Pseudomonas aeruginosa Activates PKC-Alpha to Invade Middle Ear Epithelial Cells

Mittal, Rahul; Grati, M’hamed; Yan, Denise; Liu, Xue Z.

doi:10.3389/fmicb.2016.00255

Cited by 11 publications

(9 citation statements)

References 70 publications

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“…The ability of otopathogenic P. aeruginosa to activate PKC pathway is dependent on OprF expression. The results of this study demonstrate the crucial role that the PKC pathway and OprF expression plays in the pathogenesis of COM/CSOM . The PKC pathway is responsible for the activation of many subsequent signaling cascades that can further activate the expression of proinflammatory cytokines.…”

Section: Immune Evasion By Com Pathogens Specifically Otopathogenic Pmentioning

confidence: 60%

Subversion of host immune responses by otopathogens during otitis media

Parrish

Soni

Mittal

2019

Journal of Leukocyte Biology

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Otitis media (OM) is one of the most common ear diseases affecting humans. Children are at greater risk and suffer most frequently from OM, which can cause serious deterioration in the quality of life. OM is generally classified into two main types: acute and chronic OM (AOM and COM). AOM is characterized by tympanic membrane swelling or otorrhea and is accompanied by signs or symptoms of ear infection. In COM, there is a tympanic membrane perforation and purulent discharge. The most common pathogens that cause AOM are Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis whereas Pseudomonas aeruginosa and Staphylococcus aureus are commonly associated with COM. Innate and adaptive immune responses provide protection against OM. However, pathogens employ a wide arsenal of weapons to evade potent immune responses and these mechanisms likely contribute to AOM and COM. Immunologic evasion is multifactorial, and involves damage to host mucociliary tract, genetic polymorphisms within otopathogens, the number and variety of different otopathogens in the nasopharynx as well as the interaction between the host's innate and adaptive immune responses. Otopathogens utilize host mucin production, phase variation, biofilm production, glycans, as well as neutrophil and eosinophilic extracellular traps to induce OM. The objective of this review article is to discuss our current understanding about the mechanisms through which otopathogens escape host immunity to induce OM. A better knowledge about the molecular mechanisms leading to subversion of host immune responses will provide novel clues to develop effective treatment modalities for OM.

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Section: Immune Evasion By Com Pathogens Specifically Otopathogenic Pmentioning

confidence: 60%

Subversion of host immune responses by otopathogens during otitis media

Parrish

Soni

Mittal

2019

Journal of Leukocyte Biology

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“…Ichikawa et al also reported PKC family genes to be up-regulated by PA in epithelial cells (39). In another study, it has been observed that PA activates PKC α to invade middle ear epithelial cells [41]. Activation of PKC α by its phosphorylation in human middle ear epithelial cells (HMEEC) was associated with actin condensation, and blocking the PKC pathway attenuated the ability of bacteria to invade HMEECs and subsequent actin condensation.…”

Section: Discussionmentioning

confidence: 95%

Genetic deletion of Sphk2 confers protection against Pseudomonas aeruginosa mediated differential expression of genes related to virulent infection and inflammation in mouse lung

Ebenezer¹,

Fu²,

Krishnan³

et al. 2019

Preprint

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BACKGROUND Pseudomonas aeruginosa (PA) is an opportunistic Gram-negative bacteria that causes serious life threatening and nosocomial infections including pneumonia. PA has the ability to alter host genome to facilitate its invasion thus increasing the virulence of the organism. Sphingosine-1 phosphate (S1P), a bioactive lipid is known to play a key role in facilitating infection. Sphingosine kinases (SPHK)1&2 phosphorylate sphingosine to generate S1P in mammalian cells. We reported earlier that Sphk2-/- mice offered significant protection against lung inflammation, compared to wild type (WT) animals. Therefore, we profiled the differential expression of genes between the protected group of Sphk2-/- and the wild type controls to better understand the underlying protective mechanisms Sphk2 deletion in lung inflammatory injury. Whole transcriptome shotgun sequencing (RNA seq) was performed on mouse lung tissue using NextSeq 500 sequencing system. RESULTS: Two-way ANOVA analysis was performed and differentially expressed genes following PA infection were identified using whole transcriptome of Sphk2-/- mice and their wild WT counterparts. Pathway (PW) enrichment analyses of the RNA seq data identified several signaling pathways that are likely to play a crucial role in pneumonia caused by PA such as those involved in: 1. Immune response to PA infection and NF-κB signal transduction; 2. PKC signal transduction; 3. Impact on epigenetic regulation; 4. Epithelial sodium channel pathway; 5. Mucin expression; and 6. Bacterial infection related pathways. Our data clearly suggests a role for SPHK2 in PA-induced pneumonia through elevated expression of inflammatory genes in lung tissue. Further, validation by RT-PCR on 10 differentially expressed genes showed 100% concordance in terms of vectoral changes, and 70% of genes showed concordance for significant fold change. CONCLUSION: Using Sphk2-/- mice and differential gene expression analysis, we have shown here that S1P/SPHK2 signaling plays a key role in promoting PA pneumonia. The identified genes promote inflammation, and suppress others that naturally inhibit inflammation and host defense. We therefore propose a key role for SPHK2/S1P signaling in PA-induced lung inflammation, and could serve as a potential therapeutic target to combat PA-induced pneumonia.

