k? (L16) Flashcards
Virus encounters can lead to various outcomes IN CELLS
Acute cytopathic infection Persistent infection Latent infection Cell transformation Abortive infection Null infection
Virus encounters can lead to various outcomes IN ORGANISMS
Acute infection (disease) Subclinical infection Persistent and chronic infections Latent infection Slowly progressive disease Virus-induced tumour
How do we define disease?
SYMPTOM:
Any subjective evidence of disease or of a patient’s condition, i.e. such evidence as perceived by the patient, a change in a patient’s condition indicative of some bodily or mental state (how ill you feel)
CLINICAL SIGN:
An objective physical finding found by the examiner.
- Infection may or may not result in overt disease. In the absence of observable disease, an infection is said to be subclinical or silent.
- An immune response measured in vitro may not correlate with recovery or protection
define Virus Virulence
Virulence is the capacity to cause disease.
Virulence among viruses is relative and varies from avirulent (no disease) to lethal.
Few viruses are 100% lethal. e.g. ‘virulent’ poliovirus causes paralysis in only 1% of infected individuals.
Different strains of a virus can vary in virulence
define attenuation
Attenuation is the reduction in the virulence of a virus
define pathogenicity
Pathogenicity is the ability of the virus to cause pathology: this can be microscopic or macroscopic.
Since avirulent viruses can be pathogenic the terms are not synonymous.
Pathogenicity has come to mean ‘ability to cause disease’
Virulence has come to mean ‘relative disease-causing capacity’
what does virulence depend on?
Virulence depends on a combination of viral and host factors:
Virus factors
strain/isolate - genetically determined
dose
route of infection
Host factors
species
genetic constitution e.g. MHC proteins expressed
age, sex, nutritional status
The virulence of a virus cannot be described without reference to the conditions of infection
The Iceberg Principle of Infection
TOP OF ICEBERG Death of host Classical and severe illness Mild illness Subclinical or silent infection No infection BOTTOM OF ICEBERG
this shows a spectrum
Immune Control of Virus Infections
DIAGRAM IN L16 S12
Regulation of virus infection by the immune system (IS)
The IS is made up of many different responses:
- each is graded, not all or nothing
- quality and quantity of responses vary among people
The IS is not homogeneous throughout the body:
- e.g. CNS not subject to the full range of systemic IR until the blood-brain barrier is breached
- e.g. mucosal IS comprises all mucosal surfaces, and is in many ways distinct from the systemic IS
Regulation of virus infection by the immune system (IS):
Multiple elements of the IS combine to control a virus infection
Often only one part of the IS is effective in combating a particular infection, even though all parts of the immune response are mounted:
— each virus infection may be combated by different responses
The target of the immune response can be the virion or the infected cell or both
Intracellular virus is beyond the reach of adaptive immunity, unless virus antigens are displayed on the cell surface
Network of antiviral immunity
LOOK AT L16 S15
INNATE IMMUNITY AND VIRUS INFECTION
TITLE
types of Interferons
Type 1 Interferons α and β:
closely related cellular proteins made in response to virus infection.
have antiviral activity
can upregulate expression of proteins that are antiviral
can upregulate the expression of MHC I proteins (builds adaptive response)
Type 2 Interferon γ:
a cellular protein made by activated T cells in response to their cognate antigen
is a cytokine
different in sequence from interferons α and β
has antiviral activity
can upregulate the expression of MHC I and II proteins
how are interferon responses elicited
STEPS
- induction
- priming an antiviral state
- antiviral action of ISGs
interferon response elicited - step 1 induction
Induction of a response begins with the recognition by a cell that a pathogen is around (bacteria or virus, outside or inside the cell). Detected by PAMPs
PAMPS non specific features of pathogens to distinguish between the host and pathogen (like ds rna)
Recognised by PRRS - a cell surface receptor
PAMPS recognised - initiate a signalling cascade
Orange arrow ends with the activation of NFkB (usually sits in the cytoplasm bound to an inhibitor, signalling causes the disruption of the inhibitor which allows the TF to go into the nucleus)
IRF3 and IRF7 get phosphorylated in response to a signalling cascade, and also goes to the nucleus
2 TFs bind to the promoter of the interferon of the B gene and activates it - this is how you produce interferons in response to a pathogen detected
Interferon alpha can be expressed when IRF7 is present
interferon response elicited - step 2 priming an antiviral state
Generates an antiviral stage
Interferon is a cytokine so is secreted
Interacts with cells outside the cell using the cell surface receptor
Signalling cascade
Activates TF which ends up binding to the promoter of genes in nucleus
Allows transcriptional response to the interferon
(not only one gene, many ISGs - interferon stimulating genes)
Proteins encoded by ISGs are ready to counteract an infection once the cell is infected
interferon response elicited - step 3 antiviral action of ISGs
They are virus specific and activated by the presence of viruses
PKR when it works, disrupts protein synthesis (bad for the cell so dies, but this saves the organism from more virus)
PKR is only activated when cell is infected, and virus produces ds rna
dsRNA activates the PKR, protein synthesis shuts down, cell dies, virus dies with it
Disruption of mRNA will lead to disruption of protein synthesis
Apoptosis
ISGs include multiple pro-apoptotic factors
Antiviral state promotes apoptosis when virus is present
Alter the decision making balance between survival and apoptosis
Balance has to be tightly controlled (would lead to tissue damage otherwise)
Cell that is primed by interferons will be more inclined to go to apoptosis if it came into contact with a virus
ADAPTIVE IMMUNITY AND VIRUS INFECTION
TITLE
Antibodies and Viruses
Virus particles have the potential to stimulate antibodies to many different epitopes on their surface.
