Viral families Flashcards
Lectures: -Week 2, day 2, lecture 1: Acute viral infections - Gastrointestinal disease - Noro- & rotavirus -Week 2, day 2, lecture 2: Acute viral infections - Systemic disease - Measles -Week 2, day 2, lecture 3: Acute viral infections - Respiratory disease - Influenza virus -Week 2, day 2, lecture 4: Acute viral infections - Respiratory disease - Pneumovirus -Week 2, day 2, lecture 5: Acute viral infections - Respiratory disease - Coronavirus
What are the 5 most important causes of viral gastrointestinal disease worldwide?
- Norovirus
- Rotavirus
- Sapovirus
- Astrovirus
- Adenovirus
Does norovirus mainly cause disease in children, adults, or both?
Both
Does rotavirus mainly cause disease in children, adults or both?
Both
[Norovirus/rotavirus] is more severe
Rotavirus causes more severe cases of gastrointestinal disease
Does sapovirus mainly cause disease in children, adults or both?
Both
Does astrovirus mainly cause disease in children, adults or both?
Mainly children <5 years of age
Does adenovirus mainly cause disease in children, adults or both?
Children
What kind of disease can adenovirus cause, in addition to gastrointestinal disease?
Respiratory disease
What is a common characteristic of the common viral causes of gastrointestinal disease? Why is this advantageous?
They are capsid viruses -> no envelope
This makes it easier to survive the faeco-oral transmission route, becuase these viruses are more stable
What is the Baltimore Classification of norovirus?
Group 4: (+)-ssRNA
Norovirus is non-enveloped
What is the Baltimore Classification of rotavirus?
Group 3: dsRNA
What are host defences against gastrointestinal infection? (7)
- pH of the stomach
- Intestinal mucus
- Gut mobility
- Bile salts -> destroy lipid envelopes of viruses
- Antiviral defences -> proteolytic enzymes and secretory IgA
- Microbiome
- Immune mechanisms (phagocytic, humoral, cellular)
Which rotavirus species are there?
Species A-J
What can be said about the genome of rotavirus?
dsRNA, segmented genome
Which group is most at risk for gastroenteritis caused by rotavirus?
Children 6-24 months
What is the incubation period of rotavirus?
2 days
What is the average disease duration of rotavirus?
3-8 days of watery diarrhoea
In which patients can rotavirus cause chronic infections?
Immunocompromised patients
What is the entry receptor of rotavirus?
VP4
What are the two ways for rotavirus to leave a cell?
- Lysis of the cell
- Non-classical vesicular transport
Which two mechanisms cause rotavirus evolution?
- Antigenic drift
- Reassortment
What is antigenic drift?
Accumulation of amino acid changes in antigenic epitopes -> leads to immune evasion
What is reassortment (when it comes to viral genomes)?
Exchange of segments of genetic material in viruses that have a segmented genome
Which location in the gut does rotavirus prefer?
The ‘top’ of the villi in the intestine
How does rotavirus cause diarrhoea?
- Infected cells secrete ADP ->
- ADP induces increase of [Ca2+] in neighbouring cells ->
- Leading to:
–Inflammatory response
–Release of serotonin -> activates enteric nervous system
–Water efflux
What can be said about the genome of norovirus?
(+)-ssRNA genome with three open reading frames
Why is norovirus able to cause recurrent infections?
Immunity to norovirus is low and short-lasting
What is the entry receptor of norovirus? What is special about this receptor?
Histo-blood group antigens
Since not all humans have the same histo-blood group antigens, some people are more or less susceptible to norovirus infections
Which two mechanisms cause norovirus evolution?
- Antigenic drift
- Recombination (genetic material from another norovirus copied over)
What are the three possibilities for new norovirus strains to occur?
- Unsurveilled population
- Immunocompromised patients
- Animal reservoirs
Which patients are susceptible to chronic norovirus infections?
Immunocompromised patients
Why are immunocompromised patients a source of new norovirus strains?
Because they are infected for a long time, the virus accumulates mutations
How many open reading frames does measles virus have? How many proteins does it encode?
6 open reading frames, encoding 8 proteins
What kind of genome does measles virus have?
(-)sense non-segmented RNA
How many clades of measles are there? How much variety is there between the clades?
Eight clades, A-H
Genetic variations between different clades is low
What does the low genetic diversity of measles virus clades mean for vaccines?
Vaccines against one clade immunize against all other clades
What are the two surface proteins of measles virus?
- Hemagglutinin (H)
- Fusion protein (F)
What is the function of the hemagglutinin surface protein of measles virus?
Receptor binding protein
The amount of nucleotides in Paramyxoviridae is always a multiple of a certain numer of nucleotides. How many, and why?
6; because one nucleocapsid protein (N) covers 6 nucleotides
What is the function of matrix protein (M) in measles virus?
Particle formation and stabilization
What are the functions of large protein (L) and phosphoprotein (P) in measles virus?
