Immuno 12 - Immunity to Viruses Flashcards
examples; poorly adapted viruses kill their hosts
Examples include:
* Rabies virus in dogs, cats, horses and cattle (in contrast, it survives for long periods of times in bats and skunks without causing disease)
- Feline panleukemia virus (cats die due to sloughing of infected intestinal
epithelium causing severe bloody diarrhea) - Canine parvovirus‐2 (shock and severe dehydration due to systemic
inflammatory response syndrome [SIRS] and destruction of intestinal crypts) - Virulent forms of Newcastle disease
virus in poultry
virome defintion
- Viruses are a normal part of microflora
- Most animals are infected with hundreds to thousands of non‐pathogenic viruses (known as their virome)
- These include bacteriophages (i.e., viruses that infect bacteria) in the commensal bacteria
difference between replication of DNA vs RNA viruses
-DNA includes replication, transcrption, translation
-RNA doesnt have a transcrption step so they replicate faster
-Viral proteins needed to make physical viral particle
replication of retroviruses
- Also called lentiviruses; e.g., human
immunodeficiency virus (HIV); feline
immunodeficiency virus (FIV) in cats - These integrate into the host genome as a provirus
- Animals have endogenous retroviral
(ERV) sequences integrated into their
DNA that get passed to progeny - Interesting note: porcine endogenous retroviruses (PERVs) were the reason a call was made for a world‐wide moratorium on xenotransplantation (pig‐to‐human; risk of PERVs in immunosuppressed patients recombining with and making new human viruses was deemed to high)
interferon response to viruses
- Type II interferon (IFN) = IFN‐γ; associated with a Th1‐biased adaptive immune response (i.e., targets intracellular pathogens like viruses)
- Type I IFN represents an innate anti‐viral response
- The main type I IFNs are IFN‐α and IFN‐β (there are other types and subtypes totaling about 22 in humans)
-The sequential production of interferon and antibody following intranasal vaccination of calves with infectious bovine rhinotracheitis vaccine
- Type I IFNs are induced when pattern recognition receptors (PRRs) recognize pathogen‐associated molecular patterns (PAMPs) from viruses
- TLRs that recognize viruses:
-TLR3 = retroviral double‐stranded RNA
-TLR7/8 = single‐stranded RNA
-TLR9 = viral DNA (also used to detect bacterial DNA) - Plasmacytoid dendritic cells (pDCs) are a subset of DCs capable of producing massive amounts of type I IFNs
type I interferon response
- Type I IFNs are induced when PRRs in cells sense viral components (PAMPs)
- These secreted type I IFNs are then detected by cells via the type I IFN receptor (called IFNAR)
- All types and subtypes of type I IFNs
signal through the same receptor - Detection of type I IFN up‐regulates an array of antiviral mechanisms inside a cell
- Responding cells can be the same ones that produce the type I IFN (autocrine feedback loop) or proximal or distal neighbours (paracrine and endocrine responses, respectively)
antiviral mechanisms induced by type I interferon
Sensing of type I IFN results in:
* Suppression of gene transcription
* Suppression of translation into proteins
* Sensitization of cells to apoptosis
* Induction of enzymes that degrade viral RNA
* Production of proteins that block viral assembly
* Activation of enzymes that degrade viral proteins
-These processes begin within minutes of a cell sensing type I IFN and can sometimes peak in only 5‐8 hours
antiviral mechanisms: T cells
- The most important immune response against viruses after infection is the cell‐mediated immune response
- The primary effectors are CD8+ cytotoxic T cells, which recognize virus‐derived epitopes being expressed in the context of MHC class I on the surface of infected cells
- This type of response is supported by CD4+ Th1 cells (which are also required for the production of “type 1” antibodies that can mediate the functions in the previous slide; note: Ab responses against viruses are
typically of much lower magnitude than those against extracellular bacteria)
antiviral mechanisms; antibodies
Neutralizing antibodies bind to viruses in the extracellular environment and…
* Block infection of cells
* Promote opsonization (phagocytosis via Fc receptor‐ mediated uptake of virus‐Ab complexes)
* Complement‐mediated virolysis