Crucial for mopping up virus in the system AND for providing memory protection against future infection
Can trigger complement-mediated killing of infected cells
Protein has enough diff epitopes to produce enough diff antibodies
Antibodies have a memory to minimise the outcome of an interaction with the same virus
NEUTRALISING ANTIBODIES have a variety of effects on virus infectivity/infection
- By acting on free virus particles
Aggregate virus particles together
[[ Deplete the number of infection unit by aggregating them together into one unit
(but here instead of blocking its ability to infect, we are reducing the number of infecting unit) ]] - By acting on early virus-cell interactions
Inhibit attachment of virus to cell receptors
[[ Lock the essential events in the infectious process
Blocks attachment of the virus to the cell ]] - Inhibit endocytosis of the virus particle
- Inhibit virus uncoating and/or fusion
- Inhibit a post-entry step of infection
difference between neutralising and non neutralising antibodies
Neutralizing antibodies: bind to virions and neutralize infectivity
Non-neutralizing antibodies: bind to virions, and either have no effect, or prevent binding of neutralizing antibodies
Not all antibodies are neutralising
Some epitopes elicit neutralising antibodies, some elicit non neutralising antibodies (even within the same antigen / protein)
Both are produced - neutralizing and non neutralizing
Non neutralising can get in the way. The surface of a viral particle can get loaded up with non neutralising antibodies, to prevent the neutralising antibodies from reaching the virus
Also prevents the neutralising antyibodies from being produced because the IS no longer sees the neutralising epitopes because they are blocked by the non neutralising epitopes AND VIRUS IS STILL INFECTOUS!
positive and negative effects of antibodies
Neutralizing or non-neutralizing antibodies can bind virus or infected cells and
- activate complement
- act as ligands for Fc receptors on phagocytic cells
[[ Antibodies can get mopped up
Anything bound to any antibodies have an FC (common portion of the antibody sticking out and activating complements, and causing the antibody/antigen complexes to be taken up by phagocytic cells) ]]
Neutralizing or non-neutralizing antibodies can enhance infectivity – antibody-dependent enhancement e.g. dengue
Antibodies could be negative on the body
Dengue virus infection can be enhanced by the neutralising or non neutralising antibodies
Shows we can’t generalise
Cytotoxic T cells and Viruses
Recognise antigenic peptides presented by MHC Class I ( Essentially all cell types express MHC class I )
Specificity determined by T cell receptor
Recognition can lead to:
- Target cell death through delivery of perforin, granzyme
- Inhibition of virus growth by local release of inhibitory cytokines (IFN-γ, TNF-α)
Essential for clearing (resolving) viral infection
A given virus will present different T cell epitopes in different individuals (outbred population)
( Some may be better at clearance than others )
balance between virus, host and immune system
Immune responses are crucial but excessive responses can be harmful
It is in the interests of the virus to:
- Antagonise the interferon response
- Evade premature apoptosis
- Generate non-neutralizing antibodies
- Block presentation of viral peptides by the MHC proteins
Because:
- It aids virus replication and transmission
- Excessive responses can themselves be harmful to the host (which then harms virus replication / transmission)
Most (?all) viruses encode proteins that mitigate the IS response
the 4 outcomes of infection
Extent of modulation of the virus-host interaction dictates the outcome of infection
- Virus dominates over IS: replication and spread, v likely disease
- IS dominates over virus: limited replication, little if any disease
- Extreme IS response: limited replication, v likely disease
- Balance of virus with IS: some replication and spread, maybe disease
