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

Mahdavi, Jafar; Royer, Pierre‐Joseph; Sjölinder, Hong; Azimi, Sheyda; Self, Tim; Stoof, Jeroen; Wheldon, Lee M.; Brännström, Kristoffer; Wilson, Reginald H.; Moreton, Joanna; Moir, James; Sihlbom, Carina; Borén, Thomas; Jonsson, Ann‐Beth; Soultanas, Panos; Ala’Aldeen, Dlawer A. A.

doi:10.1098/rsob.130048

Cited by 31 publications

(49 citation statements)

References 71 publications

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“…While the ability of A. actinomycetemcomitans to bind and take up cytokines has been known for some time, emHofQ is the first A. actinomycetemcomitans outer membrane protein for which it has been possible to determine the binding constant for a certain cytokine. In addition, although the HofQ homolog NmPilQ has been shown to play a role in IL-8 uptake in N. meningitides [19], no binding constants were determined in that study. A specific interaction between emHofQ and IL-8 was detected in both static (K d = 43 nM) and dynamic (K d = 2.4 μM) settings.…”

Section: Discussionmentioning

confidence: 99%

“…To survive in hostile environments, bacteria must have multiple ways to cope, and in host environments, bacteria could benefit by taking advantage of the host inflammatory mediators [19,37–40]. Moreover, by sequestering host cytokines, bacteria could manipulate the immune signaling pathways of the host, possibly establishing an imbalance that weakens the defense of the host against invaders.…”

Section: Discussionmentioning

confidence: 99%

“…Neisseria meningitidis has a pore-forming outer membrane secretin, PilQ (NmPilQ), which is involved in the production of type IV pili and binds IL-8 and TNF-α[19]. A. actinomycetemcomitans possesses a NmPilQ homolog, the secretin HofQ, which forms a channel through the outer membrane.…”

Section: Introductionmentioning

confidence: 99%

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Interactions between the Aggregatibacter actinomycetemcomitans secretin HofQ and host cytokines indicate a link between natural competence and interleukin-8 uptake

et al. 2018

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Naturally competent bacteria acquire DNA from their surroundings to survive in nutrient-poor environments and incorporate DNA into their genomes as new genes for improved survival. The secretin HofQ from the oral pathogen Aggregatibacter actinomycetemcomitans has been associated with DNA uptake. Cytokine sequestering is a potential virulence mechanism in various bacteria and may modulate both host defense and bacterial physiology. The objective of this study was to elucidate a possible connection between natural competence and cytokine uptake in A. actinomycetemcomitans. The extramembranous domain of HofQ (emHofQ) was shown to interact with various cytokines, of which IL-8 exhibited the strongest interaction. The dissociation constant between emHofQ and IL-8 was 43 nM in static settings and 2.4 μM in dynamic settings. The moderate binding affinity is consistent with the hypothesis that emHofQ recognizes cytokines before transporting them into the cells. The interaction site was identified via crosslinking and mutational analysis. By structural comparison, relateda type I KH domain with a similar interaction site was detected in the Neisseria meningitidis secretin PilQ, which has been shown to participate in IL-8 uptake. Deletion of hofQ from the A. actinomycetemcomitans genome decreased the overall biofilm formation of this organism, abolished the response to cytokines, i.e., decreased eDNA levels in the presence of cytokines, and increased the susceptibility of the biofilm to tested β-lactams. Moreover, we showed that recombinant IL-8 interacted with DNA. These results can be used in further studies on the specific role of cytokine uptake in bacterial virulence without interfering with natural-competence-related DNA uptake.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Interactions between the Aggregatibacter actinomycetemcomitans secretin HofQ and host cytokines indicate a link between natural competence and interleukin-8 uptake

et al. 2018

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“…In addition, type IV pili (T4P) have also been shown to be involved in virulence of pathogenic bacteria, including P. aeruginosa, Neisseria meningitidis, and Ralstonia solanacearum (51)(52)(53). In this study, the PilZ proteins were found to regulate sliding motility, among which PXO_00049 acts as a positive regulator, whereas both PXO_02374 and PXO_02715 function as the negative ones.…”

Section: Fig 6 Subcellular Localization Of Pilz Domain Proteins In Pxo99mentioning

confidence: 81%

The Xanthomonas oryzae pv. oryzae PilZ Domain Proteins Function Differentially in Cyclic di-GMP Binding and Regulation of Virulence and Motility

