L3. Staph A Virulence Flashcards

1
Q

What does Staph A stand for

A

Staphylococcus aureus

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2
Q

What type of bacteria is Staph A?

A

Gram-positive spherically shaped bacterium

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3
Q

What is an important factor about how Staph A replicates and what is the effect of this?

A

> Can divide in 3 alternate planes, allowing daughter cells can remain stuck together

> Important for pathogenesis, can form biofilm

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4
Q

What is a “Nosocomial infection” and what bacteria commonly causes them?

A

An infection picked up in hospital, commonly caused by Staph A (also C. diff).

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5
Q

Why are biofilms formed by S. aureus difficult to eradicate?

A

Because they form clumps of cells that are impermeable to antibiotics.

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6
Q

What percentage of the human population carries S. aureus as commensals?

A

30%

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7
Q

Where is S. aureus most commonly found in the human body?

A

Mostly in the nose, but it can also survive on the skin and get onto cuts.

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8
Q

Can S. aureus survive in abiotic environments, and if so, where?

A

Yes, it can survive in food, water, and on surfaces.

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9
Q

What characteristics makes S. aureus very resilient in different environments?

A

It is very stress-resistant, halotolerant (survives in salt), and can withstand heat.

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10
Q

What is one reason hospitals need to use disinfection?

A

To prevent S. aureus from surviving on abiotic surfaces like food, water, and hospital surfaces.

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11
Q

What is the initiating factor for many diseases caused by Staphylococcus aureus?

A

Initiated by wounds.

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12
Q

What are furuncles (boils)?

A

Superficial, self-limiting infections that have the capacity to spread to other cells.

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13
Q

What is pyomyositis?

A

An abscess under the skin that can spread and is treated by making an incision and releasing bacteria.

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14
Q

What is endocarditis caused by Staphylococcus aureus?

A

A life-threatening condition where the bacteria can grow in heart valves and deform them by forming biofilms.

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15
Q

How do indwelling devices relate to Staphylococcus aureus infections?

A

They cause breaches in the skin, which happens frequently in hospitals, leading to infections.

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16
Q

What is toxic shock syndrome caused by Staphylococcus aureus?

A

A fatal condition characterized by lesions.

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17
Q

What are some other diseases caused by Staphylococcus aureus?

A

Food poisoning, scalded skin syndrome, and septicaemia.

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18
Q

How can Staphylococcus aureus infections be metastatic?

A

The bacteria can spread through the blood, causing cytokine storm and multiple organ dysfunction syndrome.

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19
Q

What range of disease severity can Staphylococcus aureus cause?

A

It can cause diseases ranging from minor to life-threatening.

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20
Q

How does Staphylococcus aureus adapt to various environments to cause numerous diseases?

A

It is highly adaptable and opportunistic, responding to conditions in particular environments.

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21
Q

What role do multiple virulence determinants play in Staphylococcus aureus infections?

A

As Staph A has multiple virulence determinants, the Infection associated dynamics changes between individual infections as different virulence factors can be used.

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22
Q

What are the 4 overall steps of Staph A infection?

A
  1. Interaction with specific target tissue, responds to environmental signals like temperature
  2. Proliferate (avoid host defences- especially innate)
  3. Local damage (as gets nutreints from us)
  4. Dissemination of pathogen or products (systemic disease)
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23
Q

At what stage does Staph A produce surface proteins?

A

Produces surface proteins during exponential growth

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24
Q

What does Staph A start producing during stationary phase?

A

When reaching stationary phase, starts producing toxins and exoenzymes to create more nutrients; causing spreading to find near nutrients

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25
Q

How many neutrophils do we produce per day?

A

○ We produce 10 to the 9 per day by kg of neutrophils per day (short lived)

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26
Q

What is Chronic Granulations Disease, what are the effects of it, and what does it tell us about Staph A?

A

> Fatal hereditary defect

> Neutrophils fail to make H2O2 -> not oxidate killing -> frequent serious S.A infections

> Innate immune response is is very important against Staph A

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27
Q

Why do we all have high antibody titres against Staph A?

A

As we are constantly getting infections by Staph A

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28
Q

What is a basic description of a pathogen infection?

A

It is a struggle between the interacting pathogen and host’s immune system

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29
Q

What is the main method of the immune system to kill Staph A?

A

Phagocytosis by neutrophils

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30
Q

Describe how neutrophils kill Staph A in 3 steps

A
  1. Recruitment by Staph A antigen
    >Chemotactic signals IL8. C5A (part of innate immune respond), LTA (part of cell wall of bacteria), formyl peptides (at start of every protein inn bacteria).
  2. Phagocytosis of Staph A
    >Opsonisation: complement, antibodies
  3. Killing
    >ROS dependent (HOCl etc)
    >Oxygen independent (cathepsin, antimicrobial peptides etc.)
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31
Q

What are the 3 immune evasion targets by Staph A?

