Infection & Immunity Flashcards
Define
Antimicrobial
refers to those agents active against any microorganism including: Viruses and Eukaryotic pathogens such as fungi and protozoa
Define
Antibiotics
the name for the most commonly used antimicrobials that are active against bacteria
Define
Bacteriocidal
antibiotics that kill the microorganism
Define
Bacteriostatic
antibiotics that slow the growth of bacteria
Define
Penicillin
the first antibiotic, discovered in 1928 by Alexander Fleming. It targets the peptidoglycan layer of bacteria by inactivating Penicillin Binding Proteins essential for cross-linking peptidoglycan
Define
Penicillin Binding Protein (PBP)
enzyme found in bacteria responsible for crosslinking the peptidoglycan during biosynthesis
Define
Peptidoglycan
layer of the cell wall of both gram positive and gram negative bacteria and is the target for some antibiotics including beta-lactams
Define
Beta-lactam
a type of antibiotic that mimics the shape of the peptidoglycan D-ala-D-ala, preventing crosslinking. Includes penicillin
Define
Macrolide
a class of protein synthesis inhibitor that includes Erythromycin, clarithromycin and azithromycin. Acts by blocking the polypeptide exit tunnel on the 50S and preventing peptide chain elongation
Define
Tetracyclines
a class of protein synthesis inhibitor that includes Tetracycline, Doxycycline, Minocycline and Tigecycline. Acts by binding the the 30S and interfering with binding of tRNA to the ribosomal complex
Define
Aminoglycosides
a class of protein synthesis inhibitor that includes Streptomycin, gentamicin, neomycin, tobramycin and amikacin. Acts by binding to the 30S and causing mRNA codon to be misread. It also interferes with the initiation complex of the 30S and 50S with mRNA
Define
Polymyxins
a type of antibiotic that interact with the charged LPS of Gram negative bacteria and insert into the outer membrane leading to cell death. Not effective for Gram-positives
Define
Daptomycin
a type of antibiotic that disrupts the membranes of Gram-positive bacteria by inserting into the membrane and damaging it
Define
Rifamycin
a semisynthetic antibiotic that binds to DNA-dependent RNA polymerase and blocks synthesis of mRNA resulting in cell death
Define
Ergosterol
a sterol found in cell membranes of fungi and protozoa, serving many of the same functions that cholesterol serves in animal cells
Define
Multi-drug resistant (MDR)
non-susceptibility to at least one agent in three or more antimicrobial categories
Define
Extremely-drug resistant (XDR)
non-susceptibility to at least one agent in all but two or fewer antimicrobial categories
Define
Pan-drug resistant (PDR)
non-susceptibility to all agents in all antimicrobial categories
Define
Intrinsic resistance
a natural insensitivity in bacteria that have never been susceptible to a particular antibiotic
Define
Acquired resistance
said to occur when a particular microorganism obtains the ability to resist the activity of a particular antimicrobial agent to which it was previously susceptible.
