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Pro-inflammatory cytokines can act as intracellular modulators of commensal bacterial virulence.

Mahdavi J, Royer PJ, Sjölinder HS, Azimi S, Self T, Stoof J, Wheldon LM, Brännström K, Wilson R, Moreton J, Moir JW, Sihlbom C, Borén T, Jonsson AB, Soultanas P, Ala'Aldeen DA - Open Biol (2013)

Bottom Line: Interactions between commensal pathogens and hosts are critical for disease development but the underlying mechanisms for switching between the commensal and virulent states are unknown.This uptake is mediated by type IV pili (Tfp) and reliant on the PilT ATPase activity.We propose a novel mechanism by which pathogens use the twitching motility mode of the Tfp machinery for sensing and importing host elicitors, aligning with the inflamed environment and switching to the virulent state.

View Article: PubMed Central - PubMed

Affiliation: School of Life Sciences, Molecular Bacteriology and Immunology Group, University of Nottingham, Nottingham NG7 2RD, UK.

ABSTRACT
Interactions between commensal pathogens and hosts are critical for disease development but the underlying mechanisms for switching between the commensal and virulent states are unknown. We show that the human pathogen Neisseria meningitidis, the leading cause of pyogenic meningitis, can modulate gene expression via uptake of host pro-inflammatory cytokines leading to increased virulence. This uptake is mediated by type IV pili (Tfp) and reliant on the PilT ATPase activity. Two Tfp subunits, PilE and PilQ, are identified as the ligands for TNF-α and IL-8 in a glycan-dependent manner, and their deletion results in decreased virulence and increased survival in a mouse model. We propose a novel mechanism by which pathogens use the twitching motility mode of the Tfp machinery for sensing and importing host elicitors, aligning with the inflamed environment and switching to the virulent state.

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CD46 transgenic mouse model challenged with MC58, ΔpilQ, ΔpilE and ΔpglC/L mutants. (a) CD46 transgenic mice were intraperitoneally challenged (eight mice for each bacterial strain) with piliated Nm strain MC58 and isogenic mutant strains, and survival rates were assessed. The mortality rates were strain dependent. More apparent lethal disease occurred in mice that were challenged with MC58 and ΔpilE, whereas transgenic mice challenged with isogenic mutants (i.e. ΔpglC/L or ΔpilQ) survived significantly longer upon bacterial injection. (b) Relative quantification of app, mspA and pptB virulence genes. Blood samples were collected from mice infected with wt MC58 or the isogenic mutants at 6 h. The expression of examined genes in these samples was significantly higher in mice infected with the Nm MC58 strain than in mice infected with the isogenic mutant strains (lower panel). Non-infected (NI) mice were considered as negative control.
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RSOB130048F6: CD46 transgenic mouse model challenged with MC58, ΔpilQ, ΔpilE and ΔpglC/L mutants. (a) CD46 transgenic mice were intraperitoneally challenged (eight mice for each bacterial strain) with piliated Nm strain MC58 and isogenic mutant strains, and survival rates were assessed. The mortality rates were strain dependent. More apparent lethal disease occurred in mice that were challenged with MC58 and ΔpilE, whereas transgenic mice challenged with isogenic mutants (i.e. ΔpglC/L or ΔpilQ) survived significantly longer upon bacterial injection. (b) Relative quantification of app, mspA and pptB virulence genes. Blood samples were collected from mice infected with wt MC58 or the isogenic mutants at 6 h. The expression of examined genes in these samples was significantly higher in mice infected with the Nm MC58 strain than in mice infected with the isogenic mutant strains (lower panel). Non-infected (NI) mice were considered as negative control.

Mentions: The impact of the Nm surface structures required for binding to human cytokines on bacteraemia and meningitis progression was investigated in CD46 transgenic mice. Eight mice in each group were intraperitoneally infected with wt or one of the isogenic mutants (ΔpilQ, ΔpilE and ΔpglC/L) and examined for 72 h. All of the mice developed bacteraemia (see electronic supplementary material, figure S9 and table S9), but lethal instances of disease occurred only in mice that were infected with MC58 or the ΔpilE mutant. Mice that were infected with ΔpilQ and ΔpglC/L mutants exhibited significantly less mortality and enhanced survival rates (figure 6a). These results further confirmed the importance of PilQ and surface glycans for Nm virulence.Figure 6.