They form the polymerase complex
What are the 8 proteins coded for by measles virus, and what are their functions?
- H = hemagglutinin -> attaches to entry receptor
- F = fusion protein -> causes fusion
- N = nucleocapsid protein -> coats the RNA
- M = matrix protein -> particle formation & stabilization
- L = large protein -> part of the viral polymerase complex
- P = phosphoprotein -> part of the viral polymerase complex
- C-protein -> function unknown
- V-protein -> function unknown
Where in the cell do measles virus replicate?
Cytoplasm; no part of the virus requires entro into the nucleus
How does measles cause syncytium formation?
Fusion protein not only allows the viral membrane to fuse with the cell membrane, but can also cause fusion of neighbouring cells with the host cell
Which two cellular receptors does measles virus use to enter cells?
- CD150 -> immune cells
- Nectin-4 -> epithelial cells
What is the most frequent cause of death of measles virus patients?
Opportunistic infections due to measles virus-induced immunosuppression (pneumonia, gastrointestinal disease)
What is a rare complication of measles virus?
Subacute sclerosing panencephalitis (SSPE)
What gives a higher chance of SSPE after measles virus infection?
Younger age
What kind of vaccine is used to immunize against measles? What are its advantages/disadvantages?
Live attenuated vaccine
Advantages:
-Effective
-Safe (live-attenuated)
Disadvantages:
-Interference with maternal antibodies
-Cold-chain maintenance required
-Parenteral administration
What is the effect of the interference of maternal antibodies with live attenuated measles vaccines? How can this be circumvented?
Neutralization of vaccine by maternal antibodies -> no immunization of child
This can be circumvented by vaccinating after maternal antibodies have declined, usually at 14 months
What is the disadvantage of vaccinating children against measles at 14 months?
‘Gap’ in immunity between decline of maternal antibodies (~6 months) and vaccination (14 months)
Which characteristics of measles make it a potential candidate for complete eradication? (3)
- Effective intervention available
- Practical diagnostic tools available
- Humans are essential for the viral life-cycle; no animal reservoir
What are the four main steps in measles virus pathogenesis?
- Entry into the host
- Dissemination throughout the host
- Host exit
- Immune suppression
How do paramyxoviruses induce a transcriptional gradient of their genes?
They have a promotor at the start of their genome, where the transcription complex attaches. The complex tends to fall off during transcription, causing genes at the start of the genome to be transcribed more frequently than genes near the end
Which cells are most likely the first to get infected in measles infection?
DC and alveolar macrophages in the deep lung
How is measles virus disseminated throughout the body?
T-cells (mainly) & B-cells disseminate the virus throughout the body; high amounts of replication in lymphoid tissues
Also infection of submucosal tissues and epithelial cells
How does measles virus exit the host?
Nectin-4 allows measles virus to infect respiratory epithelial cells, allowing virus to leave on the apical side of epithelial cells -> virus released into the air
What is the cytopathic effect of measles virus on the respiratory tract?
Highly disrupted epithelium of tonsils and other lymphoid tissues; allows virus to be released into the air
Which receptor mediates measles virus infection of lymphocytes?
CD150
How does measles virus cause immunosuppression?
Infection and depletion of memory T-cells and naïve/memory B-cells leads to immune suppression
How does measles cause B-cell follicle destruction?
Depletion of naïve & memory B-cells
What is the effect of B-cell depletion by measles?
Significant reduction of the antibody repertoire
To which viral family do influenza viruses belong?
Orthomyxoviridae
To which viral family do measles viruses belong?
Paramyxoviridae
Which genera of influenza are known?
A, B, C, D
Which genus of influenza has the broadest host range? What are its hosts?
Influenza A
Original reservoir:
-Bats
-Wild aquatic birds
Secondary hosts:
-Poultry
-Swine
-Humans
What is the host of influenza B and C?
Exclusively humans
What is the host of influenza D?
Cattle
Which genera of influenza cause epidemics?
A & B
What are symptoms of influenza? (3)
- Fever
- Myalgia
- Respiratory symptoms
What are possible complications of influenza?
- Pneumonia
- Acute respiratory distress syndrome (ARDS)
- Bacterial superinfections
What causes bacterial superinfections in influenza virus? (2)
- The Th1-response against viruses does not effectively combat bacterial pathogens
- Damage of respiratory epithelium by influenza virus disturbs barriers and allows entry of bacterial pathogens
What kind of genome does influenza virus have?
(-)-sense segmented RNA genome, consisting of 8 fragments
How are the gene segments of influenza virus organized?
In viral ribonucleoproteins (vRNP) -> condensed RNA bound in nucleoproteins that envelop the RNA, associated with an RNA polymerase complex
How many proteins does influenza virus produce? How many auxiliary proteins are known for influenza virus?
10 genes produced, some produced by alternative splicing
8 auxiliary proteins -> not present in all virus strains
What are the structural proteins of influenza virus? (5) What is their function?
