Gene regulation in Streptococcus pneumoniae - RePub - Erasmus ...

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Introduction Figure 1. Infections caused by S. pneumoniae. Black arrows indicate the progression of infection. All pneumococcal diseases are preceded by nasopharyngeal carriage, after which the bacterium can spread to the middle ear causing otitis media or disseminate to the lungs causing pneumonia. During infection of the lungs, bacteria may penetrate into the blood circulation, from which they can spread through the whole body. Otitis media might also cause infection of the meninges. Some well-known examples of proteins, which have contributions to virulence at that particular site in the human or murine body, are indicated in dotted boxes. Ami- AliA/B, oligopeptide ABC transporter; CbpA, choline binding protein A; CiaRH, the Cia two-component system; ComDE, two-component system specific for sensing of competence stimulating peptide; Cps, polysaccharide capsule; Eno, α-enolase; GAPDH, glycerol-3-phophate dehydrogenase; HtrA, serine protease; Hyl, hyaluronate lyase; Iga, immunoglobulin A1 protease; LytA, autolysin A; LytB, autolysin B; NanA, neuraminidase A; NanB, neuraminidase B; PavA, pneumococcal adherence and virulence factor A; PCho, phosphocholine; PcpA, choline binding protein PcpA; Ply, pneumolysin; PsaA, pneumococcal surface adhesin A [Mn 2+ uptake ABC transporter]; PspA, pneumococcal surface protein A; ZmpC, metalloprotease. Virulence factors The most important virulence factor of pneumococcus is its capsule. This capsule is a shell of oligosaccharide molecules that forms a protective layer around the bacterium. The currently available pneumococcal vaccine is targeted at this sugar capsule. The proteins 9 9
Chapter 1 responsible for the production and the structure of the capsule are encoded by the capsular polysaccharide synthesis (cps) locus. Up to now, over 93 different capsular types (serotypes) have been identified, which are distinct in biochemical structure. Recent research has shown that bacteria with distinct capsular structures also have large genetic differences in their cps locus (8). The role of the capsule is mainly a protective one, as it allows pneumococci to evade phagocytosis by immune cells. However, during colonization, the capsule might mask colonization factors, and regulation of the thickness of the capsule has been shown to occur during colonization (19). Along with the oligosaccharide capsule, a cholesterol-dependent cytolysin called pneumolysin is regarded as the most prominent virulence factor (48). This protein has two important features; it can create pores in host cells and it can trigger the immune system (i.e., complement activation and pro-inflammatory responses) (11, 48). The layer below the sugar capsule is the cell wall, consisting of peptidoglycan, teichoic and lipoteichoic acids, and phosphorylcholine. To this layer a variety of proteins with different functions are attached. Given that the outside of the cell wall, with all proteins attached, comes in close proximity with host cells during infection, many pneumococcal factors important for pathogenicity are found here. In pneumococcus, outer membrane proteins can be classified into four groups on the basis of their attachment to the cell: proteins with an LPxTG motif, lipoproteins, choline binding proteins, and non-classical surface proteins (proteins lacking a classical leader sequence and membrane-anchoring motifs). Of these, a few examples with major roles in colonization or virulence are discussed below: LPxTG proteins are covalently linked to the peptidoglycan after cleavage of their LPxTG motif by a sortase (47). Examples of LPxTG proteins are the neuraminidases NanA and NanB, which have an important role in cleaving sialic acid from host molecules such as mucin and glycoproteins (5, 23, 55). Hyaluronate lyase, which damages the extracellular matrix of human epithelial cells, also belongs to this class (33). Two other cell-sorted virulence factors containing the LPxTG motif, the metalloproteinases ZmpC and Iga1 protease cleave the extracellular matrix (10, 44) and the mucosal IgA1 antibody (50), respectively. Phosphorylcholine, which is the anchor moiety for the group of choline binding proteins (CBPs), is anchored to the peptidoglycan and is also present in the plasma membrane (38). Major virulence factors belonging to the CBPs are the autolysins LytA, LytB, and LytC. These autolysins hydrolyze murein of the cell wall and are required for virulence (53). 10 10
Page 1 and 2: Gene regulation in Streptococcus pn
Page 3 and 4: Cover image by Duve van Boggelen (w
Page 5 and 6: Promotiecommissie Promotoren: Prof.
Page 8 and 9: CHAPTER 1 Introduction 7
Page 12 and 13: Interestingly, autolysis induced by
Page 14 and 15: histidine kinase is the sensor prot
Page 16 and 17: metabolism are often required for v
Page 18 and 19: egulatory systems, aiming to elucid
Page 20 and 21: 11. Cockeran, R., A. J. Theron, H.
