Viral Pathogenesis Flashcards
What are some features of the interplay between the immune system and viruses?
- The immune system has evolved to combat invasion by microorganisms including viruses.
- Viruses have likewise evolved mechanisms that enable them to evade immune attach
- by not being recognised by the immune system OR
- by interfering with functioning of particular immune mechanisms
- The large, complex DNA viruses, in particular, have acquired many strategies for immune evasion. In evolution they have picked up things from cells to aid there survival. (Immunevasion genes)
These include the herpesviruses
- herpes simplex virus (HSV)
- varicella-zoster virus (chickenpox)
- cytomegalovirus virus (CMV)
- Epstein Barr virus (EBV)
and the poxviruses eg vaccinia, myxoma viruses
What are some viral evasion strategies seen in the body?
Viral Evasion Strategies:
Antibody and T Cells:
Latency - eg HSV in neurones, Epstein Barr virus (EBV) in B cells
Antibody
Antigenic variation in B cell epitopes
- antigenic drift - eg influenza & HIV, (and shift - influenza)
T cell priming by DC
Tc cell recognition
1. Antigenic variation in Tc epitopes - HIV
2. Inhibition of processing and presentation of viral peptides (many viruses)
3. Decreased production of MHC class I molecules (HIV, RSV, adenovirus)
NK cell recognition
1. Mutations in ligand for activating receptor-MCMV
2. Virus-encoded MHC class I-like molecules - HCMV
3. Upregulation of non-classical class I molecules- HCMV
Interferon
Interference with PKR pathway
- abundant small RNAs: adenovirus, EBV
- dsRNA-binding protein: reovirus, vaccinia
- PKR-binding protein: vaccinia
Cytokines
1. Virus-encoded cytokine receptor homologues - pox viruses: vaccinia, myxoma
2. Intracellular blocking of cytokine production - eg IL-1beta by crm A protein of vaccinia, cowpox
3. Intracellular interference with cytokine function - eg TNFalpha and adenovirus Apoptosis inhibition
Complement
Virus-encoded homologues of complement control proteins
How can antigenic variation arise?
Antigenic drift eg HIV, influenza virus
- Change in the antigenic structure of the virus
- Due to selection of variant viruses with amino acid substitutions in the viral glycoproteins that allow the virus to escape neutralization by pre-existing antibody.
- Variant viruses arise spontaneously through errors in RNA replication giving rise to point mutations in the genes
- In influenza, antigenic drift occurs on a population scale with different mutations accumulating as the virus moves from person to person. In HIV infection a diversity of strains may develop within a single patient.
What is the mehanism for Inhibiting T Cell Priming by DC?
- Viruses need to subvert the DC cell maturation process that causes T cell activation and adaptive immune system response.
- For example, vaccinica encodes a homologue of the tail of TLR4 that will cause the signalling cascade to be dampened. It imaprirs the DCs from maturing
- Herpes simplex virus blocks transduction of maturation signals to the nucleus.
- Vaccinia and HCV block cytokines that are designed to recruit other dendritic cells to the site for maturation.
- There are numerous mechanisms and viruses that affect each of the steps shown above.
How do viruses evade recognition by CD8 T cells?
- while the CD8 T cell induction can be interrupted as above, some are still primes and so there are mechanisms that can interrupt the recognition of the virus by those primed T cells.
TAP: transporter of antigen peptide; loads the antigen onto the MCH molecule
- Evidently Cytotoxic T Cells are very important for clearance of these infections
What are some features of Natural Killer Cells?
- Distinct lineage of lymphocytes (non-T, non-B), FcR+
- Show spontaneous cytotoxicity towards a variety of tumour cells and virus-infected cells
- Also a major source of IFN-gamma
- Present in blood and lymphoid organs of normal uninfected individuals but become rapidly activated during infection in response to IL-12 or IFN-alpha/beta
- Humans with NK cell deficiency highly susceptible to varicella (chickenpox) and cytomegalovirus (CMV), which are both members of the herpesvirus family
- Cells of the innate immune system
- Kill virus-infected (and cancer) cells but not virus-specific
- Different NK clones have different activation and inhibitory receptors
- Activation receptor recognizes molecules on the cell surface that are there as a result of virus infection (provides something for the NK cell to engage the target cell with) and will send a killing signal
- The inhibitory receptor binds to MHC Class I molecules on the target cell. If engaged this will override the killing signal
- If class I is aberrantly expressed or absent, the inhibitory receptor will not be engaged and the NK cell will kill the target cell.
NK activity is controlled by a balance of stimulatory and inhibitory signals.
- viruses that cause reduction of MHC Class I expression evade CD8 T cell recognition but may become more susceptible to NK killing
Why are NK cells effective for intracellular viruses?
- Because many viruses downregulate MHC Class I, they immediately become more susceptible to NK cells so they need alternate mechanisms to overcome the NK effect.
What are interferons?
Interferons:
- Identified originally as a soluble factor released from virus-infected cells that inhibits viral replication in neighboring cells
- Antiviral activity of interferons is mediated by the induction of particular cellular proteins or pathways in the IFN-treated cell
What are some Genetic Factors influencing Susceptibility to Viral Infection?
- inherited defects
- eg. absence of Ig class
- polymorphisms in genes controlling immune responses
- eg. MHC genes
- interferon-inducible genes (MxA and MxB)
- receptor genes
- eg. CCR5
What are some Non-Genetic Factors Influencing Susceptibility to Viral Infection?
- age
- newborns and the aged are more susceptible to severe disease (immature and waning immune response) but young suffer less from immunopathology
- malnutrition
- decreases resistance
- hormones, pregnancy
- males and pregnant women more susceptible (why?)
- dual infections
- may result in more severe disease
What are some various outcomes of viral infection?
- fatal
- viral diseases where man is not the natural host have very high mortality rates eg. Ebola
- full recovery
- virus completely cleared by host’s immune system eg influenza
- recovery but permanent damage
- virus cleared but left with symptoms eg. poliomyelitis, cancer
- persistent infection
- virus not cleared and can resurface to cause disease