Definition
refers to those agents active against any microorganism including: Viruses and Eukaryotic pathogens such as fungi and protozoa
Antimicrobial
Definition
the name for the most commonly used antimicrobials that are active against bacteria
Antibiotics
Definition
antibiotics that kill the microorganism
Bacteriocidal
Definition
antibiotics that slow the growth of bacteria
Bacteriostatic
Definition
the first antibiotic, discovered in 1928 by Alexander Fleming. It targets the peptidoglycan layer of bacteria by inactivating Penicillin Binding Proteins essential for cross-linking peptidoglycan
Penicillin
Definition
enzyme found in bacteria responsible for crosslinking the peptidoglycan during biosynthesis
Penicillin Binding Protein (PBP)
Definition
layer of the cell wall of both gram positive and gram negative bacteria and is the target for some antibiotics including beta-lactams
Peptidoglycan
Definition
a type of antibiotic that mimics the shape of the peptidoglycan D-ala-D-ala, preventing crosslinking. Includes penicillin
Beta-lactam
Definition
a class of protein synthesis inhibitor that includes Erythromycin, clarithromycin and azithromycin. Acts by blocking the polypeptide exit tunnel on the 50S and preventing peptide chain elongation
Macrolide
Definition
a class of protein synthesis inhibitor that includes Tetracycline, Doxycycline, Minocycline and Tigecycline. Acts by binding the the 30S and interfering with binding of tRNA to the ribosomal complex
Tetracyclines
Definition
a class of protein synthesis inhibitor that includes Streptomycin, gentamicin, neomycin, tobramycin and amikacin. Acts by binding to the 30S and causing mRNA codon to be misread. It also interferes with the initiation complex of the 30S and 50S with mRNA
Aminoglycosides
Definition
a type of antibiotic that interact with the charged LPS of Gram negative bacteria and insert into the outer membrane leading to cell death. Not effective for Gram-positives
Polymyxins
Definition
a type of antibiotic that disrupts the membranes of Gram-positive bacteria by inserting into the membrane and damaging it
Daptomycin
Definition
a semisynthetic antibiotic that binds to DNA-dependent RNA polymerase and blocks synthesis of mRNA resulting in cell death
Rifamycin
Definition
a sterol found in cell membranes of fungi and protozoa, serving many of the same functions that cholesterol serves in animal cells
Ergosterol
Definition
non-susceptibility to at least one agent in three or more antimicrobial categories
Multi-drug resistant (MDR)
Definition
non-susceptibility to at least one agent in all but two or fewer antimicrobial categories
Extremely-drug resistant (XDR)
Definition
non-susceptibility to all agents in all antimicrobial categories
Pan-drug resistant (PDR)
Definition
a natural insensitivity in bacteria that have never been susceptible to a particular antibiotic
Intrinsic resistance
Definition
said to occur when a particular microorganism obtains the ability to resist the activity of a particular antimicrobial agent to which it was previously susceptible.
Acquired resistance
The more general term “______________” refers to those agents active against any microorganism
The more general term “antimicrobial” refers to those agents active against any microorganism
Why are almost all antimicrobials are small molecules rather than proteins?
Able to diffuse into the microorganism through the membrane (porins)
How are antimicrobials selective?
- Target structures that are either not present, or very different between the microorganism and eukaryotic host.
- Peptidoglycan (in bacteria)
- Reverse transcriptase (in retroviruses)
- Ergosterol membrane component in fungi
- Many proteins with divergent sequence between microorganisms and eukaryotes
In what ways do we classify antibiotics?
- Natural vs semi-synthetic vs synthetic
- Spectrum of activity
- Narrow vs Broad; Gram-positive vs Gram-negative
- Bactericidal vs bacteriostatic
- Mode of action / specific target molecule
What is the term used to describe an antibiotic that kills the bactera?
Bacteriocidal
Which parts of a bacteria are targets for antibiotics?
Cell wall synthesis
Folic acid metabolism
Cytoplasmic membrane structure
DNA gurase
RNA elongation
DNA-directed RNA polymerase
Protein synthesis (50S inhibitors)
Protein synthesis (30S inhibitors)
Protein synthesis (rRNA)
How does Penicillin target cell wall synthesis?
binds to and inactivate the transpeptidase enzymes (Penicillin Binding Proteins) essential for cross-linking peptidoglycan
How does Vancomycin target cell wall synthesis?
bind to the peptidoglycan units themselves stopping protein binding and therefore crosslinking
True or False:
Antibiotics that target cell wall synthesis are bacteriocidal against all cells
False
They are bacteriocidal only against growing cells
True or False:
Peptioglycan is found in both Gram positive and Gram negative bacteria
True
Prior to crosslinking, each side chain of peptidoglycan ends in what amino acids?
D-Ala-D-Ala
Why is the shape of beta lactams important?
