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Infection & Immunity Flashcards

1
Q

Define

Antimicrobial

A

refers to those agents active against any microorganism including: Viruses and Eukaryotic pathogens such as fungi and protozoa

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2
Q

Define

Antibiotics

A

the name for the most commonly used antimicrobials that are active against bacteria

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3
Q

Define

Bacteriocidal

A

antibiotics that kill the microorganism

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4
Q

Define

Bacteriostatic

A

antibiotics that slow the growth of bacteria

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5
Q

Define

Penicillin

A

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

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6
Q

Define

Penicillin Binding Protein (PBP)

A

enzyme found in bacteria responsible for crosslinking the peptidoglycan during biosynthesis

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7
Q

Define

Peptidoglycan

A

layer of the cell wall of both gram positive and gram negative bacteria and is the target for some antibiotics including beta-lactams

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8
Q

Define

Beta-lactam

A

a type of antibiotic that mimics the shape of the peptidoglycan D-ala-D-ala, preventing crosslinking. Includes penicillin

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9
Q

Define

Macrolide

A

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

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10
Q

Define

Tetracyclines

A

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

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11
Q

Define

Aminoglycosides

A

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

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12
Q

Define

Polymyxins

A

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

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13
Q

Define

Daptomycin

A

a type of antibiotic that disrupts the membranes of Gram-positive bacteria by inserting into the membrane and damaging it

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14
Q

Define

Rifamycin

A

a semisynthetic antibiotic that binds to DNA-dependent RNA polymerase and blocks synthesis of mRNA resulting in cell death

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15
Q

Define

Ergosterol

A

a sterol found in cell membranes of fungi and protozoa, serving many of the same functions that cholesterol serves in animal cells

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16
Q

Define

Multi-drug resistant (MDR)

A

non-susceptibility to at least one agent in three or more antimicrobial categories

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17
Q

Define

Extremely-drug resistant (XDR)

A

non-susceptibility to at least one agent in all but two or fewer antimicrobial categories

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18
Q

Define

Pan-drug resistant (PDR)

A

non-susceptibility to all agents in all antimicrobial categories

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19
Q

Define

Intrinsic resistance

A

a natural insensitivity in bacteria that have never been susceptible to a particular antibiotic

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20
Q

Define

Acquired resistance

A

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.

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21
Q

Definition

refers to those agents active against any microorganism including: Viruses and Eukaryotic pathogens such as fungi and protozoa

A

Antimicrobial

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22
Q

Definition

the name for the most commonly used antimicrobials that are active against bacteria

A

Antibiotics

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23
Q

Definition

antibiotics that kill the microorganism

A

Bacteriocidal

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24
Q

Definition

antibiotics that slow the growth of bacteria

A

Bacteriostatic

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25
Q

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

A

Penicillin

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26
Q

Definition

enzyme found in bacteria responsible for crosslinking the peptidoglycan during biosynthesis

A

Penicillin Binding Protein (PBP)

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27
Q

Definition

layer of the cell wall of both gram positive and gram negative bacteria and is the target for some antibiotics including beta-lactams

A

Peptidoglycan

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28
Q

Definition

a type of antibiotic that mimics the shape of the peptidoglycan D-ala-D-ala, preventing crosslinking. Includes penicillin

A

Beta-lactam

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29
Q

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

A

Macrolide

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30
Q

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

A

Tetracyclines

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31
Q

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

A

Aminoglycosides

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32
Q

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

A

Polymyxins

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33
Q

Definition

a type of antibiotic that disrupts the membranes of Gram-positive bacteria by inserting into the membrane and damaging it

A

Daptomycin

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34
Q

Definition

a semisynthetic antibiotic that binds to DNA-dependent RNA polymerase and blocks synthesis of mRNA resulting in cell death

A

Rifamycin

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35
Q

Definition

a sterol found in cell membranes of fungi and protozoa, serving many of the same functions that cholesterol serves in animal cells

A

Ergosterol

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36
Q

Definition

non-susceptibility to at least one agent in three or more antimicrobial categories

A

Multi-drug resistant (MDR)

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37
Q

Definition

non-susceptibility to at least one agent in all but two or fewer antimicrobial categories

A

Extremely-drug resistant (XDR)

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38
Q

Definition

non-susceptibility to all agents in all antimicrobial categories

A

Pan-drug resistant (PDR)

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39
Q

Definition

a natural insensitivity in bacteria that have never been susceptible to a particular antibiotic

A

Intrinsic resistance

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40
Q

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.

