA cytidine deaminase
* TRIM5α
- Targets incoming capsids to proteasomes; very species-specific
* Tetherin
- Blocks budding by enveloped viruses
* SAMHD1
- A phosphohydrolase that converts dNTPs to inorganic phosphate and depletes the pool of dNTPs available to reverse transcriptase
Describe Evasion of Restriction factors by HIV
Describe Epigenetic silencing
- Foreign DNA molecules that enter the cell are quickly organised into transcriptionally silent chromatin
- This is a nuclear event and involves “PML bodies”
- Silences DNA viruses, such as Adenoviruses and
Herpesviruses - Large DNA viruses that replicate in the nucleus
encode proteins (such as ICP0) that prevent the deposition of inhibitory histones and other chromatin components onto viral DNA
There are many components to innate anti-viral immunity
Describe phagocytosis
- Carried out in vertebrates by Dendritic cells,
macrophages and neutrophils - Phagocytosis clears pathogens but also presents
peptides on MHCs – this promotes development
or reactivation of the adaptive immune response
There are many components to innate anti-viral immunity
Describe the complement
- Classical pathway by direct binding of C1q to the envelope glycoproteins of some viruses (including human cytomegalovirus and certain retroviruses, such as human T cell lymphotropic virus)
- Lectin pathway; MBL binds to viral surface carbohydrates (implicated in controlling HBV and ‘flu)
- Alternative pathway on enveloped viruses
Describe the Evasion of the Complement by viruses
- Incorporation of complement control proteins into envelope
– Passive
– Active: - Vaccinia C3L gene product = VCP. Complement
control protein binds to and inactivates C3b and C4b - Vaccinia B5R gene product – recruits host
complement control proteins into envelope - KSHV(HHV-8)-encoded KCP; incorporated into the
virion; enhances the decay of classical C3 convertase and induces the degradation of activated complement factors C4b and C3b by a serine proteinase, factor I.
How do phagocytes “see” viruses?
- Phagocytosis requires receptor binding
– Some viruses infect phagocytes and use them as a
“superhighway” to establish a systemic infection (e.g.
DENV, Measles Virus). Many viruses don’t infect phagocytes - Viruses with bound complement can be cleared by
phagocytosis - Apoptotic cells have an “eat me” signal on their
surface (phosphatidylserine) which is recognised
by phagocytes - “Passive sampling” - pinocytosis
There are many components to innate anti-viral immunity
Describe Natural Killer (NK) cells
- Natural killer (NK) cells are a subset of lymphocytes found in the blood and tissues, which lack antigen specific surface receptors (TcR or immunoglobulin receptors). They are a distinct lineage of lymphocytes.
- NK cells possess the ability to recognise and lyse
virally infected cells and certain tumour cells. - Activated by IL-12, IL-15, IFN-a/b and IFN-g
- NK cells possess the ability to recognise and lyse virally infected cells and certain tumour cells.
- Selectivity is conferred by LOSS of “self” MHC
molecules on target cell surfaces, AND up-regulation of activating ligands
Describe the activation and inhibition of NK cells
- Inhibitory NK receptors (NKG2A &) typically recognize ligands
expressed on ‘normal’ host cells, such as MHC class I
molecules. Many viruses downregulate MHC class I expression on the cells they infect to limit recognition by CD8+ T cells, but this helps to trigger NK cell activation. - Activating NK receptors (e.g. typically recognize host cell
proteins that are up-regulated in response to stress or viral proteins, e.g. the natural cytotoxicity receptors NKp44 and NKp46 recognize certain viral glycoproteins including the influenza virus HA. - NK cells can also be activated via antibody coating of the target cell which mediates crosslinking of the NK
surface receptor FcgRIII. NK cells are one of the principal mediators of antibody dependent cell-mediated cytotoxicity (ADCC)
How does CMV downregulate NK cells?
CMV proteins (UL40, UL142) that act to decoy NK killer receptors
CMV protein (UL16) that acts to down-regulate NK activating receptors
