Lecture 13 - Pathogenesis of Viral Infections II Flashcards
Determinants of viral tropism 1) 2) 3) 4)
1) Availability of receptor
2) Local factors
3) Viral factors affecting accessibility to target tissue
4) Genome transcription requirements
Permissivity
Whether target cell has all of the right intracellular gene products for a virus to replicate in it
Why, if many viruses attach to receptors that are ubiquitous, can’t all viruses lead to systemic infections?
Permissivity of target cell, accessibility of target cell to virus, presence of local factors to allow viral infection
Rhinovirus receptor
ICAM-1
Why can’t rhinovirus lead to a systemic infection, even though it’s receptor is ICAM-1?
Replicates best at 33C. Can’t infect lower in the respiratory tract, as it is too hot
Why is it easier to catch rhinoviorus on a plane?
ICAM-1 is upregulated at higher altitudes
HSV receptor
Glycosaminoglycan
HSV tissue tropism
Epithelial cells, neurons
Local factors determining virus tropism
1)
2)
3)
1) Temperature (EG: rhinovirus)
2) Viral stability in extremes of pH (low in stomach, high in intestine)
3) Ability of virus to survive destruction of lipids by bile, proteins by pancreatic proteases
Example of viruses from the same family having different tissue tropisms
Both poliovirus and rhinovirus are picornaviruses.
Poliovirus is activated at low pH (stomach).
Rhinovirus is destroyed at low pH
Factors affecting ability of virus to access different tissues
1)
2)
1) Ability to replicate in macrophages (EG: dengue)
2) Ability to be released from basolateral surface of host cell (EG: vesicular stomatitis virus)
Virus that requires a cleavage-activating protease for infectiousness
Influenza.
Influenza HA is made as a single polypeptide chain. Must be cleaved by tryptase clara next to fusion peptide in order to be infectious.
This allows a conformational change at pH=5 in the endosome, which allows for membrane fusion.
How can H5N1 influenza infect tissues outside the respiratory tract?
Multiple basic amino acids inserted at tryptase clara cleavage site.
This allows cleavage by furins (ubiquitously-expressed in Golgi)
Example of a virus that uses cascade of host transcription factors to mediate protein expression
HPV
How does HPV regulate protein expression? 1) 2) 3) 4)
1) Codon usage. Different cells use different tRNAs for different amino acids.
2) HPV begins genome replication in the basal layer of the skin.
3) tRNAs required for late-stage genes aren’t available in basal cells.
4) Capsid proteins can only be made once germinal cells have migrated outwards and differentiated -> become permissive
Viruses that can result in oncogenesis
1)
2)
3)
1) Polyomaviruses
2) Adenoviruses
3) Oncogenic retroviruses
Viruses that lead to lytic infections
1)
2)
1) Enteroviruses
2) Reoviruses
Viruses that lead to chronic infection 1) 2) 3) 4)
1) HBV
2) HCV
3) HPV
4) Most retroviruses
What is a chronic infection vs a latent infection?
Chronic infection is the slow release of virus without killing the host cell
Latent infection is where there is no damage to host cell until a particular stimulus, where lytic infection begins
Types of persistent infections
Chronic infections
Latent infections
Viruses that can cause latent infections
1)
2)
3)
1) HSV
2) Varicella zoster
3) EBV
Mechanisms of viral disease progression
1)
2)
1) Viral-induced damage
2) Immunopathology
Cytocidal virus
Virus that results in cell death.
EG: Rotavirus killing enterocytes
Poliovirus killing spinal neurons
Why does influenza lead to a dry, hacking cough?
Ciliated epithelium is killed, leading to loss of mucus production
What must a virus do if it shuts down host cell functions?
Replicate quickly before host cell dies
How do most envelope-negative viruses exit host cell?
