Term
| What are two ways enveloped viruses can cross the host cell plasma membrane? |
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Definition
1. pH-dependent fusion (e.g. influenza A)
2. pH-independent, or direct, fusion
Note: Both depend on envelope protein hemagglutinin, which changes conformation to also fusion to plasma membrane
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Term
1. How does pH-dependent fusion pathway work?
2. What is the advantage of this pathway?
3. Is this an entrance mechanism of enveloped or unenveloped viruses?
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Definition
1. pH-Independent Pathway (e.g. influenza A)
-- Receptors bind and virus in endocytosed.
-- As vesicle acidifies, M2 protein (an ion channel) inserts into viral envelope, allowing virus to acidify as well
-- pH drop leads to conformational change in envelope protein hemagglutinin, which can then fuse to plasma membrane
2. Requisite pH drop prevents early fusion (e.g. fusion at surface, when virus needs to be delivered deep in cell)
3. Enveloped viruses
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Term
| How specifically does the hemagglutinin conformational change allow for fusion to the host cell plasma membrane? |
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Definition
Hydrophobic region is exposed, which fuses with membrane.
Note: called hemagglutinin due to ability to agglutinate RBC's. How? It binds sialic acid on cell surfaces.
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Term
| How does the pH-dependent pathway fusion work? Is this an entrance mechanism of enveloped or unenveloped viruses? |
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Definition
| Viral envelope proteins can bind to plasma membrane receptors, magically leading to a conformational change in viral fusion protein that allows the envelope and PM to fuse. E.g. HIV |
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Term
| How do unenveloped viruses (e.g. rhinovirus) cross the host cell membrane? |
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Definition
| After endocytosis, some carry proteins that form pores in endocytic compartment, some make it all the way to ER before escaping. (Still a mystery.) |
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Term
| What is tropism, and what are parameters that affect it? |
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Definition
Tropism refers to a virus' virulence (ability to infect cell).
Determinants:
-- host species
-- receptors (e.g. HIV depends on cytokine receptor CCR5; if it is mutated, host is HIV-resistant)
-- intracellular environment
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Term
| Describe the influenza A genome. |
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Definition
1. Minus strand RNA (not the strand that is translated, so it must also carry RNA polymerase to make + strand)
2. Multisegmented
--Note: 8 segments code 10 proteins; must splice. This may explain replication in nucleus, as virus takes advantage of host splicing machinery.
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Term
| Where and how does influenza A replicate? |
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Definition
1. Replicates in the nucleus
--Note: this is rare for an RNA virus, and is perhaps because virus needs to take advantage of host splicing machinery in nucleus.
2. Virus bring in genome AND already assembled RNA polymerase. (otherwise it couldn't start transcription because host cell has no machinery to copy from RNA template).
3. Viral RNA polymerase steals 5' end of host mRNA to use as primer.
4. RNA polymerase transcribes - strand (vRNA) to make + strand (cRNA).
-- + strand can be transcribed to make - strand for progeny
-- + strand encodes endonuclease to clip primer off host mRNA (I don't understand how first primer is clipped)
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Term
| How can multiple proteins be encoded by a single segment? |
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Definition
1. Splicing
2. IRES (internal translation initiation)
- ribosome binds to internal DNA segment, opening 2nd reading fram. E.g. Picornaviruses.
3. Polyproteins
- series of proteins synthesized as one big tandem protein, which encodes proteases that cleave it. E.g. Cornoviruses.
4. Subgenomic RNA
- RNA polymerase skips variable sections between 3' and 5' end of template.
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Term
| Viruses generally trigger an interferon response via pattern recognition receptors (e.g. Toll-like receptors). How do viruses avoid destruction by the interferon response, which shuts down translation? |
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Definition
Shut down host cell translation.
Note: Usually, interferons cause phosphorylation inhibition of eIF2, a translation initiation factor. Some viruses can inhibit phosphorylation of eIF2. |
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Term
| What is antigenic drift? Antigenic shift? |
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Definition
Antigenic drift: SMALL changes in genome due to point mutations (RNA polymerase is error prone and has no proofreading mechanism)
Antigenic shift: BIG, wholesale changes in genome due to reassortment, which only happens in multisegmented genomes.