β-lactams mimic the D-Ala-D-Ala of the peptidoglycan
How does Penicillin act as a suicide inhibitor of transpeptidases?
The shape of the molecule allows it to interact with the active site of the transpeptidase. The strained peptide (C-N) bond is broken in favour of forming a bond with a serine molecule in the active site. This permanently disables the enzyme
What are the three broad classes of protein synthesis inhibitors?
Macrolide
Tetracyclines
Aminoglycosides
How do macrolides inhibit protein synthesis?
Block the polypeptide exit tunnel on the 50S and prevent peptide chain elongation
How do aminoglycosides inhibit protein synthesis?
Bind to 30S and causes mRNA codon to be misread; interfere with the initiation complex of 30S and 50S with mRNA
How do tetracyclines inhibit protein synthesis?
Bind to 30S and interfere with binding of tRNA to ribosomal complex
What type of bacteria do Polymyxins work on? Why?
Gram negative
The initial interaction of the antibiotic is with the LPS. Only Gram-negative bacteria have LPS
How does Polymyxins lead to cell death?
The charged region of the Polymyxin interacts with the negatively charged LPS. This allows insertion of the molecule in the outer and inner cell membrane leading to cell death (mechanism unknown)
How does Daptomycin cause cell death?
Direct interaction of daptomycin with membrane lipids
Insertion leads to membrane damage
May mis-regulate localization of cell division proteins
How do Rifamycins treat bacterial infections?
Bind to DNA-dependant RNA polymerase and block synthesis of mRNA
Results in cell death (bacteriocidal)
Why are antifungal agents usually more toxic to humans than antibacterials?
Fungi are eukaryotes so most agents that have toxicity against fungi are also toxic to the human host
What differences between fungal cells and human cells can be targeted for antimicrobial agents?
Glucan biosynthesis
Nucleic acid synthesis
Microtubule synthesis
Ergosterol biosynthesis
Why is Ergosterol a crucial target for antifungals?
Ergosterol is a cell membrane sterol that is unique to fungi and protozoa and is essential in most fungi
Which type of antifungal targets Ergosterol synthesis?
Azoles
Terbinafine
Which type of antifungal targets Ergosterol permeability?
Amphotericin B
Nystatin
How do Amphotericin B and nystatin act as antifungals?
Amphotericin B and nystatin bind strongly to ergosterol and increase membrane permeability leading to cell death
What can lead to ineffective antimicrobial treatment?
Bacterial resistance
Bacterial tolerance
Suboptimal treatment regimen
True or False:
Not all bacteria that survive treatment are resistant
True
Tolerant and persistent bacteria can survive treatment and are not resistant
What are tolerant bacteria?
Tolerant bacteria show slower killing
Often show survival after normal treatment regimen
What are persistent bacteria?
Persistent bacteria are a subpopulation that show very slow killing
Often related to a non-growing population
What drives resistance?
Resistance is a consequence of antibiotic use and natural selection
Resistant cells have a strong selective advantage and will rapidly dominate the population in the face of antibiotic treatment
True or False:
After the antibiotic is removed, the resistant bacteria will continue to dominate the population
False
Depends on the fitness cost of the resistance mutation
What are the four main mechanisms of resistance?
Blocked penetration
Efflux pump
Inactivation of enzymes
Target modification
It what ways does blocked penetration contribute to resistance?
Loss of porins used by antibiotics
Modified porins
Decreased porin expression
Efflux often involved in intrinsic/acquired resistance
Efflux often involved in intrinsic resistance
How do B-lactamase inhibitors contribute to resistance?
The break the B-lactam ring of the antibiotic so it no longer fits in the active site
How do B-lactamase inhibitors overcome resistance?
Inhibitor looks like a β-lactams but has little/no antibacterial activity
But can interact with the β-lactamase to save the antibiotic from degradation
What type of antibiotic is resistant to most types of B-lactamases?