A

Acquired resistance

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41
Q

The more general term “______________” refers to those agents active against any microorganism

A

The more general term “antimicrobial” refers to those agents active against any microorganism

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42
Q

Why are almost all antimicrobials are small molecules rather than proteins?

A

Able to diffuse into the microorganism through the membrane (porins)

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43
Q

How are antimicrobials selective?

A
  • 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
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44
Q

In what ways do we classify antibiotics?

A
  • 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
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45
Q

What is the term used to describe an antibiotic that kills the bactera?

A

Bacteriocidal

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46
Q

Which parts of a bacteria are targets for antibiotics?

A

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)

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47
Q

How does Penicillin target cell wall synthesis?

A

binds to and inactivate the transpeptidase enzymes (Penicillin Binding Proteins) essential for cross-linking peptidoglycan

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48
Q

How does Vancomycin target cell wall synthesis?

A

bind to the peptidoglycan units themselves stopping protein binding and therefore crosslinking

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49
Q

True or False:

Antibiotics that target cell wall synthesis are bacteriocidal against all cells

A

False

They are bacteriocidal only against growing cells

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50
Q

True or False:

Peptioglycan is found in both Gram positive and Gram negative bacteria

A

True

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51
Q

Prior to crosslinking, each side chain of peptidoglycan ends in what amino acids?

A

D-Ala-D-Ala

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52
Q

Why is the shape of beta lactams important?

A

β-lactams mimic the D-Ala-D-Ala of the peptidoglycan

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53
Q

How does Penicillin act as a suicide inhibitor of transpeptidases?

A

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

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54
Q

What are the three broad classes of protein synthesis inhibitors?

A

Macrolide

Tetracyclines

Aminoglycosides

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55
Q

How do macrolides inhibit protein synthesis?

A

Block the polypeptide exit tunnel on the 50S and prevent peptide chain elongation

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56
Q

How do aminoglycosides inhibit protein synthesis?

A

Bind to 30S and causes mRNA codon to be misread; interfere with the initiation complex of 30S and 50S with mRNA

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57
Q

How do tetracyclines inhibit protein synthesis?

A

Bind to 30S and interfere with binding of tRNA to ribosomal complex

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58
Q

What type of bacteria do Polymyxins work on? Why?

A

Gram negative

The initial interaction of the antibiotic is with the LPS. Only Gram-negative bacteria have LPS

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59
Q

How does Polymyxins lead to cell death?

A

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)

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60
Q

How does Daptomycin cause cell death?

A

Direct interaction of daptomycin with membrane lipids

Insertion leads to membrane damage

May mis-regulate localization of cell division proteins

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61
Q

How do Rifamycins treat bacterial infections?

A

Bind to DNA-dependant RNA polymerase and block synthesis of mRNA

Results in cell death (bacteriocidal)

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62
Q

Why are antifungal agents usually more toxic to humans than antibacterials?

A

Fungi are eukaryotes so most agents that have toxicity against fungi are also toxic to the human host

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63
Q

What differences between fungal cells and human cells can be targeted for antimicrobial agents?

A

Glucan biosynthesis

Nucleic acid synthesis

Microtubule synthesis

Ergosterol biosynthesis

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64
Q

Why is Ergosterol a crucial target for antifungals?

A

Ergosterol is a cell membrane sterol that is unique to fungi and protozoa and is essential in most fungi

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65
Q

Which type of antifungal targets Ergosterol synthesis?

A

Azoles

Terbinafine

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66
Q

Which type of antifungal targets Ergosterol permeability?

A

Amphotericin B

Nystatin

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67
Q

How do Amphotericin B and nystatin act as antifungals?

A

Amphotericin B and nystatin bind strongly to ergosterol and increase membrane permeability leading to cell death

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68
Q

What can lead to ineffective antimicrobial treatment?

A

Bacterial resistance

Bacterial tolerance

Suboptimal treatment regimen

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69
Q

True or False:

Not all bacteria that survive treatment are resistant

A

True

Tolerant and persistent bacteria can survive treatment and are not resistant

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70
Q

What are tolerant bacteria?

A

Tolerant bacteria show slower killing

Often show survival after normal treatment regimen

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71
Q

What are persistent bacteria?

A

Persistent bacteria are a subpopulation that show very slow killing

Often related to a non-growing population

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72
Q

What drives resistance?

A

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

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73
Q

True or False:

After the antibiotic is removed, the resistant bacteria will continue to dominate the population

A

False

Depends on the fitness cost of the resistance mutation

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74
Q

What are the four main mechanisms of resistance?

