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Bacterial Pathogenicity > L4. Staph A Regulation > Flashcards

L4. Staph A Regulation Flashcards

1
Q

What are the characteristics of the growth phases in Staphylococcus aureus regulation?

A
  1. Exponential Phase: Surface Proteins (+++), Exoproteins (-)
    >Surface proteins: Spa, Fnbp, etc.
  2. Stationary Phase: Surface Proteins (-), Exoproteins (+++)
    >Switch to make fewer surface proteins but more exoproteins (toxins e.g., alpha haemolysin).
    >Exoproteins: Hla, TSST, etc.
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2
Q

What is the function of surface proteins on Staph A?

A

Surface proteins are adhesins.

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3
Q

Why does Staphylococcus aureus switch from producing surface proteins to exoproteins and what does this mean for expressions of genes in Staph A?

A

> Once nutrients become limiting, toxins allow dispersal (tissue damage) leading to metastatic infections.

> The organism needs to coordinate the regulation of virulence determinants accordingly.

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4
Q

What is the role of 194 specific genes in Staphylococcus aureus?

A

They coordinate virulence determinants, linking them and positively regulating each other. The organism can respond to the environment with a coordinated signal.

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5
Q

What do the abbreviations A, T, and E stand for in the context of virulence determinants?

A

A = Adhesiveness
T = Toxins
E = Evasion

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6
Q

What is the function of the accessory gene regulator (agr) in Staphylococcus aureus?

A

> Agr is a pivotal regulator that switches from making immunovasion and adhesions in the exponential phase to exotoxins in the post-exponential phase.

> It positively regulates toxins and negatively regulates surface proteins.

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7
Q

What is the role of the staphylococcal accessory regulator (sar)?

A

Sar upregulates agr expression, acting as a regulatory gene.

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8
Q

What is SarA and what does it do?

A

SarA is a DNA-binding protein that binds to the agr promoter region and is a positive regulator of agr.

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9
Q

What is meant by agr being a complex divergon?

A

Agr turns on toxins while turning off surface proteins. A divergon is composed of two divergently transcribed operons with linked functions.

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10
Q

What is the agr locus in Staphylococcus aureus?

A

The agr locus is a divergon consisting of two operons transcribed from P2 and P3 promoters. The output is an increase in secretory toxins and a decrease in surface proteins.

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11
Q

How many genes are transcribed from the P2 and P3 promoters in the agr locus?

A

Four genes are transcribed from the P2 (AgrB, D, C, A) promoter and one gene from the P3 promoter (hld)

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12
Q

What does the gene AgrD encode?

A

AgrD encodes a prepeptide of an extracellular density-dependent signaling molecule (45 amino acid peptide), from which an 8 amino acid peptide is clipped and modified to form the autoinducing peptide (AIP).

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13
Q

What is the function of the AgrB enzyme?

A

AgrB is the enzyme that processes AgrD by cleaving the 8 amino acid peptide from the 45 amino acid sequence.

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14
Q

Describe the role of the P2 promoter in the agr locus.

A

The operon from the P2 promoter has a low level of expression during the exponential phase, leading to a slow build-up of AIP in the medium until it reaches a threshold level, initiating density-dependent signaling.

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15
Q

What happens during density-dependent signaling in the agr system?

A
  1. As bacterial density increases, more AIP is produced,
  2. When the threshold concentration of AIP is reached, it binds to AgrC.
  3. AgrC which is a histidine kinase which autophosphryolates its cytoplasmic domain which interacts with AgrA by transferring phosphate to an aspartate residue on AgrA activating it.
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16
Q

What is AgrC and what is its role?

A

AgrC is a “sensor” protein (transmembrane, membrane-associated) from the third gene of the P2 operon. It is part of a two-component “sensor regulator” system that senses AIP and autophosphorylates to initiate a regulatory cascade.

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17
Q

What is the role of AgrA in the agr system?

A

AgrA is a “regulator” protein (transcriptional activator) from the fourth gene of the P2 operon. It causes changes in gene expression when activated by AgrC.

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18
Q

How does the activation of AgrC and AgrA work?

A

When enough AIP is present, it binds to AgrC, a histidine kinase that autophosphorylates and transfers phosphate to an aspartate residue on AgrA, activating it as a transcriptional activator.