Carbapenems
Why was there rapid dissemination of carbapenase?
Horizontal gene transfer; the gene is located on a transposon
What can we do to change the future of antibiotic use?
Prolong the lifespan of current antibiotics by best practice use
Use current antibiotics in combinations that give improved activity and slow resistance development
Develop new antibiotics
Develop new strategies
What is the increased activity seen in antibiotic synergy due to?
One antibiotic increasing access of the second antibiotic
Action of one antibiotic can be saved from resistance mechanisms by the second
Define
Non-inferiority Trial
a type of trial that aims to show that the new drug is no worse than standard treatment
Define
MDR Acinetobacter
a gram-negative, aerobic, non-motile, coccobacillus that survives very well in the environment will a range of resistance mechanisms making it resistant to multiple classes of antibiotic
Define
Polymyxin (Colistin)
A short, cyclic antimicrobial peptide with a positively charged and hydrophobic sections that interacts with the negative LPS and inserts into the cell membrane causing cell death in susceptible bacteria
Define
Methicillin-resistant Staphylococcus aureus (MRSA)
a skin commensal that is a common cause of hospital-acquired infections which displays resistance to Methicillin through an altered Penicillin binding protein
Define
Vancomycin-resistant Staphylococcus aureau (VRSA)
a skin commensal that is a common cause of hospital-acquired infections which displays resistance to Vancomycin through altering the D-Ala-D-Ala sequence of the peptidoglycan layer to D-Ala-D-Lac
Definition
a type of trial that aims to show that the new drug is no worse than standard treatment
Non-inferiority Trial
Definition
a gram-negative, aerobic, non-motile, coccobacillus that survives very well in the environment will a range of resistance mechanisms making it resistant to multiple classes of antibiotic
MDR Acinetobacter
Definition
A short, cyclic antimicrobial peptide with a positively charged and hydrophobic sections that interacts with the negative LPS and inserts into the cell membrane causing cell death in susceptible bacteria
Polymyxin (Colistin)
Definition
a skin commensal that is a common cause of hospital-acquired infections which displays resistance to Methicillin through an altered Penicillin binding protein
Methicillin-resistant Staphylococcus aureus (MRSA)
Definition
a skin commensal that is a common cause of hospital-acquired infections which displays resistance to Vancomycin through altering the D-Ala-D-Ala sequence of the peptidoglycan layer to D-Ala-D-Lac
Vancomycin-resistant Staphylococcus aureau (VRSA)
What two main factors affect antimicrobial development?
Scientific difficulty
Economic return on investment
What percentage of molecules put through the drug discovery and development process get approved for use?
0.6%
What is the Null Hypothesis for Non-Inferiority Trials?
new treatment’s efficacy is worse than that of current standard-of-care, on an agreed clinical end-point, by a specified margin at a given level of significance
When are Non-Inferiority trials used?
- Delaying treatment is life-threatening (i.e., placebo unethical)
- Existing treatment produces durable cure in most patients in the given indication
- New treatment has some advantage over BAT (e.g., antiMDR activity)
- Generally, new treatment will not be used until best existing treatment (BAT) fails in more than 10% of patients
What are the four proposed types of Phase III studies?
An acceptable human safety dataset plus:
A. Two Ph III randomised NI studies on a given indication (multiple pathogens, requires broad spectrum) (UDR)
B. One standard Ph III study (UDR) plus smaller salvage studies (MDR/XDR)
C. Single pathogen spectrum. Several small prospective, open-label salvage studies plus strong population PK and animal PK/PD
D. Studies in humans unethical. Strong animal PK/PD package for allometric scaling to humans
How can we decouple economic return from amount of antibiotic sold?
- Subsidise R&D in novel antimicrobials (cash, tax breaks, transferable patent extensions, etc)
- Reward market entry by a company
- Purchase an agreed number of doses in advance
- Purchase a license to use when needed
- Value of novel agent to be calculated by public health authority
When would strong animal PK/PD package for allometric scaling to humans be accepted as a Phase III study?