A
  1. Neutrophil recruitment and chemotaxis inhibition
  2. Phagocytosis evasion
  3. Inhibiting neutrophil killing
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32
Q

What is an overview for how Staph A inhibits Neutrophil recruitment and chemotaxis

A

Staph A components bind to all of the Neutrophil receptors responding to Staph A, evolved through time

33
Q

What are 6 Neutrophil receptors involved in recruitment and chemotaxis that are inhibited by Staph A proteins, and which proteins do this inhibition for each receptor?

A
  1. TLR-2 recognises liproteins
    >Inhibited by SSL3
  2. PSGL1- migration of neutrophils
    >Inhibited by SSL5
  3. CD47- migration of neutrophils
    >Inhibited by SSL6
  4. C5aR- complement receptor for opsonisation
    >Inhibited by CHIPS
  5. FPR1- recognises formyl peptides
    >Inhibited by CHIPS
  6. CXCR1 binds chemokines (migration
    >Inhibited by Staphopain
34
Q

Describe how Staph A avoids phagocytosis?

A

By inhibiting complement activation and therefore preventing opsonisation due to the covalent binding of C3b to bacterial surfaces (also preventing C5a chemoattractant).

35
Q

What are the 3 methods Staph A inhibits opsonisation by complement?

A
  1. Inhibition of Complement Activation
  2. Degradation and Inactivation of Complement Components
  3. Binding and Sequestering of Complement Proteins
36
Q

Describe 3 ways Staph A inhibits the activation of complement? (Extra Reading)

A
  1. Sbi and fH: Sbi (Staphylococcal binder of immunoglobulin) binds to C3d and recruits factor H (fH), which helps in the inactivation of C3 convertase and reduces opsonization.
  2. Cna: This protein binds to C1q, inhibiting the classical pathway of complement activation.
  3. Efb and Ecb: These proteins bind to C3d and C3b, preventing the formation and function of the C3 convertase complex.
37
Q

Describe 3 ways Staph A degrades and inactivates complement components? (Extra Reading)

A
  1. Sak (Staphylokinase): Converts plasminogen (PLG) into plasmin, which can degrade C3b and C3 convertase, reducing opsonization.
  2. Aur (Aureolysin): Cleaves C3 and C3a, preventing the formation of active complement components.
  3. Zn2+: Acts as a cofactor for certain proteases involved in complement inhibition.
38
Q

Describe 2 ways Staph A binds to and sequesters complement proteins? (Extra Reading)

A
  1. Eap (Extracellular adherence protein): Binds to C4b and inhibits the formation of the C3 convertase.
  2. SSL7 (Staphylococcal superantigen-like protein 7): Binds to C5, preventing its cleavage and the formation of C5a, an anaphylatoxin and chemoattractant.
39
Q

Describe 4 ways Staph A inhibits killing by neutrophils? (Extra Reading)

A
  1. Inhibiting ROS species produced due to NADPH oxidase producing superoxide into cascade of ROS (against oxidative stress)
    >Produces SodM which converts superoxide radicals into hydrogen peroxide and molecular. Although hydrogen peroxide is still toxic, S. aureus further breaks it down using catalases. (Valderas and Hart, 2001).
  2. Inhibit Cathepsin (protease)
    >By inhibitors like Eap
  3. Inhibit lysozyme (peptidoglycan hydrolase)
    >Staph A co acetylates residues on peptidoglycan so lysozyme degradation this doesn’t work.
  4. Blocking Antimicrobial peptides
    >Many inhibitors such as BraRS
40
Q

What makes up the cell wall of Staphylococcus aureus and can interact with the human environment?

A

Peptidoglycan and cell wall proteins

41
Q

How are many proteins required for virulence bound to the peptidoglycan wall of Staphylococcus aureus?

A

They are covalently bound and anchored to peptidoglycan by sortase binding proteins to the outer surface of the cell.

42
Q

What is the role of the cell wall protein Isd in Staphylococcus aureus?

A

They are involved in iron acquisition and innate defense resistance, derived from haem (part of haemoglobin).

43
Q

How do Isd proteins help Staphylococcus aureus overcome host defenses related to iron uptake?

A

Despite the host producing high affinity binding proteins like transferrin and lactoferrin to inhibit iron uptake, Isd proteins facilitate iron acquisition for the bacteria.

44
Q

What is the function of Protein A (Spa) in Staphylococcus aureus?

A

It is a surface protein that binds to IgG, preventing opsonization.

45
Q

What are ClfA and FnBP in Staphylococcus aureus?

A

They are adhesins (surface proteins) that bind to host ligands, aiding in attachment and biofilm formation.

46
Q

Why is the extracellular matrix (ECM) significant for Staphylococcus aureus?

A

The ECM is full of things like collagen for Staphylococcus aureus to bind to and form a biofilm, enhancing its ability to colonize and cause infection.

