Group B Streptococcal Pathogenesis in Diabetic Wounds
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ABSTRACT:
PROVIDER: PRJNA830900 | ENA |
REPOSITORIES: ENA
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Project description:Diabetic wound infections have poor healing outcomes due to the presence of numerous pathogens in addition to an impaired immune response. Group B Streptococcus (GBS) is one of the most commonly isolated bacteria from diabetic wound infections, but virulence mechanisms GBS uses during these infections have not been investigated. Here, we developed a new murine model of GBS diabetic wound infection to determine how GBS establishes infection and persists in the wound environment. Using dual RNA sequencing, we demonstrate that GBS infection of diabetic wounds triggers an inflammatory response, leading to increased transcript levels of inflammatory cytokines and chemokines as well as markers of neutrophil degranulation such as myeloperoxidase, calprotectin, and elastase. We then confirm that diabetic wounds infected with GBS have significantly higher abundance of Il-1b, KC (CXCL1), myeloperoxidase, calprotectin and elastase in wound tissues than uninfected controls . When examining how GBS adapts to this hyper-inflammatory environment we find that GBS upregulates numerous virulence factors including the surface plasminogen-binding protein pbsP, the nuclease nucA, the cyl operon which is responsible for hemolysin production and pigmentation as well as numerous effectors of type VII secretion. In addition, we recovered multiple hyper-pigmented/hemolytic GBS colonies from the murine diabetic wound environment which encode mutations in the two-component system covRS. We then go on to demonstrate that a mutant in cylE, which is repressed by CovR, is attenuated in diabetic wound infection. Finally, we examine the most highly upregulated gene pbsP in diabetic wound infection and find that PbsP is necessary for diabetic wound infection via adherence to the skin and promotion of inflammation.
2022-09-30 | GSE201342 | GEO
Project description:Choriodecidual infection is associated with preterm premature rupture of membranes (pPROM) and preterm birth. MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression and may be involved in the pathway leading to chorioamnion weakening following infection. The study objective was to determine if a miRNA profile in the chorioamnion is associated with Group B Streptococcal infection and membrane weakening.
2020-12-22 | GSE77152 | GEO
Project description:Dysregulation of macrophage populations at the wound site is responsible for the non-healing state of chronic wounds. The molecular mechanisms underlying macrophage dysfunction and its control in diabetes are largely unexplored on an epigenetic level. Here, we report that acetyl histone-H3 (Lys27), an epigenetic mark regulating the macrophage transcriptome, is lost in the hostile tissue microenvironment in diabetes. The diabetic microenvironment, profoundly suppresses the acetylation of histone by activating HDACs-dependent deacetylation pathways. This, in consequence, suppress the STAT1 signaling in macrophages maintained in diabetic conditions. Interestingly, the HDAC inhibitor butyrate - via restoring the acetyl histone-H3 (Lys27)-dependent transcriptome - effectively rescues macrophage functions in a diabetic microenvironment. Butyrate reinstalls the STAT1 mediated transcription program and consequently macrophage activity depicting a unique fingerprint of tissue regeneration and inflammation control even in a hostile diabetic microenvironment. Most interesting, butyrate breaks the vicious cycle of inflammation in diabetic wounds. Our study offers novel pathogenic insight and the unique opportunity to reverse perturbed macrophage function thus holding promise to successfully treat diabetic and other chronic wounds and conditions of unrestrained inflammation.
2021-09-14 | GSE183965 | GEO
Project description:Monocytes isolated from skin wounds on non-diabetic and diabetic mice on day 6 post-injury, subjected to enzymatic digestion to obtain single cells and pooled from two mice per strain. Fresh cells with viability over 85% processed using the 10x Chromium platform . Libraries sequenced on HiSeq with paired-end reads. Fastq files were generated and iesdemultiplexed into single cells using Cell Ranger software
2020-11-24 | GSE154400 | GEO
Project description:Impaired healing of diabetic wounds causes significant morbidity and mortality. This study aimed to identify novel mechanisms of diabetic wound healing defects and test a therapeutic intervention using diabetic mouse and pig models. We found Smad7 transgene expression in mouse epidermis promoting wound healing in diabetic db/db mice, with reductions in obesity and blood glucose. To isolate effects of Smad7 on wounds, we created a Smad7-based biologic (Tat-PYC-Smad7) that penetrates wound cells. Topical application of Tat-PYC-Smad7 to diabetic pig and mouse wounds accelerated healing compared to controls. RNAseq analysis of mouse wound samples showed reduced TGFβ/NFκB signaling, leading to faster re-epithelialization and better extracellular matrix remodeling. Tat-PYC-Smad7 also attenuated neutrophil degranulation and NETosis by blocking histone 3 citrullination and inhibiting myeloperoxidase activities. Our study reveals that Tat-PYC-Smad7 promotes diabetic wound healing by targeting keratinocytes and neutrophils, providing insight into cellular mechanisms of diabetic wound healing defects targetable by Smad7-based therapy.
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Project description:Chronic wounds are a common and costly complication of diabetes, where multifactorial defects contribute to dysregulated skin repair, inflammation, tissue damage, and infection. We previously showed that aspects of the diabetic foot ulcer microbiota were correlated with poor healing outcomes, but many microbial species recovered remain uninvestigated with respect to wound healing. Here we focused onAlcaligenes faecalis, a Gram-negative bacterium that is frequently recovered from chronic wounds but rarely causes infection. Treatment of diabetic wounds withA. faecalisaccelerated healing during early stages. We investigated the underlying mechanisms and found thatA. faecalistreatment promotes re-epithelialization of diabetic keratinocytes, a process which is necessary for healing but deficient in chronic wounds. Overexpression of matrix metalloproteinases in diabetes contributes to failed epithelialization, and we found thatA. faecalistreatment balances this overexpression to allow proper healing. This work uncovers a mechanism of bacterial-driven wound repair and provides a foundation for the development of microbiota-based wound interventions.
2024-03-30 | GSE261418 | GEO
Project description:Circular RNA (circRNA) microarray analysis was performed to examine the expression profiles of circRNAs in diabetic foot ulcers (DFU) and in human excisional skin wounds 7 days after injury.
2019-10-01 | GSE114248 | GEO
Project description:To investigate the expression of circRNAs, miRNAs, and related co-expression and competitive endogenous RNA (ceRNA) in diabetic chronic refractory wounds
2022-08-30 | GSE212163 | GEO
Project description:To investigate the expression of circRNAs, miRNAs, and related co-expression and competitive endogenous RNA (ceRNA) in diabetic chronic refractory wounds
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Project description:Severe angiopathy is a major driver for diabetes associated secondary complications. Knowledge on underlying mechanisms essential for advanced therapies to attenuate these pathologies is limited. Injection of ABCB5+ stromal precursors (SPs) at the edge of non-healing diabetic wounds in a murine db/db model, closely mirroring human type II diabetes, profoundly accelerates wound closure. Strikingly, enhanced angiogenesis was substantially enforced by the release of the ribonuclease angiogenin from ABCB5+ SPs. This compensates for the profoundly reduced angiogenin expression in non-treated murine and human chronic diabetic wounds. Silencing of angiogenin in ABCB5+ SPs prior to injection significantly reduced angiogenesis, reduced numbers of M2 macrophages and delayed wound closure in diabetic db/db mice implying an unprecedented key role for angiogenin in tissue regeneration in diabetes. These data hold significant promise for further refining SPs-based therapies of non-healing diabetic foot ulcers and other pathologies with impaired angiogenesis.
2021-08-12 | GSE181881 | GEO