- Proteins that make up vRNP’s
- M1-> found just under the viral membrane
- M2 -> proton channel
- NA = neuraminidase -> glycoprotein found on the viral surface
- HA = hemagglutinin -> glycoprotein found on the viral surface
What are the two main influenza antigens?
The glycoproteins:
1. Hemagglutinin
2. Neuraminidase
What determines the different antigenic subtypes of influenza virus?
Different combinations of HA and NA
What allows different combinations of HA and NA in influenza virus?
The segmented genome of influenza virus allows for reassortment of NA and HA, allowing the virus to quickly obtain new combinations of HA/NA
What are important characteristics of a zoonosis? (3)
- Sporadic human infections with viruses coming from animal reservoirs
- No human-to-human transmissibility
- Result from close-contact with animals
When does reassortment of viruses with a segmented genome occur?
When multiple virus strains infect the same cells at the same time
Why does antigenic shift in influenza viruses have a high pandemic potential?
Leads to a completely new virus variant in the human population
What is the interaction between epidemic influenza viruses and influenza pandemics?
After a pandemic, the pandemic virus usually replaces the formerly circulating epidemic virus and becomes the ‘new’ epidemic virus
Why did the introduction of H1N1 virus in 1977 not cause a complete replacement of the originally circulating virus?
There was still a high amount of immunity against H1N1 within the population, because it had only been replaced by H2N2 in 1957. Older people were still resistant to H1N1, while younger people were dispropportionately affected by H1N1
What kind of genome do coronaviruses have?
(+)-RNA non-segmented
What are the general steps of the replication of coronavirus? (6)
- Virus entry
- Fusion and uncoating
- Production of viral RNA
- Translation of viral RNA
- Assembly of viral particles
- Exocytosis
Do coronaviruses have a RNA-dependent RNA-polymerase in their virus particle?
They don’t; since they are (+)-sense, they can be translated right away by the host cell
Which coronavirus protein is the target for vaccines, and why?
The spike protein; neutralization of the spike protein by antibodies prevents entry of virus into cells, thus preventing disease
Which coronavirus protein mutates to escape immunity?
Spike protein
What is the entry-receptor for SARS-CoV-2?
ACE2 -> found in the respiratory tract and lung
What triggers fusion of coronavirus particles with their host cell?
Proteases
What are the two major entry routes of coronaviruses?
- Plasma membrane fusion using serine proteases
- Endocytosis and fusion using caphepsins
Why does MERS-CoV outbreaks typically follow peaks and periods without transmission?
MERS-CoV is a zoonotic disease -> outbreak started upon contact with animals, after which containment of the outbreak by isolation/quarantine ends the outbreak
Why can dromedaries effectively transmit MERS-CoV, while humans can’t?
MERS-CoV uses DPP4 to enter cells
Dromedaries express DPP4 in the upper respiratory tract -> effective viral transmission
Humans express DPP4 in the lower respiratory tract -> viral transmission less effective
Why were vaccines not required to contain the SARS-CoV outbreak? (3)
- Effective use of diagnostics for isolation/quarantine
- Few asymptomatic cases -> carriers easily recognized
- Virus excretion in SARS-patients peaked after lower respiratory tract symptoms peaked -> these people are usually already hospitalized
Why was isolation/quarantine not sufficient to contain the spread of SARS-CoV-2?
SARS-CoV-2 is transmissible before symptoms occur -> hard to identify people carrying the virus
Why are elderly more at risk of severe COVID-19?
Antiviral immune responses are more likely to turn into an inflammatory type than in younger individuals
What are the two main pathological mechanisms of severe COVID-19?
- Inflammatory response/cytokine storm
- Hypercoagulability
Which cytokines are characteristic of a hyperinflammatory response to COVID-19 (4), and where do they originate?
IL-1, IL-8, IL-6 & IP-10, originating in the inflammasome
How does a ‘younger’ immune system respond to SARS-CoV-2?
Production of protective interferons without cytokine storm
What are the three stages of COVID-19, and what are their respective treatment strategies?
- Early phase -> aimed at viral proliferation through anti-infectives or antivirals
- Mid-phase -> aimed at preventing cytokine injury and pneumonia through corticosteroids and immunomodulators
- Late phase -> aimed at coagulation through antiplatelet agents and anticoagulants
True or false: the amount of SARS-CoV-2 viral replication is related to the amount of symptoms
Not true; highest viral replication can be found in the asymptomatic/mild-disease phase
During severe disease phases, viral replication is low
Why did SARS-CoV-2 cause a pandemic and many casualties? (5)
- Relatively efficient transmission due to replication the upper respiratory tract
- Large portion of asymptomatic/mildly ill individuals -> isolation and quarantine not effective
- Transmission of novel virus to immunologically naïve individuals
- Continuous antigenic evolution
- Lower respiratory tract infection causes dysregulated immune responses in risk groups