Lysis
Cytocidal virus mechanisms of cell damage 1) 2) 3) 4) 5)
1) Shutdown of cellular protein synthesis
2) Shutdown of cellular nucleic acid synthesis
3) Cytopathic effects
4) Synsitia formation
5) Apoptosis
Example of viral shutdown of host-cell protein synthesis
Poliovirus
Cellular elF-4G cleaved by viral 2A. This prevents translation of cellular mRNA (cap-dependent translation shut down)
Example of viral shutdown of host-cell nucleic acid synthesis
Poxviruses encode a DNase
Effect of ebola GP protein on cells
Expression of ebola envelope protein (GP) in cells without ebola virus infection leads to necrosis
Virus causing cytoplasmic inclusions
Reoviruses
Viruses causing nuclear inclusions
Adenoviruses
Primary role of apoptosis in viral infection
Stop viral replication in host cell
Non-cytocidal viral mechanisms of cell damage 1) 2) 3) 4) 5)
1) Cells lose ability to perform functions
2) Target for immune attack
3) Transformation
4) Immunopathology
5) Immunosuppression
Example of a virus stopping host cells from performing a funciton
LCMV (herpesvirus) causes a non-lytic persistent infection of cells in the pituitary glad that produce growth hormone. Specifically reduces transcription of growth hormone mRNAs
Example of a virus that can lead to oncogenesis
HPV
How can non-cytocidal viruses lead to immune attack of host cell? 1) 2) 3) 4)
1) CTL detect viral protein presented on MHCI.
2) Detection of viral glycoproteins on cell surface
3) Antibody-mediated pathology
4) T-cell (type IV) mediated pathology
Example of a virus that uses antiobdy response to promote replication
Dengue virus
How does dengue haemorrhagic shock syndrome occur? 1) 2) 3) 4)
1) Previous infection with dengue
2) Infection with a different serotype of dengue results in binding of antibodies to virus, but not neutralising virus.
3) Macrophages recognise opsonised virus, endocytose virus. Dengue’s host cells are macrophages/monocytes
4) Haemorrhagic shock from massive viral release
Example of a virus that causes immune-complex immunopathology
Hepatitis B chronic sufferers form immune complexes which deposit in kidneys (glomerulonephritis) blood vessels (vasculitis)
Example of a virus that causes lymphocyte-mediated immunopathology
Measles.
CD4 T cells mount an immune response to measles in endothelial cells of small blood vessels of the skin, leading to rash.
Koplik spots form in mouth
Infants with respiratory syncitial virus have CD4 T cells release factors that lead to eosinophil recruitment, leading to bronchiolitis
What are Koplik spots?
Where CD4 response to measles forms ulcers in the mouth
Example of a virus that leads to CD8 T cell pathology
Hepatitis B.
Infected hepatocytes are lysed.
Why do people with chronic hep B infection have yellow skin and eyes?
1)
2)
3)
1) Old RBCs are destroyed in the liver and spleen.
2) Haem from haemoglobin is converted to bilirubin (yellow). Bilirubin travels to the liver via the blood stream, is secreted in bile to faeces.
3) Damaged liver cells can’t convert bilirubin to bile. Bilirubin remains in blood.
Example of a virus leading to molecular mimicry immunopathology
Influenza proteins resemble myelin basic protein on neurons. This leads to destruction of myelin (Guillain-Barre syndrome).
Coxsackie B4 virus proteins resemble heart muscle, leading to endocarditis
Virus that leads to polyclonal B cell activation
EBV
Viruses that immunosuppress
1)
2)
3)
1) HIV
2) Norovirus lives in macrophages, dendritic cells
3) Measles temporarily immunosuppresses from nonproductive replication in T cells, macrophages.
How does measlesvirus immunosuppress?
Measles surface glycoproteins bind to CD46 on T cells. This results in IL-12 suppression
Viruses that immunosuppress
1)
2)
3)
1) HIV
2) Norovirus lives in macrophages, dendritic cells
3) Measles temporarily immunosuppresses from nonproductive replication in T cells, macrophages.
How does measlesvirus immunosuppress?
Measles surface glycoproteins bind to CD46 on T cells. This results in IL-12 suppression