Page 22 and 23: 33. Li, S., S. J. Kelly, E. Lamani,
Page 24 and 25: 53. Romero, P., R. Lopez, and E. Ga
Page 26 and 27: CHAPTER 2 Regulation of gene expres
Page 28 and 29: Introduction Streptococcus pneumoni
Page 30 and 31: Materiaals and Meethods Gene regula
Page 32 and 33: (Invitrogen), 0.2 mM aminoallyl dUT
Page 34 and 35: Isolation of pneumococcal RNA durin
Page 36 and 37: Resultss and Discuussion Gene regul
Page 38 and 39: Table 1. Genes regulated by RR09 in
Page 40 and 41: phosphofructokinase, and a fructose
Page 42 and 43: Figure 4. Expression of rlrA and rr
Page 44 and 45: correlated well with our in vitro m
Page 46 and 47: Figure 7. Bacterial loads in blood
Page 48 and 49: Acknowledgments This work was suppo
Page 50 and 51: 10. Ibrahim, Y. M., A. R. Kerr, J.
Page 52 and 53: genome sequence of a virulent isola
Page 54 and 55: Gene regulation by RR09 in S. pneum
Page 56 and 57: Gene regulation by RR09 in S. pneum
Page 58 and 59: Table S4. Genes up- and downregulat
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Table S6. Genes up- and downregulat
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Chapter 3 Abstract 62 62 Previous s
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Chapter 3 between the wild-type and
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Chapter 3 S. pneumoniae TIGR4 by CS
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Chapter 3 performance liquid chroma
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Chapter 3 Results Transcriptional a
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Chapter 3 Table 3. Differentially e
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Chapter 3 Figure 2. Colonization mo
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Chapter 3 than the D39ΔpsaR-infect
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Chapter 3 effect was more severe fo
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Chapter 3 in TIGR4ΔpsaR. However,
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Chapter 3 References 1. Adrian, P.
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Chapter 3 21. Hemsley, C., E. Joyce
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Chapter 3 40. McCluskey, J., J. Hin
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CHAPTER 4 CodY of Streptococcus pne
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Introduction Bacteria encounter var
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Materials and Methods Bacterial str
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Table 2. Oligonucleotide primers us
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The CodY regulon of S. pneumoniae I
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The CodY regulon of S. pneumoniae w
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Accession numbers The microarray da
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Table 3. Differentially expressed g
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Binding of CodY to target promoters
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The CodY regulon of S. pneumoniae E
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The CodY regulon of S. pneumoniae F
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Discussion CodY has been described
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levels of adherence in D39. Using a
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References The CodY regulon of S. p
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Glass. 2001. Genome of the bacteriu
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40. Shivers, R. P., S. S. Dineen, a
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CHAPTER 5 Regulation of glutamine a
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Introduction Regulation of nitrogen
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Materials and Methods Nitrogen Meta
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TK136 D39 Δcps; Km R capsule-less
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gene from pORI28, was fused to the
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Construction of lacZ fusions Chromo
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Enzyme assays Cell-free extracts, u
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Reverse-transcriptase PCR RNA isola
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Table 3. Summary of transcriptome c
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effect caused by altered intracellu
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examine whether zwf is only transcr
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(http://www.bd.com/ds/technicalCent
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H6-GlnR alone at the concentration
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Discussion In this study, we charac
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Acknowledgements TK, JB and HB are
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11. den Hengst, C. D., S. A. van Hi
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Nitrogen Metabolism in S. pneumonia
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52. Wray, L. V., Jr., J. M. Zalieck
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CHAPTER 6 Site-specific contributio
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Introduction GlnR-regulon and pneum
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Materials and Methods Bacterial str
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eferred to as t=0. Bacteriology res
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Results GlnR-regulon and pneumococc
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Figure 3. Colonization model. Bacte
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GlnR-regulon and pneumococcal virul
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Table 2. Differentially expressed g
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Discussion The ability to adequatel
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The microarray data showed that pre
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Acknowledgments WTH is supported by
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12. Ibrahim, Y. M., A. R. Kerr, J.
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33. Zalieckas, J. M., L. V. Wray, J
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CHAPTER 7 Pneumococcal gene regulat
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Introduction Regulation of gene exp
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Gene regulation and metabolism in S
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makes it possible for the pneumococ
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A CcpA homologue exists in the pneu
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double mutant, suggesting direct re
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References Gene regulation and meta
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23. Kerr, A. R., P. V. Adrian, S. E
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45. Sonenshein, A. L. 2005. CodY, a
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CHAPTER 8 Summarizing discussion 20
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that the observed virulence phenoty
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CodY was found to be required for a
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References Summarizing discussion 1
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Summarizing discussion 21. Orihuela
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Samenvatting en discussie Curriculu
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Samenvatting en discussie kunnen ge
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Bevindingen die dit onderbouwen, we
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Curriculum Vitae Curriculum Vitae W
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Dankwoord Jeetje, dat het dan toch
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oekje en ik kijk uit naar de bijbeh
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