When studies in humans is unethical (i.e. bioterror agents like anthrax)
What are the resistance mechanisms seen in MDR Acinetobacter?
All four classes of β-lactamases often intrinsically present
Multiple efflux systems (including tetracycline efflux)
Reduced expression or inactivation of porins (insertion of transposons)
Various aminoglycoside modifying enzymes
Wide range of mutations altering targets
True or False:
MDR A. baumannii resistance is usually associated with a resistance island
True
What is the last line treatment option for MDR A. baumannii?
Polymyxin (Colistin)
How does Polymyxin kill bacter?
Polymyxin has a positivly charged section and a hydrophobic section. The positive section interacts with the negative LPS of Gram-negative bacteria and then the hydrophobic region inserts into the membrane. This destabilises the mebrane, killing the cell
What are the two main mechanisms of Polymyxin/Colisin resistance?
Complete LPS loss
Phosphoethanolamine (PETn) addition to LPS
How does a Colistin resistant bacteria lose it’s LPS?
Spontaneous mutations in lipid A biosynthesis genes IpxA, IpxC or IpxD results in complete loss of Lipid A and hence LPS layer
Why does loss of LPS make a bacteria resistant to Polymyxin?
Loss of LPS alters membrane charge
Reduced interaction with positively charged Polymyxin
True or False:
Loss of LPS has a strong fitness cost associated with in
True
How does a Colistin resistant bacteria add Phosphoethanolamine (Petn) to it’s LPS?
Mutations in two-component regulatory system genes, pmrA or pmrB
Results in increased expression of Petn transferase PmrC
Why does addition of Phosphoethanolamine addition to LPS make bacteria resistant to Polymyxin?
It makes the membrane positively charged
Repels positive Polymyxin
Which has a larged fitness cost: loss of LPS or addition of phosphoethanolamine to the LPS?
Loss of LPS
How do we currently treat Pan-drug resistant A. baumannii?
Combined antibiotic treatment
Novel treatment options (Phage therapy)
How did S. aureus become resistant to Penicillin?
Degradative enzymes
How did S. aureus become resistant to methicillin?
Acquiring the mecA gene (HGT) which encodes a modified PBP with very low affinity for all B-lactams
How do we treat MRSA?
- Vancomycin is a critical treatment option for MRSA
- Vancomycin binds to the peptidoglycan not the PBP
- Combination treatments
- Rifampicin (targets RNA polymerase) and fusidic acid (protein synthesis, elongation factor Ef-Tu targeting)
- Linezolid (protein synthesis inhibition)
- Vancomycin resistance now observed
How are Vancomycin intermediate S. aureus partially resistant to vancomycin?
Thickened cell wall
Reduced peptidoglycan cross-links
Why is complete resistance to Vancomycin uncommon in S. aureus?
The resistance gene is located on an unstable plasmid
Fitness cost
How does S. aureus become fully resistant to vancomycin?
Conversion of D-Ala-D-Ala into D-Ala-D-Lac
How do we treat vancomycin resistant S. aureus?
- Daptomycin an alternative (see slides from previous lecture)
- Daptomycin targets membrane
- But again resistance seen
- Changes to the Gram-positive membrane
- Lysine addition gives positive charge
- Repels daptomycin
How is TB highly intrisically drug resistant?
Unusual cell wall
Peptidoglycan, arabinogalactan, and thick layer of mycolic acids
Hydrophobic and hydrophilic compounds excluded
What is the current treatment regimen for TB?
Six month course of four drugs
Isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin
How does Isoniazid treat TB?
Isoniazid targets the Mycobacterial cell wall synthesis
- Is a pro-drug, inactive unless activated by metabolism inside the cell; KatG enzyme converts isoniazid to isonicotinic acyl-NADH
- Inhibits fatty acid synthesis
- Resistance often due to mutations in KatG
How does Pyrazinamide treat TB?