Antibody‐dependent cell‐mediated cytotoxicity (ADCC):
* Antibodies can bind to viral proteins expressed on the surface of cells (a feature of some viral infections)
* Cytotoxic cells (e.g., natural killer [NK] cells) can then bind the Ab via their Fc receptors, become activated
and then kill the virus‐infected target cell
viral evasion of the immune system
Some of the mechanisms used by viruses:
* Block production of type I IFN
* Down‐regulate expression of type I IFN receptors
* Synthesize soluble IFN receptors
(decoy receptors that “mop up” IFN)
* Block production of IFN‐γ, which inhibits a Th1‐type response
* Blocking antigen processing and/or presentation
* Down‐regulating expression of MHC molecules (but this is a trigger for NK cell activation)
* Up‐regulate ligands that inhibit NK cell activation
* Use antibodies to access phagocytic cells where some viruses can survive and replicate
* Infect and kill lymphocytes
* Become latent (reversible non-productive infection)
* Inhibition of apoptosis
antigenic variation; drift vs shift
-Viruses can change their antigens, allowing them to evade previously induced immune responses
-Antigenic drift: a gradual change in antigenic structure due to an accumulation of minor genetic mutations over time
-Antigenic shift: a sudden change in antigenic structure due to recombination of genetic material between two different viral strains
-Influenza A virus strains are notorious for antigenic variation making the development of new vaccines an annual chore
veterinary viral disease; blue eye (interstitial keratitis) in dogs
- Caused by a type III hypersensitivity reaction in the cornea to canine adenovirus serotype I (which causes infectious canine hepatitis)
- Antibody‐virus complexes form in the cornea
- This activates complement proteins
- These recruit neutrophils
- Enzymes and oxidants from neutrophils damage corneal epithelial cells
- This causes edema and opacity in the cornea
- Spontaneously resolves in 90% of cases
veterinary viral disease; aleutian disease of mink
- Parvovirus infection of mink
- Causes a lymphoproliferative disorder of B cells similar to myeloma (cancerous plasma cells) but involving multiple clones (i.e., polyclonal)
- Primary problem is development of
immune complexes containing antibodies and viruses - Immune complexes form in blood vessel walls and the kidneys and adsorb onto red blood cells
- RBCs get phagocytosed by macrophages = anemia
- Best treatment is suppression of B cells (e.g,. cyclophosphamide)
- The serum protein electrophoretic patterns seen in normal and Aleutian disease‐infected mink
- The serum of the infected animal shows a polyclonal gammopathy, so the γ‐ globulins account for 62.4% of the serum proteins in contrast to the normal level of 14.3%
veterinary viral disease; feline infectious peritonitis
- Caused by feline infectious peritonitis virus (FIPV; a type of feline coronavirus)
- Uniformly incurable and fatal (1 week ‐ 6 months)
- This virus usurps the immune system
- FIPV replicates in macrophages, which distribute the virus in the body
- A Th1 cell‐mediated immune response is somewhat protective
- Some cats mount a Th2 response, which makes matters worse because the primary effectors are antibodies that promote Fc‐receptor‐mediated uptake of the virus by macrophages (i.e., this is where the virus wants to be)
- A modified live virus vaccine is available for prophylaxis (efficacy questionable; a DNA vaccine promoted disease severity)
- The vaccine is given intra‐nasally and induces IgA in the lungs, which blocks the virus without inducing significant systemic antibodies
- Antiviral drugs are available
veterinary viral disease; equine infectious anemia
- Equine Infectious Anemia Virus (EIAV is a type of lentivirus)
- Characterized by anemia, fever,
thrombocytopenia, weight loss, and
depression - EIAV binds to red blood cells (RBCs)
- Antibodies against the virus result in complement‐mediated lysis and phagocytosis of RBCs = anemia
- Following recovery, horse remains clinically healthy for weeks to months
- However, relapse occurs
- This cycle of recovery followed by relapse can happen numerous times, with clinical severity of the disease progressively decreasing
- This feature is due to antigenic variation of the virus (it mutates rapidly)
- Eventually the spectrum of neutralizing antibodies becomes so broad that viremia drops to a low level