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19
Q

Summarize the agr locus process for autoinducing peptide (AIP) in 4 steps.

A
  1. AgrD produces the pre-peptide of AIP.
  2. AgrB cleaves and modifies the pre-peptide to produce AIP, which is secreted into the environment.
  3. Over time, AIP builds up in the environment.
  4. AgrC senses the AIP buildup, autophosphorylates, and transfers a phosphate to AgrA, activating it.
20
Q

How does activated AgrA upregulate expression from P2 and P3 promoters in the agr locus?

A

Activated AgrA forms an autoregulatory circuit through density-dependent signaling. AIP in the environment activates AgrC, which activates AgrA, increasing P2 transcription and making more AIP, AgrC, and activated AgrA, forming a loop. Once the threshold is reached, the circuit is triggered, turning on P3 promoters and increasing RNAIII expression.

21
Q

What role does RNAIII play in the agr regulatory system?

A

RNAIII encodes delta-hemolysin (a small peptide that lyses red blood cells) and acts as a regulatory RNA molecule controlling the production of virulent determinants, turning on toxins and turning off surface proteins.

22
Q

Describe the expression dynamics of RNAII and RNAIII in the agr regulatory system.

A

During early exponential growth, RNAII is produced at low levels. Once the AIP threshold is reached, the autoregulatory circuit increases RNAII expression, leading to the activation of P3 and a rapid increase in RNAIII expression.

23
Q

What is the P3 promoter’s role in the agr regulatory system?

A

he P3 promoter controls the expression of RNAIII. RNAIII encodes delta-hemolysin, a phenol-soluble modulin that lyses red blood cells. However, the regulatory function of RNAIII itself, not delta-hemolysin, is crucial for controlling the production of virulence determinants.

24
Q

What does RNA III encode for

A

RNAIII encodes delta-hemolysin, which is a phenol soluble modulins a small peptide that lysis red blood cells, this is the only translated product from RNAIII.

25
Q

How does RNAIII act at the level of transcription and translation?

A
  1. Transcription: The mechanism is unknown, but RNAIII may bind to transcriptional regulators.
  2. Translation: RNAIII acts as antisense RNA, interacting with transcripts to control virulence determinants. It turns off spa and turns on hla by binding complementary sequences to block or upregulate translation.
26
Q

How does RNAIII negatively regulate spa translation and other surface proteins?

A

RNAIII binds to the Spa transcript to block ribosome binding. Downstream bases form a stem loop structure, making the transcript a substrate for RNAase, leading to its degradation of surface proteins like Protein A (an adhesion)

27
Q

Describe how alpha-hemolysin (hla) isn’t produced during early growth, and how RNAIII positively regulate hla translation?

A
  1. In early growth, the 5’ region of the hla transcript forms a stem loop covering the ribosome binding site, preventing translation.
  2. In dense environments, RNAIII binds antisense to the 5’ end of the hla transcript, preventing stem loop formation, making the ribosome binding site free for translation promoting translation of toxins
28
Q

What is the function of delta-hemolysin in the agr regulatory system?

A

Delta-hemolysin is a small peptide encoded by RNAIII that lyses red blood cells. However, its primary role is as an indicator of RNAIII transcription rather than being directly involved in the regulation of other virulence factors.

29
Q

What is the role of the stem loop structure in the regulation of hla and spa transcripts?

A
  1. hla Transcript: In early growth, the stem loop structure at the 5’ region of the hla transcript covers the ribosome binding site, preventing translation. RNAIII binding in dense environments prevents the stem loop from forming, allowing translation.
  2. spa Trasncript: RNAIII binding forms a structure that blocks the ribosome binding site, leading to transcript degradation and preventing translation.
30
Q

What is the role of SarA in the agr regulatory system?

A

SarA acts as a repressor of proteases, controlling virulence determinant stability by hydrolyzing unwanted proteins. This allows swift adaptation by turnover of adhesins and other proteins. SarA acts both via and independently of Agr.

31
Q

At what levels does the control of virulence determinants occur in response to the environment?

A

Control occurs at the levels of transcription, translation, and stability, allowing adaptation to a wide range of niches, making Staphylococcus aureus a versatile pathogen.

