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Oral Pathogen ‘Neutralizes’ the Human Innate Immune Defence

ABSTRACT: Our present findings show for the first time that the virulence factor PPAD protects the oral pathogen P. gingivalis against neutrophil insults at three distinct levels, namely phagocytosis, NETosis and CAMP activity. This identifies PPAD as a major agent in the evasion of human innate immunity, a view that is supported by studies from Potempa and co-workers showing PPAD-dependent citrullination of complement29. Why is this important? Every day, millions of people lose teeth due to periodontitis. This has a serious impact on their quality of life, not only for aesthetic reasons but much more so because tooth loss causes difficulties in eating and interferes with interpersonal communication. Yet, only few people realize that there is a major bacteriological component in periodontitis where our immune defences are breached with potentially serious implications, especially systemic and chronic diseases ranging from bacteraemia to rheumatoid arthritis.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Macrophage

SUBMITTER: Thomas Sura

LAB HEAD: Doerte Becher

PROVIDER: PXD010798 | Pride | 2018-10-15

REPOSITORIES: Pride

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Oral Pathogen ‘Neutralizes’ the Human Innate Immune Defence

Project description:Our present findings show for the first time that the virulence factor PPAD protects the oral pathogen P. gingivalis against neutrophil insults at three distinct levels, namely phagocytosis, NETosis and CAMP activity. This identifies PPAD as a major agent in the evasion of human innate immunity, a view that is supported by studies from Potempa and co-workers showing PPAD-dependent citrullination of complement.

2018-10-15 | PXD009081 | Pride

The Extracellular Proteome and Citrullinome of the Oral Pathogen Porphyromonas gingivalis

Project description:Porphyrmonas gingivalis is an oral pathogen associated with the inflammatory disease periodontitis. The colonization of oral epithelial surfaces by P. gingivalis may also lead to the autoimmune disease rheumatoid arthritis. One of the hallmarks of rheumatoid arthritis is the loss of tolerance against citrullinated proteins. Citrullination is a post-translational modification of arginine residues, leading to a change in structure and function of the respective protein. This modification is catalysed by peptidylarginine deiminases (PAD). Interestingly, P. gingivalis secretes a citrullinating enzyme, known as P. gingivalis PAD (PPAD), which targets bacterial and human proteins. Since the extent of P. gingivalis protein citrullination by PPAD was not yet known, the present study was aimed at identifying the extracellular proteome and citrullinome of P. gingivalis. To this end, extracellular proteins of two reference strains, two PPAD-deficient mutants and three clinical isolates of P. gingivalis were analysed by mass spectrometry. The results uncovered substantial heterogeneity in the extracellular proteome and citrullinome of P. gingivalis, especially in relation to the extracellular detection of typical cytoplasmic proteins. In contrast, major virulence factors were identified in all investigated isolates although their citrullination was shown to vary. This may be related to post-translational processing of the PPAD enzyme.

2018-02-28 | PXD003444 | Pride

Transcriptome profiling of gingival fibroblasts treated by vitamin D3

Project description:In humans, vitamin D3 is a secosteroid, a prohormonal precursor of biologically active hydroxyforms. Vitamin D3 is related to periodontitis. The third American Health and Nutrition Survey found that plasma 25(OH)D3 levels are negatively correlated with attachment loss in people aged >50 years. The relationship between vitamin D3 and periodontitis remains to be investigated. We sent human gingival fibroblasts treated by vitamin D3 for transcriptome sequencing.

2022-09-09 | GSE212728 | GEO

Thioredoxin-1 promotes the restoration of alveolar bone in periodontitis with diabetes

Project description:Treatment of periodontitis in people with diabetes remains challenging. Diabetes-enhanced oxidative stress is a primary cause of aggravation of periodontitis. The present study aimed to investigate the therapeutic potential of thioredoxin-1 (TRX1), an essential endogenous antioxidant protein, in the management of periodontitis with diabetes, as well as its role in modulating osteogenic differentiation. Our findings indicated that the production of reactive oxygen species (ROS) was elevated, while the expression of TRX1 was significantly reduced in the periodontal tissues of periodontitis mice with diabetes. Furthermore, knockdown of TRX1 in periodontal ligament stem cells (PDLSCs) resulted in the inhibition of osteogenic differentiation through disrupting Wnt/β-catenin signal pathway. However, this inhibition was restored upon administration of recombinant human TRX1 (rhTRX1). Importantly, rhTRX1 treatment decreased ROS generation, activated Wnt/β-catenin signal pathway and considerably promoted the alveolar bone repair of periodontitis mice with diabetes. These findings highlighted the crucial protective role of TRX1 in periodontitis with diabetes and suggested that it may serve as a potential therapeutic target for refractory periodontitis associated with oxidative stress.