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“…Ichikawa et al also reported PKC family genes to be up-regulated by PA in epithelial cells (39). In another study, it has been observed that PA activates PKC α to invade middle ear epithelial cells [51]. Activation of PKC α by its phosphorylation in human middle ear epithelial cells (HMEEC) was associated with actin condensation, and blocking the PKC pathway attenuated the ability of bacteria to invade HMEECs and subsequent actin condensation.…”

Section: Discussionmentioning

confidence: 99%

Genetic deletion of Sphk2 confers protection against Pseudomonas aeruginosa mediated differential expression of genes related to virulent infection and inflammation in mouse lung

Ebenezer

Krishnan

et al. 2019

BMC Genomics

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BackgroundPseudomonas aeruginosa (PA) is an opportunistic Gram-negative bacterium that causes serious life threatening and nosocomial infections including pneumonia. PA has the ability to alter host genome to facilitate its invasion, thus increasing the virulence of the organism. Sphingosine-1- phosphate (S1P), a bioactive lipid, is known to play a key role in facilitating infection. Sphingosine kinases (SPHK) 1&2 phosphorylate sphingosine to generate S1P in mammalian cells. We reported earlier that Sphk2−/− mice offered significant protection against lung inflammation, compared to wild type (WT) animals. Therefore, we profiled the differential expression of genes between the protected group of Sphk2−/− and the wild type controls to better understand the underlying protective mechanisms related to the Sphk2 deletion in lung inflammatory injury. Whole transcriptome shotgun sequencing (RNA-Seq) was performed on mouse lung tissue using NextSeq 500 sequencing system.ResultsTwo-way analysis of variance (ANOVA) analysis was performed and differentially expressed genes following PA infection were identified using whole transcriptome of Sphk2−/− mice and their WT counterparts. Pathway (PW) enrichment analyses of the RNA seq data identified several signaling pathways that are likely to play a crucial role in pneumonia caused by PA such as those involved in: 1. Immune response to PA infection and NF-κB signal transduction; 2. PKC signal transduction; 3. Impact on epigenetic regulation; 4. Epithelial sodium channel pathway; 5. Mucin expression; and 6. Bacterial infection related pathways.Our genomic data suggests a potential role for SPHK2 in PA-induced pneumonia through elevated expression of inflammatory genes in lung tissue. Further, validation by RT-PCR on 10 differentially expressed genes showed 100% concordance in terms of vectoral changes as well as significant fold change.ConclusionUsing Sphk2−/− mice and differential gene expression analysis, we have shown here that S1P/SPHK2 signaling could play a key role in promoting PA pneumonia. The identified genes promote inflammation and suppress others that naturally inhibit inflammation and host defense. Thus, targeting SPHK2/S1P signaling in PA-induced lung inflammation could serve as a potential therapy to combat PA-induced pneumonia.

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Pseudomonas aeruginosa Activates PKC-Alpha to Invade Middle Ear Epithelial Cells

Cited by 11 publications

References 70 publications

Subversion of host immune responses by otopathogens during otitis media

Subversion of host immune responses by otopathogens during otitis media

Genetic deletion of Sphk2 confers protection against Pseudomonas aeruginosa mediated differential expression of genes related to virulent infection and inflammation in mouse lung

Genetic deletion of Sphk2 confers protection against Pseudomonas aeruginosa mediated differential expression of genes related to virulent infection and inflammation in mouse lung

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