32
Q

What is the role of SarA in the regulation of virulence determinants in Staphylococcus aureus?

A

SarA acts as a repressor of proteases and controls the stability of virulence determinants. It also enhances the expression of the agr locus, thereby indirectly influencing RNAIII levels and the production of toxins and surface proteins.

33
Q

How does SarA interact with the agr regulatory system?

A

SarA positively regulates the expression of the agr locus by binding to its promoter region, enhancing the production of RNAIII. This leads to increased production of toxins and decreased expression of surface proteins.

34
Q

How does RNAIII regulate surface proteins and toxins in Staphylococcus aureus?

A
  1. RNAIII negatively regulates surface proteins such as Spa by binding to their transcripts and blocking ribosome binding, leading to transcript degradation.
  2. RNAIII positively regulates toxins such as alpha-hemolysin by binding to the 5’ end of their transcripts and preventing inhibitory stem loop formation, allowing translation.
35
Q

What are the key factors involved in causing disease at the bacterial interface?

A

Causing disease involves a struggle between the immune system and the pathogen, as well as competition with other bacteria living in the same niche. This competition can be between different bacteria or different strains of the same bacteria and is mediated by AgrD autoinducing peptide (AID) made by different Staph A strains.

36
Q

What is the role of AgrD autoinducing peptide (AID) in the bacterial interface of Staph A?

A

AgrD autoinducing peptide (AID) mediates a novel mode of competition between related strains of bacteria, including different strains of the same species. This competition is facilitated by the AgrD peptide (AIP).

37
Q

How do different strains of Staphylococcus aureus compete with each other?

A

Different strains of Staphylococcus aureus compete with each other through interactions mediated by AgrD autoinducing peptide (AID). This involves a novel mode of competition facilitated by the AgrD peptide (AIP).

38
Q

Are the agr gene sequences similar or different between the pathogenic strains of Staph A? (extra reading)

A

The three main groups of pathogenic Staphylococcus aureus differ in their AgrD peptides. The only conserved part is the cysteine residue, which is crucial for forming a thiolactone ring, while the rest of the AIP sequence varies significantly.

39
Q

What is the common feature among the AIPs of different Staphylococcus aureus strains? (extra reading, Malone et al (2007)

A

The common feature among the AIPs of different Staphylococcus aureus strains is the presence of a thiolactone ring, which is formed through a cysteine residue.

40
Q

How is the thiolactone ring in AIPs formed? (extra reading, Malone et al (2007)

A

The thiolactone ring is formed when AgrD is processed by AgrB, which clips out an 8 amino acid peptide. The cysteine side chain attacks the peptide bond, creating a covalent bond that results in the ring structure.

41
Q

Why is the thiolactone ring important for AIPs? (extra reading, Malone et al (2007)

A

The thiolactone ring is crucial for the biological activity of AIPs, as it is required for binding to the AgrC receptor and initiating the quorum-sensing response.

42
Q

What happens when AIPs from different Staphylococcus aureus groups are mixed together?

A

The AIPs will compete, and one will inhibit the toxin production of the other groups. For example, AIP from group II will turn on group II but turn off groups I and III. This allows each group to turn on its own toxin production but inhibit others.

43
Q

What advantages do differing AIPs provide in Staphylococcus aureus?

A
  1. Inhibits toxin production in other groups.
  2. Gives competitive advantage in mixed infections.
44
Q

How can the competition between different strains of Staphylococcus aureus be tested?

A

By taking the supernatant from the culture of one group with lots of AIP and adding this AIP to the culture of another Staph A strain. This will inhibit the toxin production of the other group, demonstrating the competitive interaction.

45
Q

What is the role of the conserved cysteine residue in the AgrD peptide of Staphylococcus aureus?

A

The conserved cysteine residue is essential for forming the thiolactone ring in the AgrD peptide. This ring is crucial for the biological activity of autoinducing peptides (AIPs), enabling them to bind to the AgrC receptor and initiate the quorum-sensing response resulting in increased toxin production and decreased surface protein expression. The thiolactone ring also allows for specific activation or inhibition of Agr systems in different strains, providing a competitive advantage in mixed infections.

Bacterial Pathogenicity (11 decks)

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