A

Blocked penetration

Efflux pump

Inactivation of enzymes

Target modification

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75
Q

It what ways does blocked penetration contribute to resistance?

A

Loss of porins used by antibiotics

Modified porins

Decreased porin expression

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76
Q

Efflux often involved in intrinsic/acquired resistance

A

Efflux often involved in intrinsic resistance

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77
Q

How do B-lactamase inhibitors contribute to resistance?

A

The break the B-lactam ring of the antibiotic so it no longer fits in the active site

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78
Q

How do B-lactamase inhibitors overcome resistance?

A

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

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79
Q

What type of antibiotic is resistant to most types of B-lactamases?

A

Carbapenems

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80
Q

Why was there rapid dissemination of carbapenase?

A

Horizontal gene transfer; the gene is located on a transposon

81
Q

What can we do to change the future of antibiotic use?

A

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

82
Q

What is the increased activity seen in antibiotic synergy due to?

A

One antibiotic increasing access of the second antibiotic

Action of one antibiotic can be saved from resistance mechanisms by the second

83
Q

Define

Non-inferiority Trial

A

a type of trial that aims to show that the new drug is no worse than standard treatment

84
Q

Define

MDR Acinetobacter

A

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

85
Q

Define

Polymyxin (Colistin)

A

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

86
Q

Define

Methicillin-resistant Staphylococcus aureus (MRSA)

A

a skin commensal that is a common cause of hospital-acquired infections which displays resistance to Methicillin through an altered Penicillin binding protein

87
Q

Define

Vancomycin-resistant Staphylococcus aureau (VRSA)

A

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

88
Q

Definition

a type of trial that aims to show that the new drug is no worse than standard treatment

A

Non-inferiority Trial

89
Q

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

A

MDR Acinetobacter

90
Q

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

A

Polymyxin (Colistin)

91
Q

Definition

a skin commensal that is a common cause of hospital-acquired infections which displays resistance to Methicillin through an altered Penicillin binding protein

A

Methicillin-resistant Staphylococcus aureus (MRSA)

92
Q

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

A

Vancomycin-resistant Staphylococcus aureau (VRSA)

93
Q

What two main factors affect antimicrobial development?

A

Scientific difficulty

Economic return on investment

94
Q

What percentage of molecules put through the drug discovery and development process get approved for use?

A

0.6%

95
Q

What is the Null Hypothesis for Non-Inferiority Trials?

A

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

96
Q

When are Non-Inferiority trials used?

A
  • 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
97
Q

What are the four proposed types of Phase III studies?

A

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

98
Q

How can we decouple economic return from amount of antibiotic sold?

A
  • 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
99
Q

When would strong animal PK/PD package for allometric scaling to humans be accepted as a Phase III study?

A

When studies in humans is unethical (i.e. bioterror agents like anthrax)

100
Q

What are the resistance mechanisms seen in MDR Acinetobacter?

A

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

101
Q

True or False:

MDR A. baumannii resistance is usually associated with a resistance island

A

True

102
Q

What is the last line treatment option for MDR A. baumannii?

A

Polymyxin (Colistin)

103
Q

How does Polymyxin kill bacter?

A

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

104
Q

What are the two main mechanisms of Polymyxin/Colisin resistance?

A

Complete LPS loss

Phosphoethanolamine (PETn) addition to LPS

105
Q

How does a Colistin resistant bacteria lose it’s LPS?

A

Spontaneous mutations in lipid A biosynthesis genes IpxA, IpxC or IpxD results in complete loss of Lipid A and hence LPS layer

106
Q

Why does loss of LPS make a bacteria resistant to Polymyxin?

A

Loss of LPS alters membrane charge

Reduced interaction with positively charged Polymyxin

107
Q

True or False:

Loss of LPS has a strong fitness cost associated with in

A

True

108
Q

How does a Colistin resistant bacteria add Phosphoethanolamine (Petn) to it’s LPS?

A

Mutations in two-component regulatory system genes, pmrA or pmrB

Results in increased expression of Petn transferase PmrC

109
Q

Why does addition of Phosphoethanolamine addition to LPS make bacteria resistant to Polymyxin?

A

It makes the membrane positively charged

Repels positive Polymyxin

110
Q

Which has a larged fitness cost: loss of LPS or addition of phosphoethanolamine to the LPS?

A

Loss of LPS

111
Q

How do we currently treat Pan-drug resistant A. baumannii?

