20. Viral immunopathology Flashcards
what are the 3 ways viruses cause injury?
direct injury
immune mediated injury
virus induced autoimmunity
How do cytolytic viruses cause cell damage?
- inhibition of essential processes like translation, DNA/RNA synthesis and vesicular transport
- increased permeability of membranes
- membrane fusion
- depolymerisation of cytoskeleton
- induce/block apoptosis
what happens in response to cytolytic virus cell damage?
inflammation
necrotic cell death
release of cytokines
what is the process of apoptosis?
injection of granzymes which activation caspases and effector caspases trigger apoptosis
what can activate caspases?
- receptor mediated killing by engaging the Fas receptor with FAS ligand
- P53 detects DNA damage and activates caspases
how can some virus incorporate apoptosis into its lifecycle?
many cells infected are in a resting state so the DNA isn’t active.
the infection drives the cell into activity to induce apoptosis
HOWEVER viruses have genes that stall apoptosis long enough to fully replicate themselves
how can apoptosis be inhibited?
inhibition of caspases by serpins
interfere with Fas or TNF signalling
altering p53 concentrations/functions
produce Bcl-2 homologs
what is most injury in non cytolytic viral infection caused by?
the immune response
CD8+ mediated
CD4+ mediated
cytokine mediated
antibody mediated
what do different types of viral infection influence?
whether the role of the immune system is protective or causes damage
what is most CD8+ T cell mediated damage caused by?
inappropriate CD8+ response either too many CTLs or too few.
What should CD8+ T cells be doing in the immune response?
recognise and destroy virus infected cells
release of proinflammatory cytokines
the balance between too much or too little tips the scales between protective and damaging
What have experimental LCMV studies in mice shown?
TLDR: CTL kills the virus but causes lethal damage
the initial virus is not cytopathic
immunosupressed mice end up with a persistent infection but not death
once CTL are injected the mouse dies
shows that the T cell reaction to the virus is the thing causing the damage
How does CD4+ T cells cause indirect injury?
due to an inappropriate Th1/Th2 repsonse
What is the normal Th1 response?
promotes the cell mediated pro inflammatory response
when can the Th1 response go wrong?
in viruses like measles, mumps and rubella Th1 cells activate monocytic phagocytes which demyelinates neurons
What does the Th1 response do in herpes simplex in the eye?
the virus can infect the cornea epitheilium
T cells shouldn’t be in the cornea but the viruses replicates in the eye.
Th1 cells are recruited and produce cytokines
effect bystander cells and cause damage and vision loss
doesnt succeed in stopping viral replication
what is the normal Th2 response?
promotion of antibody response and recruitment of eosinophils
what have RSV immunosuppressed mice studies shown us?
without Th2 cells there is only minor damage from the virus
with Th2 cells there were severe lesions possibly due to the recruitment of eosinophils
why does incorrect Th1/Th2 response effect vaccine development?
Th2 is important for antibodies
formalin treatment kills the virus but can change the protein conformation inducing a Th1 response instead of Th2
this meant vaccines weren’t as effective and most people died after infection
what is a cytokine storm?
massive release of cytokines when the viral load is actullay quite low
in what infections can cytokine storms happen?
Covid
Influenza
dengue
what causes a cytokine storm?
viruses induce interferon and proinflammatory cytokine production
normally there is balance between causing anti viral state and inflammation
an imbalance (too many cytokines compared to viral load) causes a storm
lots of inflammation and cell damage
Cytokine storm in covid
inhale covid
infection of alveoli
production of interferons and proinflammatory cytokines
endothelium becomes permeable to immune cells
fluid builds up in the lungs
immune cells produce more cytokines and release granules and cause cell death
more immune cells
more cytokines = storm
How can antibodies cause damage?
excessive formation of antibody virus complexes in infections at site of immune privilege
depositing the antibody virus complexes in capillaries in the brain and kidney causing lesions and more cell damage.
what happens in the disease progess of severe Dengue fever?
endothelium cells are effects
plasma leaks out of the blood
circulatory collapse leads to shock as the blood has no volume
causes by cytokines
does the same antibody protect against all 4 serotypes of Dengue?
no
What happens in the primary infection during antibody dependant enhacement of Dengue infection?
Homologous antibodies form non infectious neutralising complexes with the virus
these Antibodies provide life long protection
What happens in the secondary infection during antibody dependant enhacement of Dengue infection?
A different serotype of Dengue infects the person
the antibodies that bind are heterologous and are not neutralising
the antibodies bind to Fc receptors for phagocytosis but the virus uses this to infect macrophages
macrophage then produce lots of cytokines leading to plasma leakage
How can viruses initiate autoimmunity?
some B and T cell epitopes are the same as host proteins
these antibodies or T cells can react to the host cell epitopes
anti host response causes autoimmune disease
What are a few examples of autoimmune disease and viral infections?
type 1 diabetes and enterovirus
Crohn’s disease and norovirus
asthma and rhinovirus
MS and epstein barr virus
What is important to remeber with autoimmunity and viruses?
autoimmune diseases are multifactoral and not always caused by viruses
what can make someone more suseptible to reinfection or autoimmune disease?
having a very strong initial immune response