- Also a pro-drug, M. tb enzyme pyrazinamidase converts it to pyrazinoic acid
- Mechanism of action unclear (maybe fatty acid synthesis)
How does Ethambutol treat TB?
Mechanism of action also unclear but likely involves inhibition of conversion of arabinose to arabinogalactan (cell wall component)
What is MDR-TB resistant to?
at least isoniazid and rifampin
What is XDR-TB resistant to?
- isoniazid and rifampin, plus any fluoroquinolone and at least one of three injectable second-line drugs (i.e., amikacin, kanamycin, or capreomycin).
- Cure very difficult (30-50% of cases)
Define
Influenza
a highly contagious viral infection of the respiratory passages causing fever, severe aching, and catarrh, and often occurring in epidemics.
Define
Zoonotic
a disease that can be transmitted from animals to people or, more specifically, a disease that normally exists in animals but that can infect humans
Define
Pandemic
a disease prevalent over a whole country or the world.
Define
Hemagglutinin
a homotrimeric glycoprotein found on the surface of influenza viruses and is integral to its infectivity. It is a Class I Fusion Protein, having multifunctional activity as both an attachment factor and membrane fusion protein
Define
Sialic acid
found on the surface of human erythrocytes and on the cell membranes of the upper respiratory tract and play an important role in several human viral infections. The influenza viruses have hemagglutinin activity (HA) glycoproteins on their surfaces that bind to these
Define
Antigenic drift
A mechanism for variation by viruses that involves the accumulation of mutations within the antibody-binding sites so that the resulting viruses cannot be inhibited well by antibodies against previous strains making it easier for them to spread throughout a partially immune population.
Define
Spanish flu
an unusually deadly influenza pandemic caused by the H1N1 influenza A virus in 1918
Define
Swine flu
any strain of the influenza family of viruses that is endemic in pigs.
Define
Low pathogenic avian influenza (LPAIs)
commonly found in the wild bird reservoir and normally cause mild clinical symptoms or no apparent disease [6]. Wild birds shed these viruses in their droppings which can result in transmission to susceptible poultry and other birds via the faecal-oral route
Define
Highly pathogenic avian influenza (HPAIs)
an extremely contagious, multi-organ systemic disease of poultry leading to high mortality, and caused by some H5 and H7 subtypes of type A influenza virus
Definition
a highly contagious viral infection of the respiratory passages causing fever, severe aching, and catarrh, and often occurring in epidemics.
Influenza
Definition
a disease that can be transmitted from animals to people or, more specifically, a disease that normally exists in animals but that can infect humans
Zoonotic
Definition
a disease prevalent over a whole country or the world.
Pandemic
Definition
a homotrimeric glycoprotein found on the surface of influenza viruses and is integral to its infectivity. It is a Class I Fusion Protein, having multifunctional activity as both an attachment factor and membrane fusion protein
Hemagglutinin
Definition
found on the surface of human erythrocytes and on the cell membranes of the upper respiratory tract and play an important role in several human viral infections. The influenza viruses have hemagglutinin activity (HA) glycoproteins on their surfaces that bind to these
Sialic acid
Definition
A mechanism for variation by viruses that involves the accumulation of mutations within the antibody-binding sites so that the resulting viruses cannot be inhibited well by antibodies against previous strains making it easier for them to spread throughout a partially immune population.
Antigenic drift
Definition
an unusually deadly influenza pandemic caused by the H1N1 influenza A virus in 1918
Spanish flu
Definition
any strain of the influenza family of viruses that is endemic in pigs.