A

Combined antibiotic treatment

Novel treatment options (Phage therapy)

112
Q

How did S. aureus become resistant to Penicillin?

A

Degradative enzymes

113
Q

How did S. aureus become resistant to methicillin?

A

Acquiring the mecA gene (HGT) which encodes a modified PBP with very low affinity for all B-lactams

114
Q

How do we treat MRSA?

A
  • 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
115
Q

How are Vancomycin intermediate S. aureus partially resistant to vancomycin?

A

Thickened cell wall

Reduced peptidoglycan cross-links

116
Q

Why is complete resistance to Vancomycin uncommon in S. aureus?

A

The resistance gene is located on an unstable plasmid

Fitness cost

117
Q

How does S. aureus become fully resistant to vancomycin?

A

Conversion of D-Ala-D-Ala into D-Ala-D-Lac

118
Q

How do we treat vancomycin resistant S. aureus?

A
  • 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
119
Q

How is TB highly intrisically drug resistant?

A

Unusual cell wall

Peptidoglycan, arabinogalactan, and thick layer of mycolic acids

Hydrophobic and hydrophilic compounds excluded

120
Q

What is the current treatment regimen for TB?

A

Six month course of four drugs

Isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin

121
Q

How does Isoniazid treat TB?

A

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
122
Q

How does Pyrazinamide treat TB?

A
  • Also a pro-drug, M. tb enzyme pyrazinamidase converts it to pyrazinoic acid
  • Mechanism of action unclear (maybe fatty acid synthesis)
123
Q

How does Ethambutol treat TB?

A

Mechanism of action also unclear but likely involves inhibition of conversion of arabinose to arabinogalactan (cell wall component)

124
Q

What is MDR-TB resistant to?

A

at least isoniazid and rifampin

125
Q

What is XDR-TB resistant to?

A
  • 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)
126
Q

Define

Influenza

A

a highly contagious viral infection of the respiratory passages causing fever, severe aching, and catarrh, and often occurring in epidemics.

127
Q

Define

Zoonotic

A

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

128
Q

Define

Pandemic

A

a disease prevalent over a whole country or the world.

129
Q

Define

Hemagglutinin

A

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

130
Q

Define

Sialic acid

A

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

131
Q

Define

Antigenic drift

A

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.

132
Q

Define

Spanish flu

A

an unusually deadly influenza pandemic caused by the H1N1 influenza A virus in 1918

133
Q

Define

Swine flu

A

any strain of the influenza family of viruses that is endemic in pigs.

134
Q

Define

Low pathogenic avian influenza (LPAIs)

A

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

135
Q

Define

Highly pathogenic avian influenza (HPAIs)

A

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

136
Q

Definition

a highly contagious viral infection of the respiratory passages causing fever, severe aching, and catarrh, and often occurring in epidemics.

A

Influenza

137
Q

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

A

Zoonotic

138
Q

Definition

a disease prevalent over a whole country or the world.

A

Pandemic

139
Q

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

A

Hemagglutinin

140
Q

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

A

Sialic acid

141
Q

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.

A

Antigenic drift

142
Q

Definition

an unusually deadly influenza pandemic caused by the H1N1 influenza A virus in 1918

A

Spanish flu

143
Q

Definition

any strain of the influenza family of viruses that is endemic in pigs.

A

Swine flu

144
Q

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

A

Low pathogenic avian influenza (LPAIs)

145
Q

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

A

Highly pathogenic avian influenza (HPAIs)

146
Q

Define

SARS-COV2

A

the strain of coronavirus that causes coronavirus disease 2019 (COVID-19), a respiratory illness. It is a positive-sense single-stranded RNA virus.

147
Q

Define

COVID-19

A

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

148
Q

Define

SARS

A

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)

149
Q

Define

MERS

A

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

150
Q

Define

Endemic

A

a disease regularly found among particular people or in a certain area

151
Q

Define

Reproductive number (R0)

A

the expected number of cases directly generated by one case in a population where all individuals are susceptible to infection

152
Q

Definition

the strain of coronavirus that causes coronavirus disease 2019 (COVID-19), a respiratory illness. It is a positive-sense single-stranded RNA virus.

A

SARS-COV2

153
Q

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

A

COVID-19

154
Q

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)

A

SARS

155
Q

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

A

MERS

156
Q

Definition

a disease regularly found among particular people or in a certain area

A

Endemic

157
Q

Definition

the expected number of cases directly generated by one case in a population where all individuals are susceptible to infection

A

Reproductive number (R0)

158
Q

Why are viruses considered obligate intracellular parasites?

