Influenza Flashcards
Influenza genome
Neg. Sense ssRNA => 8 segments
Influenza envelope
Host-derived envelope with 2 glycoproteins (Hemagglutinin and Neuraminidase)
M2 ion channel embedded in membrane
Nucleoprotein
Covers RNA of Influenza viruses => protection?
Viral polymerase complex
Holds together ends of viral RNA
consists of 3 proteins
transcribes -ssRNA to mRNA for translation by host machinery & copy RNA as template = replication
Influenza virus life cycle
Entry upon bindingbof HA with sialic acid on cell membrane
Endosome, at low pH e.g. 5.5 => conf change in HA enables fusion woth endosomal membrane
Release genome
import RNA into nucleus
transcription and replication in nucleus
assembly at plasma membrane
Neuraminidase (sialidase) => cleaves interactions btw HA and sialic acid => ensures release
Antigenic variability of influenza
diff. subtypes
Infection with one does not protect from infection with other
And variation within subtypes
e.g. H1N1 2005 only weak protection against H1N1 2014
Viral pathogenesis
• cell death caused by cytolytic viruses (e.g. influenza destroys respiratory cells)
• immune suppression (e.g. measles)
• immune pathology (Hepatitis B/C) => virus doesn’t kill cells, but reaction to virus by immune system does
• oncogenesis (Hepatitis B/C)
What impacts pathogenesis?
Viral strategy (acute, persistent)
Viral tropism (where does virus replicate => respiratory, gut etc
Virus strain
Infectious dose
Host fitness
Host genetics
What are viral strategies?
Acute
Latent
Persistent (asymptomatic and pathogenic)
What are advantages and disadvantages of mice and ferrets as model organisms?
Mice:
+ low cost
+ transgenic mice
+ immunological reagents => track infection
- don’t reflect disease very well: have to use high doses and causes lower airway tract infection
Ferrets:
+ clinical disease manifestation similar to humans
+ suceptible to unadapted human influenza virus isolates
- complex husbandry requirements
- expensive
Polybasic cleavage site in HA
Precursor (HA0) needs to be cleaved into H1 and H2 => connected via disulfide bond
=> marker of virulence
Which proteases cleave viral HA
Host cell proteases
HAT (cytoplasmamembrane) TMPRSS2 (cytoplasmamembrane, Golgi)
Furin (Golgi)
HAT and TMPRSS2 limited to respiratory epithelium
Furin ubiquitously expressed in host body
HA Cleavage of diff viral strains
Monobasic cleavage site => TMPRSS2 & HAT => local infection (only in respiratory epithelium)
Polybasic cleavage site => Furin => (avian viruses) => systemic infection
Transmission of viruses
Vertical transmission
Shedding:
Respiratory secretions
Salvia
Feces
Blood
Urine
Semen
Milk
Skin lesions
Animal models for influenza virus transmission
Ferrets
+ display flu-like symptoms
+ transmission pattern reflects situation in humans
- expensive, low numbers of animals
Guinea pigs
+ less expensive, more animals
+/- transmission patterns similar for H3N2 viruses
- do not display flu-like symptoms
What types of transmission can be studied?
Contact transmission
Respiratory droplet transmission
Transmission of influenza viruses depends on
Temp.
Low temp. favours virus transmission
Humidity
Low humidity favours transmission
Vaccines
Biological perpetration that provides immunity against a disease, typically contains a modified form of a pathogen
Goal: faster and less harmful immune response, avoid disease upon encountering a pathogen
First vaccine
Smallpox
Milkmaids immune => injected a boy with fluid from lesion of a milkmaid
=> infects boy with smallpox and boy survived
Vaccine led to eradication of smallpox in 1980
What are conditions for virus eradication programs?
Virus must have only one host (human specific)
Vaccine must confer lifelong protection
Current programsto eliminate polio and measles
What conditions must be met for enabling virus eradication programs
The virus must have only one host (human-specific)
The vaccine must confer lifelong protection
Current programs to eliminate polio and measles
Passive immunization
Components of immune response (antibodies) from donor
(Post-exposure e.g. rabies or prophylaxis for immuno-compromised)
Active immunization
Induction of a protective immune response in a patient
Attenuated live vaccines
Weakened virus
Can replicate and induce potent immune responses but not cause disease in humans and not transmit
=> passage viruses in animals/cell cultures => adaption to other hosts => bring back into humans
Rationale design for attenuation
Study pathogenesis of virus => genetically modulate viruses
Pros and Cons of live attenuated vaccines
Pros:
Potent, long-lived immunity
Cons:
Transmission of undiscovered viruses from cell line/medium used
Viruses may gain back virulence
Pros and cons of inactivated vaccines
+Inactivation with formalin or beta-propiolactone is fast and virologically safe
- inactivation may lead to alteration in antigenic surface
- not suitable for all viruses
- inactivating substances often present in injection solution
How many doses of vaccines?
Inactivated: multiple boosts
Live attenuated: replication, strong immune response after one dose => & more long lived
mRNA vaccine
Two doses required
Strong antibody and T cell response
safe
duration of protection not clear yet
Chemically modified (not immunogenic => should get translated in cells => reaction to protein) mRNA of vaccine encodes for spike protein
=> enveloped in lipid nanoparticles
Antivirals against
HIV & Hepatitis C (no vaccine available)
Herpes
Influenza (limited success)
Less success than vaccines
Not many
Most of the ones we have against HIV
HIV treatment
Different drug classes inhibit different (all) steps of viral lifecycle
Standard triple therapy (usually 2 reverse transcriptase inhibitors and 1 integrase inhibitor)
Multiple combinations possible => low chance of resistance and even then there is the possibility to switch to other drugs
Control of viral replication, no cure!
Hepatitis
Inflammation of the liver
HCV can cause chronic infection that increases risk of liver cirrhosis and hepatocellular carcinoma
Transmission through blood/sexual contact/vertical transmission
Anti-HCV treatments
Previous:
INF + Ribavirin (50% success)
HCV protease inhibitors + INF + Ribavirin (70-80%)
Current:
IFN-free, combination of 2-3 HCV protease, polymerase and NS5A inhibitors
(95-100% success rate, very few side effects)
HepC vs HIV treatment
HIV infection cannot be cleared, HCV can
Influenza antivirals
Inhibitors of viral ion channel M2: Amantadine, Rimantadine (also used for parkinson’s disease)
=> block entry: release of genome
=> current strains all resistant to M2 inhibitors!
Inhibitors of viral neuraminidase NA: Oseltamivir, Zanamivir, Peramivir, Laninamivir
=> block release of virus
=> have to be given early!
Inhibitors of viral endonuclease PA:
Baloxavir: inhibits part of viral polymerase
=> block transcription