Swine flu
Definition
commonly found in the wild bird reservoir and normally cause mild clinical symptoms or no apparent disease [6]. Wild birds shed these viruses in their droppings which can result in transmission to susceptible poultry and other birds via the faecal-oral route
Low pathogenic avian influenza (LPAIs)
Definition
an extremely contagious, multi-organ systemic disease of poultry leading to high mortality, and caused by some H5 and H7 subtypes of type A influenza virus
Highly pathogenic avian influenza (HPAIs)
Define
SARS-COV2
the strain of coronavirus that causes coronavirus disease 2019 (COVID-19), a respiratory illness. It is a positive-sense single-stranded RNA virus.
Define
COVID-19
an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It was first identified in December 2019 in Wuhan, China, and has since spread globally, resulting in an ongoing pandemic
Define
SARS
a viral respiratory disease of zoonotic origin that surfaced in the early 2000s caused by severe acute respiratory syndrome coronavirus (SARS-CoV or SARS-CoV-1), the first-identified strain of the SARS coronavirus species severe acute respiratory syndrome-related coronavirus (SARSr-CoV)
Define
MERS
a viral respiratory infection caused by the MERS-coronavirus (MERS-CoV). Symptoms may range from none, to mild, to severe. Typical symptoms include fever, cough, diarrhea, and shortness of breath
Define
Endemic
a disease regularly found among particular people or in a certain area
Define
Reproductive number (R0)
the expected number of cases directly generated by one case in a population where all individuals are susceptible to infection
Definition
the strain of coronavirus that causes coronavirus disease 2019 (COVID-19), a respiratory illness. It is a positive-sense single-stranded RNA virus.
SARS-COV2
Definition
an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It was first identified in December 2019 in Wuhan, China, and has since spread globally, resulting in an ongoing pandemic
COVID-19
Definition
a viral respiratory disease of zoonotic origin that surfaced in the early 2000s caused by severe acute respiratory syndrome coronavirus (SARS-CoV or SARS-CoV-1), the first-identified strain of the SARS coronavirus species severe acute respiratory syndrome-related coronavirus (SARSr-CoV)
SARS
Definition
a viral respiratory infection caused by the MERS-coronavirus (MERS-CoV). Symptoms may range from none, to mild, to severe. Typical symptoms include fever, cough, diarrhea, and shortness of breath
MERS
Definition
a disease regularly found among particular people or in a certain area
Endemic
Definition
the expected number of cases directly generated by one case in a population where all individuals are susceptible to infection
Reproductive number (R0)
Why are viruses considered obligate intracellular parasites?
They can only replicate when they are inside a cell
What are the 5 steps for viral replication?
- Attachment and entry
- Translation of proteins
- Genome replication
- Assembly
- Release
What is tissue tropism?
Tissue tropism is the cells and tissues of a host that support growth of a particular virus or bacterium.
What determines the tropism of a virus?
The target receptor
What is zoonotic spillover?
transmission of a pathogen from a vertebrate animal to a human
What are the characteristics of a pandemic?
- Associated with introduction of virus into human circulation with no pre-existing immunity
- Sudden onset, no real warning
- Rapid global spread, easy human to human transmission
- Get waves of infection, increasing virulence
Roughly how many people died from Spanish influenza?
30-50 million people
What are the natural viral reservoir for influenza viruses?
Wild aquatic birds
What does viral hemagglutinin recognise?
Sialic acids
True or False:
Viral hemagglutinin is a dimer
False
Viral hemagglutinin is a trimer
Hemagglutinin binds to ___________ groups on cell surface proteins
Hemagglutinin binds to sialic acid groups on cell surface proteins
Human viruses bind to sialic acid in a ____ galactose linkage
Human viruses bind to sialic acid in a a2,6 galactose linkage
Bird viruses bind to sialic acid in a ____ galactose linkage
Bird viruses bind to sialic acid in a a2,3 galactose linkage
What must happen to hemagglutinin for it to activate? Why does this contribute to tissue tropism?
It must be cleaved by a trypsin-like protease located in the lung. Since it can only activate in the lung, it effects mainly the cells in the lung
What are the characteristics of Influenza epidemiology?