E.g H1N1 -> H5N1: totally different hemagglutinin gene
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Term
| What are requisites for antigenic shift? |
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Definition
| Two different strains (one from an animal reservoir) with segmented genomes and multiple gene subtypes must infect the same cell in a mixing species that is susceptible to both strains. |
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Term
| How does the innate immune system defend against viruses? |
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Definition
Pattern recognition receptors (e.g. TLRs) stimulate the interferon response to shut down host cell translation by phosphorylating (inactivating) translation initiation factor EIF2.
Viral antigens also trigger innate cell-mediated immunity (NK cells, cytotoxic T cells, macrophages)
Viral infection can trigger apoptotic response (which virus tries to inhibit)
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Term
| How does the adaptive immune system defend against viruses? |
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Definition
Recognition of viral antigens produces antibody response; antibodies tie up or "neutralize" virus.
Note: Antibodies are strain-specific
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Term
| How do viruses hurt the host? |
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Definition
1. Toxicity (buildup of viral proteins in cell)
2. Repression of host replication (virus steals some ribosomes)
3. Cell lysis
4. Uncontrolled cell division (oncogenic viruses)
5. Host immune response to infection destroys own cells
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Term
| What are potential outcomes of a viral infection? |
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Definition
1. Productivity - virus successfully makes progeny. Can be lytic or non-lytic (budding off)
2. Latency (e.g. herpes)
3. Abortive infection - host cell wins, no viral progeny.
4. Oncogenesis - host cell divides uncontrollably
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Term
How do viral vaccines work?
What are the two types of viral vaccines?
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Definition
| They either stimulate cell-mediated immunity and/or neutralizing antibody production |
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Term
| What type(s) of viral vaccine stimulate(s) cell-mediated immunity? |
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Definition
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Term
| How do live, attenuated virus vaccines work? |
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Definition
Viruses are made benign, e.g. by serial replication in environment different from host (FluMist is serially passaged at low temperatures, so selected-for viruses are not effective at body temp). Mild virus primes/triggers cell-mediated immunity against virus.
e.g. MMR
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Term
| What types of viral vaccines stimulate antibody production. |
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Definition
Killed vaccines: dead virus still has antigens. E.g. Salk polio
Subunit vaccines: parts of virus are antigenic. E.g. Hep B
Virus-like particles (VLPs): Antigenic capsids without nucleic acid core. E.g. HPV
Recombinant vaccines: recombined DNA is not virulent
Passive immunization: direct administrations of Ig. E.g. rabies
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Term
| Influenza A strains are named H#N#. What is the "H" and what does it do? The "N"? |
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Definition
Both are proteins on the viral envelope.
H = Hemagglutinin.
1. Receptor for sialic acid on cell surfaces.
2. Conformational change important in membrane fusion
Note: Target of neutralizing antibodies
N = Neuraminidase
1. Cleaves sialic acid, allowing virion release from host
Note: Target of NA inhibitors
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Term
| Explain the influenza life cycle. Which steps can we target pharmacologically? |
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Definition
1. Hemagglutinin-mediated attachment and fusion
2. M2-mediated acidification, uncoating (influenza A only)
3. Transport to nucleus, replication
4. Export from nucleus, assembly in host cell cytoplasm
5. Budding off
6. Cleavage of sialic acid by neuraminidase; otherwise, bud with HA sticks to cell surface sialic acid.
Targets:
1. Neutralizing antibodies can block HA-sialic acid attachment.
2. M2 channel blockers can inhibit viral escape from endosome by preventing virus acidification. E.g. amantidine, rimantidine
6. Neuraminidase inhibitors can prevent release of budding virion. E.g. osteltamavir, zanamivir
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Term
| How does influenza cause illness? (Pathogenesis) |
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Definition
Primary mechanism is direct cell lysis, in both upper and lower respiratory tracts.
Note: Immune response is primarily protective, not pathogenic. Influenzas code for NS1 protein, which suppresses immune response.
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Term
| Which influenza types exhibit antigenic drift? Antigenic shift |
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Definition
A, B, C all undergo antigenic drift. This isn't going to cause a major pandemic.
Epi- and pandemics are the results of wholesale changes of antigenic shift, which only influenza A undergoes (requires multisegment genome and multiple HA and NA subtypes).