2023-09-06 | GSE235930 | GEO

Differential virulence of Aggregatibacter actinomycetemcomitans serotypes explained by exoproteome heterogeneity

Project description:Aggregatibacter actinomycetemcomitans (Aa) is a Gram-negative bacterial pathogen associated with periodontitis and non-oral diseases like rheumatoid arthritis and Alzheimer´s disease. Aa isolates with the serotypes a, b and c are globally most prevalent. Importantly, isolates displaying these serotypes have different clinical presentations. While serotype b isolates are predominant in severe periodontitis, serotypes a and c are generally encountered in mild periodontitis or healthy individuals. It was so far not known how these differences are reflected in the overall secretion of virulence factors. Therefore, this study was aimed at a comparative analysis of exoproteomes from different clinical Aa isolates with serotypes a, b or c by mass spectrometry, and a subsequent correlation of the recorded exoproteome profiles with virulence. Overall, we identified 425 extracellular proteins. Significant differences in the exoproteome composition of isolates with different serotypes were observed in terms of protein identification and abundance. In particular, serotype a isolates presented more extracellular proteins than serotype b or c isolates. These differences are mirrored in their virulence in infection models based on human salivary gland epithelial cells and neutrophils. Remarkably, serotype a isolates displayed stronger adhesive capabilities and induced more lysis of epithelial cells and neutrophils than serotype b or c isolates. Conversely, serotype c isolates showed relatively low leukotoxicity, while provoking NETosis to similar extents as serotype a and b isolates. Altogether, we conclude that the differential virulence presentation by Aa isolates with the dominant serotypes a, b or c can be explained by their exoproteome heterogeneity.

2022-12-16 | PXD036160 | Pride

Strand-specific transcriptome profiles of the oral pathogen Porphyromonas gingivalis using genomic tiling microarray and RNA sequencing

Project description:High-density tiling microarray and RNA sequencing technologies were used to analyze the transcriptome of Porphyromonas gingivalis. The compiled P. gingivalis transcriptome were based on total RNA samples isolated from three different laboratory culturing conditions and the strand-specific transcription profiles generated covered the entire genome including both protein coding and non-coding regions. The transcription profiles revealed various operon structures, 5' and 3' end untranslated regions (UTRs), differential expression patterns, and several not-yet annotated transcripts within intergenic and antisense regions. Further transcriptome analysis identified the majority of the genes to be expressed within operons and most 5' and 3' ends to be protruding UTRs of which several 3M-CM-"M-BM-^@M-BM-^Y UTRs were extended to overlap genes encoded on the opposite/antisense strand. Extensive antisense RNAs were identified opposite to most of insertion sequence (IS) elements. With the growing realization that non-coding RNAs play important biological functions, the comprehensive transcriptome profiles compiled in this study are of great value for the further understanding of gene regulation and virulence mechanism in this periodontal pathogen. The transcriptome profiles can be viewed at and downloaded from the 'Microbial Transcriptome Database' web site http://bioinformatics.forsyth.org/mtd. 3 total RNA samples from growing P. gingivalis strain W83 under different media conditions subjected to RNA-Seq.

2011-10-01 | E-GEOD-30452 | biostudies-arrayexpress

Host nasopharyngeal transcriptome analysis in a SARS-CoV-2 positive Italian cohort

Project description:The ongoing COVID-19 pandemic caused by SARS-CoV-2 has affected millions of people worldwide and has significant implications for public health. Host transcriptomics profiling provides comprehensive understanding of how the virus interacts with host cells and how the host responds to the virus. COVID-19 disease alters the host transcriptome, affecting cellular pathways and key molecular functions. To contribute to the global effort to understand the virus’s effect on host cell transcriptome, we have generated a dataset from nasopharyngeal swabs of 35 individuals infected with SARS-CoV-2 from the Campania region in Italy during the three outbreaks, with different clinical conditions. This dataset will help to elucidate the complex interactions among genes and can be useful in the development of effective therapeutic pathways

2023-05-25 | E-MTAB-13028 | biostudies-arrayexpress

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2011-10-13 | E-GEOD-29629 | biostudies-arrayexpress

Computational drug repositioning identifies niclosamide and tribromsalan as inhibitors of Mycobacterium tuberculosis and Mycobacterium abscessus

Project description:Tuberculosis (TB) is still a major global health challenge, killing over 1.5 million people each year, and hence, there is a need to identify and develop novel treatments for Mycobacterium tuberculosis (M. tuberculosis). The prevalence of infections caused by nontuberculous mycobacteria (NTM) is also increasing and has overtaken TB cases in the United States and much of the developed world. Mycobacterium abscessus (M. abscessus) is one of the most frequently encountered NTM and is difficult to treat. We describe the use of drug-disease association using a semantic knowledge graph approach combined with machine learning models that has enabled the identification of several molecules for testing anti-mycobacterial activity. We established that niclosamide (M. tuberculosis IC90 2.95 μM; M. abscessus IC90 59.1 μM) and tribromsalan (M. tuberculosis IC90 76.92 μM; M. abscessus IC90 147.4 μM) inhibit M. tuberculosis and M. abscessus in vitro. To investigate the mode of action, we determined the transcriptional response of M. tuberculosis and M. abscessus to both compounds in axenic log phase, demonstrating a broad effect on gene expression that differed from known M. tuberculosis inhibitors. Both compounds elicited transcriptional responses indicative of respiratory pathway stress and the dysregulation of fatty acid metabolism. Further testing against drug-resistant isolates and other NTM is warranted to clarify the usefulness of these repurposed drugs for mycobacteria.

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Palmitate-induced gene expression in human gingival fibroblasts (HGF)

Project description:DNA microarray analysis was performed to investigate the expression of genes in HGF stimulated with palmitate Type 2 diabetes (T2D) is characterized by decreased insulin sensitivity and higher concentrations of free fatty acids (FFAs) in plasma. Among FFAs, saturated fatty acids (SFAs), such as palmitate, have been proposed to promote inflammatory responses. Although many epidemiological studies have shown a link between periodontitis and T2D, little is known about the clinical significance of SFAs in periodontitis. The goal of this study is to demonstrate a potential link between the pathogenesis of periodontitis and SFAs in plasma. HGF were treated with either with 0 (1% Bovine serum albumin) or 100 ÂµM Palmitate for 36 hours (n=2 each).

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