47
Q

Why and when does Staphylococcus aureus produce toxins?

A

> When running out of nutrients, by eating us or moving to new sites.

> During stationary phase (when nutrients are low the growth phase stops and surface proteins are downregulated e.g. adhesions, and toxins are upregulated, to move to a new area and produce more toxins from degrading host cells- more on this in L4)

48
Q

What is one type of hemolysin produced by Staphylococcus aureus?

A

Alpha hemolysin.

49
Q

What is the structure and function of alpha hemolysin?

A

Heptameric pore forming lysin with more than one function in virulence.

50
Q

What are two functions of alpha hemolysin?

A
  1. Lysing red blood cells.
  2. Interacting with ADAM10 on epithelial cells, enhancing its activity, cleaving E-cadherin, and disrupting adherens junctions between epithelial cells to get to deeper tissue.
51
Q

How many types of enterotoxins does Staphylococcus aureus produce?

A

9 types.

52
Q

What type of toxin is associated with toxic shock syndrome?

A

Toxic shock syndrome toxin (TSST).

53
Q

What do enterotoxins and toxic shock syndrome toxin cause?

A

Food poisoning.

54
Q

How do enterotoxins and TSST act?

A

As superantigens.

55
Q

How do superantigens work?

A

They cause indiscriminate binding to antigen-presenting cells (APCs) and T cells.

56
Q

What happens when superantigens are taken up by APCs and presented to T cells?

A

They lead to indiscriminate binding and excessive production of cytokines like IL-2 or TNF-alpha, causing a cytokine storm and potentially leading to shock.

57
Q

What are the effects of IL-2 administration?

A

Causes nausea and vomiting, similar to the effects of enterotoxins.

58
Q

What are the four main effects of TSST?

A
  1. IL-2 production.
  2. Production of other proinflammatory cytokines.
  3. Fever.
  4. Shock (death).
59
Q

What historical factor provided a niche for TSST-related infections?

A

The Rely tampon provided a perfect anaerobic niche for Staphylococcus aureus to grow, causing deaths to women; now most deaths are in children who can get it more than once.

60
Q

What is notable about the crystal structure of TSST?

A

The MHC binding site and T cell binding site have a bridge formed.

61
Q

Can all strains of Staphylococcus aureus make these (TSST and enterotoxins) toxins?

A

No, only some strains can make these toxins.

62
Q

What is the role of Exfoliative Toxin A & B?

A

They are proteases that cause sloughing of skin (scalded skin syndrome).

63
Q

In which population is scalded skin syndrome most common?

A

Mostly in children

64
Q

Can all strains of Staphylococcus aureus produce Exfoliative Toxin A & B?

A

No, only some strains make these toxins.

65
Q

What are leukocidins and what do they do?

A

Leukocidins are toxins made to damage white blood cells.

66
Q

Name two types of leukocidins produced by Staphylococcus aureus.

A

Panton Valentine Leukocidin and LukeED.

67
Q

What are phenol soluble modulins (PSMs) and their significance?

A

PSMs are small peptides produced by community-acquired MRSA strains, which can kill neutrophils in 5 minutes.

68
Q

Why are PSMs concerning in communities treated with antibiotics?

A

If PSMs get out into the population, they can’t be treated effectively with antibiotics.

69
Q

What does coagulase do in Staphylococcus aureus?

A

Coagulase clots plasma, forming a fibrin clot that blocks wounds and protects bacteria in abscesses.

70
Q

What two factors are needed for coagulation by Staphylococcus aureus?

A

Coagulase (Coa) and von Willebrand factor-binding protein (vWbp).

71
Q

Describe the coagulation process involving coagulase.

A

Coagulase converts prothrombin to staphylothrombin, which then converts fibrinogen to fibrin, forming a protective clot.

72
Q

Why do Staphylococcus aureus virulence determinants change during infection?

A

Because the environment often changes due to the bacteria themselves, requiring different virulence determinants.

73
Q

How does Staphylococcus aureus regulate virulence determinant production?

A

In response to environmental stimuli, producing specific virulence determinants at different times as needed (more on L4)

74
Q

What allows Staphylococcus aureus to adapt to specific niches?

A

Coordinated regulation of virulence determinant production and growth phase-dependent virulence determinant production (more in L4)

75
Q

Why does Staphylococcus aureus not need to produce toxins when in the nose?

A

Because it does not face a hostile environment there and can thrive without the need for toxin production.

76
Q
A
77
Q

Why is it important for Staph A to have many different virulent factors?

A

As all the virulent factors have different functions, Staph A can respond to changes in the environment, these changes are usually caused by the bacteria itself (e.g. degrading epithelial cells).

78
Q

How do coagulases protect Staphylococcus aureus in abscesses?

A

By forming a fibrin clot that prevents access to the bacteria, thus protecting them from the host immune response.