Yang

Tian

Chen

et al. 2015

Appl Environ Microbiol

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bThe PilZ domain proteins have been demonstrated to be one of the major types of receptors mediating cyclic di-GMP (c-di-GMP) signaling pathways in several pathogenic bacteria. However, little is known about the function of PilZ domain proteins in c-di-GMP regulation of virulence in the bacterial blight pathogen of rice Xanthomonas oryzae pv. oryzae. Here, the roles of PilZ domain proteins PXO_00049 and PXO_02374 in c-di-GMP binding, regulation of virulence and motility, and subcellular localization were characterized in comparison with PXO_02715, identified previously as an interactor with the c-di-GMP receptor Filp to regulate virulence. The c-di-GMP binding motifs in the PilZ domains were conserved in PXO_00049 and PXO_02374 but were less well conserved in PXO_02715. PXO_00049 and PXO_02374 but not PXO_02715 proteins bound to c-di-GMP with high affinity in vitro, and the R 141 and R 10 residues in the PilZ domains of PXO_00049 and PXO_02374, respectively, were crucial for c-di-GMP binding. Gene deletion of PXO_00049 and PXO_02374 resulted in significant increases in virulence and hrp gene transcription, indicating their negative regulation of virulence via type III secretion system expression. All mutants showed significant changes in sliding motility but not exopolysaccharide production and biofilm formation. In trans expression of the fulllength open reading frame (ORF) of each gene in the relevant mutants led to restoration of the phenotype to wild-type levels. Moreover, PXO_00049 and PXO_02374 displayed mainly multisite subcellular localizations, whereas PXO_02715 showed nonpolar distributions in the X. oryzae pv. oryzae cells. Therefore, this study demonstrated the different functions of the PilZ domain proteins in mediation of c-di-GMP regulation of virulence and motility in X. oryzae pv. oryzae. Cyclic dimeric GMP (c-di-GMP) was originally identified as a positive allosteric regulator of cellulose synthase in Gluconacetobacter xylinus (1). Now, it has been recognized as an important intracellular signaling molecule implicated in the control of various bacterial properties, including motility, biofilm formation, adherence, and production of virulence factors (2, 3). The intracellular level of c-di-GMP is controlled by diguanylate cyclases (DGCs), which contain the GGDEF domain, and phosphodiesterases (PDEs), which harbor EAL or HD-GYP domains (4). Also, the downstream cellular functions regulated by c-di-GMP often depend on signal transduction by its receptors or effectors. A wide variety of c-di-GMP receptors have been discovered, such as PilZ domains (5), the transcription factors (6-8), proteins containing degenerate GGDEF or EAL domains (9-11), and the RNA processing polynucleotide phosphorylase (PNPase) and riboswitches (12-14). Therefore, c-di-GMP can exert a regulatory function at various levels of gene transcription, translation, and posttranslation.The PilZ domain is the first c-di-GMP binding module identified in G. xylinus and is named PilZ domain after being identified from Pseudomonas aerug...

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“…A recent study suggests that the host-inflammatory responses affect the physiol ogy of bacteria, for example, by utilizing inflammatory mediators as transcription factors [37]. It thus seems quite reasonable that bacteria have evolved mechanisms to sense their environ ment and to respond to their surrounding by using inflammatory mediators as regulators to be able to adjust and adapt to a changing environment.…”

Section: Mechanisms Of P Gingivalis Interaction With Host Cellsmentioning

confidence: 99%

Cellular Response Mechanisms in Porphyromonas gingivalis Infection

Khalaf¹,

Palm²,

Bengtsson³

2017

Periodontitis - A Useful Reference

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The pathogenicity of the periodontal biofilm is highly dependent on a few key species, of which Porphyromonas gingivalis is considered to be one of the most important pathogens.P. gingivalis expresses a broad range of virulence factors, of these cysteine proteases (gin gipains) are of special importance both for the bacterial survival/proliferation and for the pathological outcome. Several cell types, for example, epithelial cells, endothelial cells, dendritic cells, osteoblasts, and fibroblasts, reside in the periodontium and are part of the innate host response, as well as platelets, neutrophils, lymphocytes, and monocytes/mac rophages. These cells recognize and respond to P. gingivalis and its components through pattern recognition receptors (PRRs), for example, Toll-like receptors and protease-acti vated receptors. Ligation of PRRs induces downstream-signaling pathways modifying the activity of transcription factors that regulates the expression of genes linked to inflamma tion. This is followed by the release of inflammatory mediators, for example, cytokines and reactive oxygen species. Periodontal disease is today considered to play a significant role in various systemic conditions such as cardiovascular disease (CVD). The mechanisms by which P. gingivalis and its virulence factors interact with host immune cells and contribute to the pathogenesis of periodontitis and CVD are far from completely understood.

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

Cited by 31 publications

References 71 publications

Interactions between the Aggregatibacter actinomycetemcomitans secretin HofQ and host cytokines indicate a link between natural competence and interleukin-8 uptake

Interactions between the Aggregatibacter actinomycetemcomitans secretin HofQ and host cytokines indicate a link between natural competence and interleukin-8 uptake

The Xanthomonas oryzae pv. oryzae PilZ Domain Proteins Function Differentially in Cyclic di-GMP Binding and Regulation of Virulence and Motility

Cellular Response Mechanisms in Porphyromonas gingivalis Infection

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