A

They can only replicate when they are inside a cell

159
Q

What are the 5 steps for viral replication?

A
  1. Attachment and entry
  2. Translation of proteins
  3. Genome replication
  4. Assembly
  5. Release
160
Q

What is tissue tropism?

A

Tissue tropism is the cells and tissues of a host that support growth of a particular virus or bacterium.

161
Q

What determines the tropism of a virus?

A

The target receptor

162
Q

What is zoonotic spillover?

A

transmission of a pathogen from a vertebrate animal to a human

163
Q

What are the characteristics of a pandemic?

A
  • 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
164
Q

Roughly how many people died from Spanish influenza?

A

30-50 million people

165
Q

What are the natural viral reservoir for influenza viruses?

A

Wild aquatic birds

166
Q

What does viral hemagglutinin recognise?

A

Sialic acids

167
Q

True or False:

Viral hemagglutinin is a dimer

A

False

Viral hemagglutinin is a trimer

168
Q

Hemagglutinin binds to ___________ groups on cell surface proteins

A

Hemagglutinin binds to sialic acid groups on cell surface proteins

169
Q

Human viruses bind to sialic acid in a ____ galactose linkage

A

Human viruses bind to sialic acid in a a2,6 galactose linkage

170
Q

Bird viruses bind to sialic acid in a ____ galactose linkage

A

Bird viruses bind to sialic acid in a a2,3 galactose linkage

171
Q

What must happen to hemagglutinin for it to activate? Why does this contribute to tissue tropism?

A

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

172
Q

What are the characteristics of Influenza epidemiology?

A
  • Spread by aerosol and/or droplet
  • Rapid spread of infection
  • Several days before onset of symptoms
  • Virus shed before onset of symptoms
173
Q

In what way does Influenza A virus infection induces a robust immune response?

A
  • 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)
174
Q

Who are most at risk from Influenza A infection? Why?

A

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

175
Q

Why does immunity to influenza wane fase?

A

Mutagenic drift means mutations accumulate in the antibody binding sites of the hemagglutinin. Therefore, immunity to previous year’s strain not as effective

176
Q

______ cells recognize peptide fragments from highly conserved viral proteins (NP, M1, pol)

A

CD8+ T cells recognize peptide fragments from highly conserved viral proteins (NP, M1, pol)

177
Q

What is the primary mode of proteiction from influenza infection?

A

Protection from influenza infection is primarily via neutralizing antibody

178
Q

What conditions favour an Influenza A virus pandemic?

A
  • 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).
179
Q

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?

A

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

180
Q

Why was the Spanish flu so deadly?

A

It caused a cytokine storm

181
Q

Why did 2009 swine flu not affect older adults as much?

A

Pre-existing immunity to the virus in older adults likely resulted in a ameliorated impact on these people

182
Q

What are the two types of bird flu?

A

Low pathogenic avian influenza

Highly pathogenic avian influenza

183
Q

What are the usualy characteristics of highly pathogenic avian infleunzas?

A
  • 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
184
Q

What type of genetic material do Coronaviruses have?

A

Positive sense RNA

185
Q

What is unusual about the genetic composition of Coronaviruses?

A
186
Q

Which Coronavirus protein is the main target for antiviral drugs?

A

Spike protein

187
Q

True or False:

Coronavirus genetic material can be immediatedly translated by host ribosomes

A

True

Positive sense RNA is the same as mRNA

188
Q

Which has the highest mortality rate: SARS, MERS or COVID-19?

A

MERS

189
Q

MERS is endemic in which animal?

A

Camels

190
Q

Why does data suggest that kids don’t get COVID-19?

A

Potential testing bias

Kids are tested less than other age groups

191
Q

What percentage of COVID-19 patients are hospitalised? What percentage of hospitalisations require ICU?

A

20% hospitalised

3-5% hospitalisations require ICU

192
Q

What is the mortality rate of COVID-19 once someone is in the ICU?

A

40-50%

193
Q

Why does COVID-19 cause people to get so sick?

A

Cytokine storm

194
Q

Which receptor does SARS-COV2 target?

A

Human ACE2

195
Q

What must occur for a spike protein to go from closed to open?

A

Cleavage

196
Q

Which part of the virus interacts with the host receptor?

A

Spike protein

197
Q

What is the most likely sources of SARS-COV2?

A

Bats

198
Q

What is the R0 of SARS-COV2?

A

~2.5

199
Q

What R0 is required for a virus to burn out?

A

R0 < 1

STUFF (6 decks)

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