- Spread by aerosol and/or droplet
- Rapid spread of infection
- Several days before onset of symptoms
- Virus shed before onset of symptoms
In what way does Influenza A virus infection induces a robust immune response?
- Symptoms include fever, pneumonia (take a 5-7 days to appear); due to production of cytokines (eg TNF)
- Generate excellent antibody response to spike (HA> NA) proteins; provide protective immunity
- Generate excellent T cell responses (cell mediated immunity)
Who are most at risk from Influenza A infection? Why?
Individuals most at risk from Influenza A infection are: Young, elderly, immunocompromised
This is because Influenza A virus infection induces a robust immune response and these individuals are likely to have a weakened immune system
Why does immunity to influenza wane fase?
Mutagenic drift means mutations accumulate in the antibody binding sites of the hemagglutinin. Therefore, immunity to previous year’s strain not as effective
______ cells recognize peptide fragments from highly conserved viral proteins (NP, M1, pol)
CD8+ T cells recognize peptide fragments from highly conserved viral proteins (NP, M1, pol)
What is the primary mode of proteiction from influenza infection?
Protection from influenza infection is primarily via neutralizing antibody
What conditions favour an Influenza A virus pandemic?
- No existing immunity in the population
- Ability to spread from human to human
- Acquisition of favorable mutations.
- Chance for avian (?) viruses to re-assort with human viruses (direct transmission).
- Pre-cursors are endemic in animal reservoir, contact between human and animal reservoirs (high density).
What was the difference between the sialic acid conformation recognised by the viruses in the first wave and the second wave of the Spanish flu?
First wave viruses recognised both a1,3 sialic acid linkages and a2,6 linkages.
Second wave only recognised a2,6 linkages
Indicates that the virus adapted and specialised to the human host
Why was the Spanish flu so deadly?
It caused a cytokine storm
Why did 2009 swine flu not affect older adults as much?
Pre-existing immunity to the virus in older adults likely resulted in a ameliorated impact on these people
What are the two types of bird flu?
Low pathogenic avian influenza
Highly pathogenic avian influenza
What are the usualy characteristics of highly pathogenic avian infleunzas?
- Virulence associated with insertion of multiple basic amino acids in cleavage site of HA
- More efficient cleavage of HA by proteases such as plasmin and furin (systemic)
- Direct transmission from birds to human, no need for pig as intermediate host - evidence this was also the case for Spanish influenza pandemic
- H5N1 viruses have become endemic in wild acquatic bird populations
- Continuing to evolve in bird reservoir in S.E Asia, Southern China
- H5N1 viruses have not yet acquired the ability to spread from human to human efficiently
What type of genetic material do Coronaviruses have?
Positive sense RNA
What is unusual about the genetic composition of Coronaviruses?
Which Coronavirus protein is the main target for antiviral drugs?
Spike protein
True or False:
Coronavirus genetic material can be immediatedly translated by host ribosomes
True
Positive sense RNA is the same as mRNA
Which has the highest mortality rate: SARS, MERS or COVID-19?
MERS
MERS is endemic in which animal?
Camels
Why does data suggest that kids don’t get COVID-19?
Potential testing bias
Kids are tested less than other age groups
What percentage of COVID-19 patients are hospitalised? What percentage of hospitalisations require ICU?
20% hospitalised
3-5% hospitalisations require ICU
What is the mortality rate of COVID-19 once someone is in the ICU?
40-50%
Why does COVID-19 cause people to get so sick?
Cytokine storm
Which receptor does SARS-COV2 target?
Human ACE2
What must occur for a spike protein to go from closed to open?
Cleavage
Which part of the virus interacts with the host receptor?
Spike protein
What is the most likely sources of SARS-COV2?
Bats
What is the R0 of SARS-COV2?
~2.5
What R0 is required for a virus to burn out?
R0 < 1
