Interaction of Pneumococcal Histidine Triad Proteins with Human Complement

Melin, Merit; Paolo, Emmanuel Di; Tikkanen, Leena; Jarva, Hanna; Neyt, Cécile; Käyhty, Helena; Meri, Seppo; Poolman, Jan; Väkeväinen, Merja

doi:10.1128/iai.00811-09

Cited by 48 publications

(46 citation statements)

References 57 publications

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“…This assumption is further sustained by the fact that the group B Streptococcus Pht homologue (named streptococcal histidine triad) seems also to bind factor H (Maruvada et al, 2009). However, other authors, through the use of Pht-deficient strains, concluded that these proteins do not bind factor H (Melin et al, 2010). In addition, a role in adherence is also suspected.…”

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confidence: 99%

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Transcriptional regulation, occurrence and putative role of the Pht family of Streptococcus pneumoniae

Rioux¹,

Neyt²,

Paolo³

et al. 2011

Microbiology

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Restricted to the genus Streptococcus, the Pht protein family comprises four members: PhtA, PhtB, PhtD and PhtE. This family has the potential to provide a protein candidate for incorporation in pneumococcal vaccines. Based on sequence analysis and on RT-PCR experiments, we show here that the pht genes are organized in tandem but that their expression, except that of phtD, is monocistronic. PhtD, PhtE, PhtB and PhtA are present in 100, 97, 81 and 62 % of the strains, respectively, and, by analysing its sequence conservation across 107 pneumococcal strains, we showed that PhtD displays very little variability. To analyse the physiological function of these proteins, several mutants were constructed. The quadruple Pht-deficient mutant was not able to grow in a poor culture medium, but the addition of Zn 2+ or Mn 2+ restored its growth capacity.Moreover, the phtD mRNA expression level increased when the culture medium was depleted in zinc. Therefore, we suggest that these proteins are zinc and manganese scavengers, and are able to store these metals and to release them when the bacterium faces an ion-restricted environment. The data also showed that this protein family, and more particularly PhtD, is a promising candidate to be incorporated into pneumococcal vaccines.

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confidence: 99%

“…Construction of the mutator vectors and the pneumococcal transformation protocol were carried out as fully described by Melin et al (2010). All deletions were realized from start to stop codon, leaving the promoters and pre-and post-gene sequences untouched.…”

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Transcriptional regulation, occurrence and putative role of the Pht family of Streptococcus pneumoniae

Rioux¹,

Neyt²,

Paolo³

et al. 2011

Microbiology

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“…Binding of complement inhibitor C4b-binding protein is restricted to certain serotypes, which possess a particular PspC allele (9). Pneumococcal histidine triad proteins may also play a role in complement evasion (35), but the impact they have on complement deposition seems to depend on the genetic background (29).…”

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The Capsular Serotype ofStreptococcus pneumoniaeIs More Important than the Genetic Background for Resistance to Complement

et al. 2010

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The polysaccharide capsule of Streptococcus pneumoniae inhibits phagocytic killing by innate immune mechanisms. Certain serotypes are associated with invasive disease while others with a nasopharyngeal carriage. The invasiveness of serotypes may partly be explained by ability to resist deposition of complement (C3) on the bacterial surface and consequent opsonophagocytic killing. In our previous studies, we observed that clinical isolates of serotypes 1 and 5, which are rarely detected in asymptomatic carriage, were resistant to complement deposition and opsonophagocytosis, whereas serotypes 6B and 23F, both common in carriage, were more sensitive to deposition of C3 and opsonophagocytic killing. However, presence of significant variation in C3 deposition between isolates of the same serotype indicated that factors other than the capsule also affect complement resistance. To distinguish the relative effect of the capsular serotype and other virulence factors on C3 deposition, we compared capsule-switched mutants prepared in genetic backgrounds of pneumococcal strains TIGR4, 603, and 618. Clinical isolates which had the same multilocus sequence type but expressed different serotypes were also compared. We found that the serotype had a significant impact on complement resistance and that the more resistant the strain was to complement, the higher was the concentration of polysaccharide-specific antibodies required for opsonophagocytic killing. Comparison of strains expressing the same capsular polysaccharides in the different genetic backgrounds and various capsular mutants of the same strain suggests that while the genotype affects complement resistance, the serotype is the most important determinant. Differences between serotypes were more significant than the differences between strains.

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“…The biological function of Pht proteins in pneumococcal viru-lence is still poorly understood, but roles in metal scavenging (9), complement inhibition (27,28), and in adherence to respiratory epithelium (29) have been suggested. Our aim in this study was to further assess the possible role of Pht proteins in pneumococcal colonization by comparing the ability of wild-type and mutant pneumococcal strains lacking one or more of the Pht proteins to bind to respiratory epithelial cell lines and also to assess the possible inhibitory function of Pht antibodies in the adherence.…”

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Role of Pht Proteins in Attachment of Streptococcus pneumoniae to Respiratory Epithelial Cells

et al. 2014

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Pneumococcal adherence to mucosal surfaces is a critical step in nasopharyngeal colonization, but so far few pneumococcal adhesins involved in the interaction with host cells have been identified. PhtA, PhtB, PhtD, and PhtE are conserved pneumococcal surface proteins that have proven promising as vaccine candidates. One suggested virulence function of Pht proteins is to mediate adherence at the respiratory mucosa. In this study, we assessed the role of Pht proteins in pneumococcal binding to respiratory epithelial cells. Pneumococci were incubated with human nasopharyngeal epithelial cells (Detroit-562) and lung epithelial cells (A549 and NCI-H292), and the proportion of bound bacteria was measured by plating viable counts. Strains R36A (unencapsulated), D39 (serotype 2), 43 (serotype 3), 4-CDC (serotype 4), and 2737 (serotype 19F) with one or more of the four homologous Pht proteins deleted were compared with their wild-type counterparts. Also, the effect of anti-PhtD antibodies on the adherence of strain 2737 to the respiratory epithelial cells was studied. Our results suggest that Pht proteins play a role in pneumococcal adhesion to the respiratory epithelium. We also found that antibody to PhtD is able to inhibit bacterial attachment to the cells, suggesting that antibodies against PhtD present at mucosal surfaces might protect from pneumococcal attachment and subsequent colonization. However, the relative significance of Pht proteins to the ability of pneumococci to bind in vitro to epithelial cells depends on the genetic background and the capsular serotype of the strain.

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Interaction of Pneumococcal Histidine Triad Proteins with Human Complement

Cited by 48 publications

References 57 publications

Transcriptional regulation, occurrence and putative role of the Pht family of Streptococcus pneumoniae

Transcriptional regulation, occurrence and putative role of the Pht family of Streptococcus pneumoniae

The Capsular Serotype ofStreptococcus pneumoniaeIs More Important than the Genetic Background for Resistance to Complement

Role of Pht Proteins in Attachment of Streptococcus pneumoniae to Respiratory Epithelial Cells

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