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Term
| Fun fact: How did the 2009 H1N1 strain come about? |
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Definition
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Term
| Why are swine considered the "mixing vessel" for influenza reassortment? |
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Definition
They are susceptible to both avian and human influenza, so their cells can be infected simultaneously, leading to reassortment.
The basis for this is the sialic acid linkage; birds have a2,3-linkages, humans have a2, 6 linkages, swine have both.
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Term
| What are some clinical complications of influenza? |
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Definition
Viral and secondary bacterial pneumonia
Encephalitis
Reye's syndrome (related to aspirin use in kids; rarely seen anymore)
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Term
| How is influenza treated? |
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Definition
1. M2 Channel blockers (type A only)
-- Amantidine and rimantadine
2. Neuraminidase inhibitors
-- Oseltamivir (Tamiflu) and zanaminvir
*3. Symptomatic treatment
*4. Prophylaxis, vaccinaton
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Term
What types of vaccines are available for influenza?
Who should get vaccinated?
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Definition
Vaccines: contains 2 A and 1 B strain
-- Killed vaccine: TIV: trivalent inactivated influenza vaccine. Anyone not allergic to eggs can get this.
-- Live attenuated: LAIV. People aged 2-50, not pregnant, not immunocompromised, not caretakers of immunocompromised people, not young children with reactive airway disease.
Note: New recommendation = yearly vaccine for everyone >6mo.
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Term
What type of virus is rhinovirus?
Is it enveloped or unenveloped?
What nucleic acid does it carry?
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Definition
Picornavirus (small RNA)
Unenveloped (can transmit via fomites)
Non-segmented + strand RNA
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Term
| How does rhinovirus infect humans? |
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Definition
| Binds ICAM, a cellular receptor on mucous membranes. Replication is cytoplasmic and most effective at 33oC, so it stays in upper respiratory tract. |
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Term
What type of virus is RSV (respiratory syncitial virus)?
Is it enveloped or unenveloped?'
What it its nucleic acid?
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Definition
Paramyxovirus
Enveloped
Non-segmented - strand RNA
Note: Two major groups (A and B)
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Term
| What are important virulence factors on RSV?, though target is unclear. |
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Definition
F protein
-- Promotes host cell-cell fusion --> syncitia
-- Target of preventive antibody (palivizumab)
G protein
-- HN - Hemagglutinin-Neuraminidase; like influenza, but on RSV it's encoded as a single protein. Involved in receptor binding, though target is unclear.
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Term
Why don't we passively immunize against RSV (Palivizumab)
What don't we vaccinate with inactivated vaccine?
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Definition
Palivizumab costs $77, 000 to prevent one hospitalization annually.
Inactivated vaccine can lead to 2o infections that are even worse than primary RSV infections.
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Term
| Coronavirus? (Unfinished...) |
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Definition
-- Enveloped (spiked envelope = corona)
-- + strand RNA
-- Mild respiratory tract symptoms, similar to rhinovirus
-- Life cycle: receptor binding, entry of genome, - RNA strand made, but then RNA polymerase jumps around to different spots on genome à generates subgenomic segments, also opportunity for RNA poly to jump to another genome à weird way to do recombination
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Term
| Adenovirus? (Unfinished)... |
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Definition
-- Non-enveloped, non-segmented DNA viruses
-- Associated with mild URI symptoms, pharngoconjunctivitis, GI disease/ diarrhea
-- Can cause severe pneumonia
- -- Life cycle: attachment by CAR, entry, then temporal regulation of genome expression
- Uses cellular DNA replication machinery by forcing S phase à E1A, E1B proteins (oncogenic)
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Term
| Fun fact: URI's are the top cause of antibiotic overuse. |
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Definition
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Term
| Why doesn't adaptive immunity protect against repeated rhinovirus infections? |
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Definition
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Term
| How does rhinovirus cause disease? |
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Definition
| Symptoms are host cell immune response. |
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Term
| Rhinovirus generally causes very mild symptoms. When is it worrisome? |
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Definition
| Rhinovirus can dangerously exacerbate disease in patients with COPD and asthma. |
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Term
| Are enveloped or unenveloped viruses more stable? |
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Definition
| Unenveloped; lipid envelope is less stable than protein capsid. Only unenveloped viruses transmit by fomites. |
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