Viral pathogenesis Flashcards
(30 cards)
Difference between productive, abortive and latent infections
Productive infection
New virus particles are made
Abortive infection
No new virus particles are made
Latent infection
Virus does not produce offspring, but retains the capacity to to do later (reactivation)
Difference between acute and chronic/persistent infection
Acute infection
Non-equilibrium
Chronic/persistent infection
Continuation of infection beyond the time when the clearance of virus after an acute infection is expected.
Often equilibrium
What is virulence? Can it be compared between viruses?
Capacity of a virus to cause disease.
Can be graded: virulent, avirulent, attenuated…
Influenced by dose, route of infection, species, age, sex, and susceptibility of host.
Relative measure, difficult to compare between different viruses. Similar viruses: assays must be the same.
Some aspects can be quantified:
Virus titer, mortality (mean time to death), mean time to appearance of signs, weight loss, number of lesions, degree of fever, etc.
HIV-1: reduction in blood CD4+ lymphocytes
What can be focuses of pathogenesis research?
Often starts with clinical or epidemiological observations
Syndrome related to a virus
Causality or association
Virulence factors
What are advantages and disadvantages with cell models?
Advantages:
- Manipulation and standardization (easy)
- Inexpensive
- Quick
- Useful for isolated study of intracellular processes
- Diagnosis of virus infections
Disadvantage:
- Loose bigger picture (organ, organism, immune response)
How can we use animal models to study viral pathologenesis?
Studies in permissive animals (and modified host animals).
Can study animal viruses related to (modified) human viruses.
Caution: interpretation when transferring results between species (ex. mice vs. humans)
Does increased virus replication always increase transmission? Example?
No
High mortality rates may reduce virus transmission.
Effective transmission -> virulence cannot be too high -> selection for less virulence.
Example: Myxoma virus of rabbits
Introduced to reduce rabbit population in Australia (1950). Too pathogenic -> mortality sunk.
Selection against less pathogenic viruses and more resistant rabbits = Equilibrium
Describe an acute infection
Incubation period (virus replication)
Host response. Symptoms after 1-2 days (respiratory viruses). Brief
Usually mild symptoms. May cause serious (or deadly) diseases, especially zoonoses.
Non-equilibrium
How do virus and host contribute to the balance (equilibrium)?
Virus:
Virulence factors
Evasion
Subversion
Host:
Innate immunity
Antibodies, cell mediated immunity
Increased production of new cells
Describe latency
Start: acute infection
Little production of virus in latent phase.
DNA storage in nucleus (episomes or incorporated in host genome).
Limited gene expression.
Reactivation can give different clinical pictures than primary infection.
What is the connection between HSV and latency?
Infect slowly dividing or nondividing (nonpermissive) cells, limited cell division.
Stimuli -> reactivation -> transmission
Survive even with low transmissibility in low dense populations.
Describe a HSV infection briefly
Genome exists as free circular dsDNAs in nucleus.
1 in 6 neurons (non-dividing) are infected.
Ganglia = latency site
HSV immediate early genes not expressed.
Latency-associated transcripts (LATs) - RNAs which inhibit cellular functions (apoptosis, transcription) and viral replication.
Symptoms:
- Pronounced stomatitis
- Cold sores, vesicular lesions
- Many are asymptomatic
Mention five viral virulence factors
- Facilitate viral entry
- Facilitate replication
- Modify host defense (evasion and subversion)
- Enable spread in the host
- Direct cell killing
Give an example of virulence factors for virus entry (IAV)
Influenza virus
Virulence factors: Neuraminidase (NA) and hemagglutinin (HA).
NA increases access of HA to host cell receptors (sialic acid)
Give an example of virulence factors that facilitate viral replication (papillomavirus)
Cell cycle:
Virulence factor: E7 protein
Stimulates cell division -> facilitates viral replication (subversion mechanism)
Give three examples on how viruses can mediate direct killing of the host cell
i. Inhibition of cellular processes by viral proteins (poliovirus destroys capped mRNA)
ii. Vital toxins (rotavirus, RS-virus)
iii. Disruption of cell membranes due to overwhelming viral production or production of porins (IAV M2 protein)
Can you give an example of immune-mediated disease due to virus infection?
Hepatitis B virus infection.
- Viral replication before symptoms appear
- Strong immune response -> symptoms:
- Considerable liver damage’
- Fever, jaundice, rashes, inflamed joints, abdominal pain, enlarged lever
Newborn children:
-Few symptoms
- Higher risk of getting a chronic lifelong infection
What factors determines the symptom picture?
- Virulence factors
- Route of entry
- Host factors
- Cell receptor location
(IAV alpha receptor, a2,3 vs a2,6) - Genetic variants in host organism
- Receptor mutations
- Mutations in genes associated with innate
responses.
- MHC/HLA-variation
- Cell receptor location
- Age
- Sex: males are slightly more susceptible -
correlate with elevated estradiol among
females - Malnutrition increases susceptibility (compromised physical barriers and immune responses)
- Stress
- Air pollution
What are examples of symptoms for respiratory tract infections? Why do we get the symptoms?
Depends on how deep down the viruses and the inflammation go.
Runny nose
Sneezing
Cough
Tonsillitis
Laryngitis
Bronchitis/bronciolitis
Pneumonia
Inflammation -> stimulation of sensory nerve endings -> cough + sneezing
Infected cells loose cilium function -> mucus stagnation -> more coughing. Increased risk of bacterial super-infections.
Asthma
Small children: Narrowing bronchioles -> dyspnea
Describe gastroenteritis briefly.
Cause, symptoms, response
Causes: norovirus, rotavirus, some adenoviruses.
Symptoms: vomiting, diarrhea, abdominal cramps, dehydration.
Response:
- Kill epithelial cells directly (toxins)
- Disturbed electrolyte balance -> loss of electrolytes and water into the lumen -> diarrhea
How can animal models be used when examining COVID-19? Challenges?
Mice are not susceptible to infection of human SARS-CoV-2.
Two aa changes in spike allow binding to mouse ACE2 receptor.
Can use ACE2 transgenic mice.
Can allow passage of virus through 3-9 mice -> SARS-CoV-2 adaptation
Can use other animal models e.g., nonhuman primates such as ferrets and hamsters
What is tissue tropism and what are examples of determinants?
Spectrum of tissues infected by a virus. Examples: enterotropic, neurotropic, hepatotropic.
Range: limited to pantropic
Determinants: susceptibility (receptor etc.), permissivity (e.g., internal cellular environment), accessibility, defense
What are the four classes of viral virulence genes? Examples?
1 Genes (or products) that affect viral replication
2 Encoding toxins
3 Encoding modifiers of host defense mechanisms
4 Enable virus to spread in the host
NB! Mutations in the last two classes often have no impact on virus reproduction in cells in culture. Removal may give attenuation.
Can be found in untranslated regions
Examples:
1 -
2 - NSP4 secreted from infected cells -> PLC -> Ca2+ efflux -> water out of cells -> diarrhea
3 - M3 gene of murine gammaherpesvirus 68 produced by infected cells. M3 binds chemokines -> no immune cell recruitment
4 -
Can you describe why the cornea can be degraded after herpes infection?
Herpes stromal keratitis.
Immunopathological (caused by CD4+ Th1 cells). Repeated infection -> reduced vision.
Virus replication in corneal epithelium. Inflammation in underlying uninfected stromal cells .
Infected cells in epithelium secrete cytokines -> recruitment of CD4+ Th1 cells, produce cytokines recruiting neutrophils -> damage
