Lecture 1. Virus Infection and Disease Flashcards
What are viruses and what does this mean for their replication?
Obligate intracellular parasites
They can only replicate within other cells
What is the normal pattern for a productive replication cycle of a virus?
Virus need to attach to a host cell
Viruses need to get inside the host cell and uncoat the genetic material
They need to replicate their genome and produce new viral proteins
They need to assemble these viral proteins into new viral particles and have them successfully exit the host cell to infect other host cells
At a cellular level, what outcomes can virus encounters lead to?
Acute cytopathic infection (rapid replication within the host cell kills the host cell)
Persistent infection (cell not destroyed, virus replicates slowly)
Latent infection (virus present in cell but not actively replicating/no active virus being produced)
Cell transformation (cell becomes a cancer cell)
Abortive infection (Virus replication cycle incomplete, no new viral particles produced)
Null infection (Attaches but can’t get in, no infection at all)
In organisms, what outcomes can virus encounters lead to?
Acute infection (disease)
Subclinical infection (Unaware of infection, no symptoms)
Persistent and chronic infections (Infection going on for a long time)
Latent infection (Initial acute disease, virus remains latent in the body for years and can be reactivated)
Slowly progressive disease (may or may not be aware of the symptoms)
Virus-induced tumour
What are examples of viruses that causes persistent and chronic infections?
Hepatitis B and C
What are examples of viruses that causes latent infection?
Herpes and chickenpox
What are examples of viruses that causes slow progressive disease?
Measles (in the brain)
What are symptoms?
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
What are clinical signs?
An objective physical finding found by the examiner
In the absence of observable disease, what is the infection classed as?
Subclinical or silent
What is virulence?
The capacity to cause disease
How does virulence vary among diseases?
Varies from avirulent (no disease) to lethal
Are there any viruses that are 100% lethal?
Few (e.g ‘virulent’ poliovirus causes paralysis in only 1% of infected individuals)
Do different strains of virus have different virulence?
Yes, different strains of a virus can vary in virulence
What is attenuation?
The reduction in the virulence of a virus (can be used in vaccines)
What is pathogenicity?
The ability of the virus to cause pathology: this can be microscopic or macroscopic
Why can’t pathogenicity and virulence be used synonymously?
Avirulent viruses can be pathogenic
What is the difference between pathogenicity and virulence?
Pathogenicity has come to mean ‘ability to cause disease’
Virulence has come to mean ‘relative disease-causing capacity’
What does virulence depend on?
A combination of viral and host factors
What are examples of virus factors that influence virulence?
Strain/isolate - genetically determined dose
Route of infection
What are examples of host factors that influence virulence?
Species
Genetic constitution e.g MHC proteins expressed age, sex, nutritional status
Environmental factors also have an effect (diet, age, sex)
What can the virulence of a virus not be described without?
Without reference to the conditions of infection
What is the iceberg principle of infection?
There are a far greater number of virus infections that will cause mild illness and subclinical/silent infections as well as many encounters that will lead to no infection
Only a minority of viral encounters will cause sevre illness and death
What can excessive immune response result in?
Can be harmful
What cells are involved with innate immunity?
Neutrophils
Monocytes/macrophages
Dendritic cells
Natural killer cells
What are produced by the cells involved with innate immunity that result in virus elimination?
Interferons
Cytokines
Chemokines
What is involved with humoural adaptive immunity?
B lymphocytes that produce antibodies
What cells are involved in cellular adaptive immunity?
T lymphocytes
CD4+
CD8+
Regulatory T cells
Th17 cells
NKT cells
What processes are in the interest of the virus and why?
Antagonise the interferon response, evade premature apoptosis, generate non-neutralising antibodies, block presentation of viral peptides by the MHC proteins
Because it aids virus replication and transmission and excessive responses can themselves be harmful to the host (which then harms virus replication/transmission)
What do most (all?) viruses encode?
Proteins that mitigate the immune response
What is the outcome of infection when the virus dominates over the immune response?
Replication and spread, very likely disease
What is the outcome of infection when the immune response dominates over the virus?
Limited replication, little if any disease
What is the outcome of infection when there is an extreme immune response?
Limited replication, very likely disease
What is the outcome of infection when there is a balance of virus within the immune response?
Some replication and spread, maybe disease
What are type 1 interferons (IFN 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)
What are type 2 interferons (IFN 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 is virus invasion detected by the host cell?
Toll-like receptors on the membrane of the cell or on the endosomal compartment, with each type of Toll-like receptor recognising different pathogenic parts
What are the names of the two proteins within the cell that can recognise viral RNAs?
RIG-I and mda5
How are interferons created?
Signalling pathways from Toll-like receptors and protein trigger phosphorylation of IκB disabling the inhibition of NFκB which binds to a promotor of IFN in the nucleus
Signalling pathways also phosphorylate IRF3/7 which binds to IFN promoter in the nucleus
How is the antiviral state primed?
Type 1 interferons binds to IFNA receptors which causes the phosphorylation of STAT proteins (STAT 1 and 2). STAT proteins enter the nucleus and binds to the promoter of interferon stimulator genes along with IRF9, creating interferon stimulating genes
What are examples of interferon stimulator genes (ISG)?
PKR
2’-5’OAS
RNase L
How does PKR work?
Activated by viral dsDNA (double-stranded)
Activates phospho-eIF2α which blocks ribosomes
This prevents protein synthesis
How do 2’-5’OAS and RNase L work?
2’-5’OAS is activated by dsDNA
2’-5’OAS activates RNase L which degrade all mRNA
This prevents protein synthesis
What do many interferon stimulator genes (ISGs) include?
Pro-apoptotic factors
Antiviral state promotes apoptosis when virus is present
What do virus particles have the potential to stimulate?
Antibodies to many different epitopes on their surface
What are antibodies crucial for?
Mopping up virus in the system AND for providing memory protection against future infection
What can antibodies trigger?
Complement-mediated killing of infected cells
What are neutralising antibodies?
Bind to virions and neutralise, i.e. destroy infectivity, in a number of ways
How do neutralising antibodies function?
By acting on free virus particles (aggregate virus particles together)
By acting on early virus-cell interactions (inhibit attachment of virus to cell receptors)
What can neutralising antibodies inhibit?
Endocytosis of the virus particle or virus uncoating and/or fusion or a post-entry step of infection
What are non-neutralising antibodies?
Bind to virions, and either have no effect, or prevent binding of neutralising antibodies
Neutralising or non-neutralising antibodies can bind virus or infected cells and what else?
Activate complement
Act as ligands for Fc receptors on phagocytic cells
What downside do neutralising and non-neutralising antibodies possess?
Can enhance infectivity – antibody-dependent enhancement e.g. dengue
What role do cytotoxic T cells have in the cellular adaptive response?
Recognise antigenic peptides presented by MHC Class I (essentially all cell types express MHC class I)
Specificity determined by T cell receptor
What can recognition by cytotoxic T cells lead to?
Target cell death through delivery of perforin, granzyme
Inhibition of virus growth by local release of inhibitory cytokines (IFN-γ, TNF-α)
What are cytotoxic T cells 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
What is the immune system made up of?
Many different responses
Each is graded, not all or nothing
Quality and quantity of responses vary among people
Is the immune response homogenous throughout the body or not?
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
What immune system is activated by immunisation by injection?
Activates the systemic immune system only
What immune system is activated by immunisation into the gut/airway?
The mucosal and systemic IS
How is virus infection regulated by the immune system?
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