Pro-inflammatory cytokines can act as intracellular modulators of commensal bacterial virulence.

Mahdavi J, Royer PJ, Sjölinder HS, Azimi S, Self T, Stoof J, Wheldon LM, Brännström K, Wilson R, Moreton J, Moir JW, Sihlbom C, Borén T, Jonsson AB, Soultanas P, Ala'Aldeen DA - Open Biol (2013)

CD46 transgenic mouse model challenged with MC58, ΔpilQ, ΔpilE and ΔpglC/L mutants. (a) CD46 transgenic mice were intraperitoneally challenged (eight mice for each bacterial strain) with piliated Nm strain MC58 and isogenic mutant strains, and survival rates were assessed. The mortality rates were strain dependent. More apparent lethal disease occurred in mice that were challenged with MC58 and ΔpilE, whereas transgenic mice challenged with isogenic mutants (i.e. ΔpglC/L or ΔpilQ) survived significantly longer upon bacterial injection. (b) Relative quantification of app, mspA and pptB virulence genes. Blood samples were collected from mice infected with wt MC58 or the isogenic mutants at 6 h. The expression of examined genes in these samples was significantly higher in mice infected with the Nm MC58 strain than in mice infected with the isogenic mutant strains (lower panel). Non-infected (NI) mice were considered as negative control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3814720&req=5

RSOB130048F6: CD46 transgenic mouse model challenged with MC58, ΔpilQ, ΔpilE and ΔpglC/L mutants. (a) CD46 transgenic mice were intraperitoneally challenged (eight mice for each bacterial strain) with piliated Nm strain MC58 and isogenic mutant strains, and survival rates were assessed. The mortality rates were strain dependent. More apparent lethal disease occurred in mice that were challenged with MC58 and ΔpilE, whereas transgenic mice challenged with isogenic mutants (i.e. ΔpglC/L or ΔpilQ) survived significantly longer upon bacterial injection. (b) Relative quantification of app, mspA and pptB virulence genes. Blood samples were collected from mice infected with wt MC58 or the isogenic mutants at 6 h. The expression of examined genes in these samples was significantly higher in mice infected with the Nm MC58 strain than in mice infected with the isogenic mutant strains (lower panel). Non-infected (NI) mice were considered as negative control.
Mentions: The impact of the Nm surface structures required for binding to human cytokines on bacteraemia and meningitis progression was investigated in CD46 transgenic mice. Eight mice in each group were intraperitoneally infected with wt or one of the isogenic mutants (ΔpilQ, ΔpilE and ΔpglC/L) and examined for 72 h. All of the mice developed bacteraemia (see electronic supplementary material, figure S9 and table S9), but lethal instances of disease occurred only in mice that were infected with MC58 or the ΔpilE mutant. Mice that were infected with ΔpilQ and ΔpglC/L mutants exhibited significantly less mortality and enhanced survival rates (figure 6a). These results further confirmed the importance of PilQ and surface glycans for Nm virulence.Figure 6.

Bottom Line: Interactions between commensal pathogens and hosts are critical for disease development but the underlying mechanisms for switching between the commensal and virulent states are unknown.This uptake is mediated by type IV pili (Tfp) and reliant on the PilT ATPase activity.We propose a novel mechanism by which pathogens use the twitching motility mode of the Tfp machinery for sensing and importing host elicitors, aligning with the inflamed environment and switching to the virulent state.

View Article: PubMed Central - PubMed

Affiliation: School of Life Sciences, Molecular Bacteriology and Immunology Group, University of Nottingham, Nottingham NG7 2RD, UK.

ABSTRACT
Interactions between commensal pathogens and hosts are critical for disease development but the underlying mechanisms for switching between the commensal and virulent states are unknown. We show that the human pathogen Neisseria meningitidis, the leading cause of pyogenic meningitis, can modulate gene expression via uptake of host pro-inflammatory cytokines leading to increased virulence. This uptake is mediated by type IV pili (Tfp) and reliant on the PilT ATPase activity. Two Tfp subunits, PilE and PilQ, are identified as the ligands for TNF-α and IL-8 in a glycan-dependent manner, and their deletion results in decreased virulence and increased survival in a mouse model. We propose a novel mechanism by which pathogens use the twitching motility mode of the Tfp machinery for sensing and importing host elicitors, aligning with the inflamed environment and switching to the virulent state.

Show MeSH
Related in: MedlinePlus