Immune Evasion by Viruses Flashcards
Interferons
(innate Immune response)
Type 1 Interferons (alpha, beta & omega)
- Produced by virus-infected cells, in response to presence of dsRNA, recognized by PRRs
- Switches on IFN gene, cell–> IFNs–> switches on viral resistance genes in neighbouring cells
- Makes cells more resistant to virus replication- ↑ degradation of viral mRNA & ↓ synthesis of proteins
- Enhances antigen presentation (MHC class I)
Mechanisms Used to Subvert/ Avoid Interferons
- Pestiviruses produce non-structural proteins early on, that influence the biology of the cell they’re infecting:
- Can block the signalling pathway of the PRR, so no IFNs are produced
- Or can switch off IFN receptors, preventing cells becoming more virus resistant
Virus Neutralizing Antibodies
Antigens give viruses their species specificity and tissue tropism as they can only interact with & attach to specific host cell receptors.
- Canine parvovirus- main antigen= VP2 on its capsid, binds to transferrin receptor on host enterocytes means it only affects host enterocytes and is specific for dogs as well
- Influenza virus- hemagglutinin antigens to bind to sialic acid residues found in respiratory epithelium.
Virus Neutralisation- B cell antigen receptors recognize whole virus particles, recognize proteins on surface of these viruses, antibodies in extracellular fluid coat surface of virus and prevent it attaching (virus neutralisation)
Mechanisms Used to Avoid Virus Neutralizing Antibodies
(Avoid Leaving the Cell)
- Spread contiguously instead- produce fusion proteins which causes the cell membrane to fuse with surrounding cells (coalesce), so can travel to the next cell without going out –> syncytia formation –
- Respiratory syncytial virus (RSV)–> pneumonia
- Force infected cell to multiply (transformation)- copies the virus into the new cells as it multiplies
- Some retroviruses: FeLV preferentially infect immature t cells in thymus–> thymic lymphoma
Mechanisms Used to Avoid VN Antibodies
(Producing Decoys)
- Produce soluble decoy antigens within cell as they replicate, identical to their structural protein, force the cell to secrete huge amounts of these–> ECF, which saturate the antibody binding sites
- Ebola
- Express decoy proteins on their surface which are big & noticeable so the IS focuses on those & ignores the smaller, important ones, therefore the antibodies produced aren’t effective
- Important to use subunit vaccines in this case otherwise the same response occurs
- Important in diagnostics, ↑ no. of antiviral antibody in blood doesn’t mean they’re functional, this is when a VN assay is much more informative than an ELISA
Mechanisms Used to Avoid VN Antibodies
(Antigenic Variation)
- Antigenic Drift- Virus genes are subject to mutation. These slight changes at a nucleic acid level can alter the protein sequence so the antigen is no longer recognised by the original antibody- slow process
- Antigenic Shift- Whole genes are swapped between viruses to radically change the antigens expressed- Much quicker process- influenza viruses do this all the time chimeric viruses potential pandemics
- Human & bird influenza virus can both infect pigs. In pig they can swap genes around and the virus that emerges can become highly pathogenic towards humans or birds
CD8+ Killer T-Cells
- Antigens get broken down–> peptides by cell proteasomes & translocated via TAP transporters into ER where they bind to newly synthesised MHC Class I & are presented on surface for CD8+ cells to detect
Blockade of MHC I Presentation of Antigen
- Viruses can stop this pathway by producing early, non-structural proteins to block TAP transporters
- Or can produce proteins which grab hold of the MHC class 1 molecules & retain them in the ER
Some retroviruses produce superantigens which “glue” MHC and TCR together non-specifically–> every T cell in body gets activated –>massive polyclonal response which dilutes the antigen specific one
Tolerance
- BVDV (pestivirus)- Clinical problem= reproductive disease, not an enteric disease
- 2 biotypes:
- Cytopathic strain- quite virulent, cause lots of tissue damage–> Diarrhea and abortions
- Non Cytopathic strain- ↓ tissue damage but can cross placenta & replicate in fetal tissues particularly bad if it gets into primary lymphoid organs
- Replicates in enterocytes–> placenta in pregnant animal–> foetus infected whilst immuno-incompetent
- Viral antigen enters primary lymphoid tissues during lymphocyte development–> Clonal deletion of virus-reactive lymphocytes as if it was self-antigen tolerant to BVDV
- Calves= persistently infected (PI) –> shedding- main source of infection
- Can develop mucosal disease:- Endogenous non cytopathic virus strain mutates –> cytopathic, or
- Superinfection with cytopathic strain of BVDV from environment
- Calf has no immunity/ ability to develop immunity against the virus, so dies of mucosal disease (massive ulcers and haemorrhagic lesions develop throughout alimentary tract)
Direct Immunosupression
- Targeted infection and destruction of cells of immune system (lymphocytes)- Typically T helper cells, macrophages and DCs, as without these the rest of the adaptive IS falls apart.
- Feline Immunodeficiency Virus (FIV) –> profound immunosuppression –> many die from opportunistic infections & cancer (due to suppressed tumour surveillance)
Indirect Immunosuppression
- Innate & adaptive IS communicate via cytokines, viruses can produce fake cytokines to hijack this
- Epstein-Barr virus (glandular fever) produces an IL-10 like molecule, IL-10 is usually released by regulatory T cells to dampen down the IR, so this allows the virus to replicate unchecked.
- Orf virus in sheep does this too
Sequestration in Immune Privileged Sites
- CNS, eye and testes= hidden from IS to prevent collateral damage due to the inflammatory response
- Blood brain barrier provides a physical defence against infection (as does blood-tested barrier etc)
- Some viruses deliberately target these area (e.g. Rabies) as no IS present there to destroy them.
Latency
- Initial infection is rapid- virus infects, destroys cells & spreads to next host (viral shedding)
- Virus then enters quiescent/ dormant stage of development, usually in a different cell type to the one it destroys (often a lymphocyte/ neuron)
- Viral genome is maintained in host cell but doesn’t replicate, integrate with DNA & no protein synthesis
Recrudescence
(revival of material or behavior that had previously been stabilized, settled, or diminished)
- Triggering factor in host: Stress, medication or ↓immunity–> re-activation of virus
- Replication, reappearance of clinical disease & shedding of virus can occur again
In Humans: Herpes virus cold sores, Chicken pox shingles
In Cats- ‘cat flu’- caused by calici virus/ FHV-1- stress of cattery/ ↓IS can recrudescence
In Horses- EHV- affects endothelial cells (wipes out blood vessels) respiratory disease & abortions
