Graphical Abstract Highlights d Natural C. elegans microbiota confer protection against pathogen infection d Different Pseudomonas isolates protect C. elegans through distinct mechanisms d P. lurida isolates produce massetolide E and directly inhibit pathogen growth d P. fluorescens-mediated protection may depend on indirect, host-mediated mechanisms
Purpose: Post-treatment follow-up in women with cervical pre-cancers (CIN3) is mandatory due to relapse in up to 10% of patients. Standard follow-up based on hrHPV-DNA/cytology co-testing has high sensitivity but limited specificity. The aim of our prospective, multicenter, observational study was to test the hypothesis that an individualized viral-cellular-junction test (vcj-PCR) combined with cytology has a lower false positive rate for the prediction of recurrence compared to standard co-testing. Methods: Pre-surgical cervical swabs served for the identification of HPV16/18 DNA integration sites by next-generation-sequencing (NGS). Samples taken at 6, 12 and 24 months post-surgery were evaluated by cytology, hrHPV-DNA and the patients’ individual HPV-integration sites (vcj-PCR on the basis of NGS). Results: Integration sites were detected in 48 of 445 patients (10.8%), 39 of them had valid follow-up data. The false positive rate was 18.2% (95% CI 8.6–34.4%) for standard hrHPV/cytology at six months compared to 12.1% (95% CI 4.8–27.3%) for vcj-PCR/cytology, respectively (McNemar p = 0.50). Six patients developed recurrences (1 CIN2, 5 CIN3) during follow-up. Standard co-testing detected all, whereas vcj-PCR/cytology detected only five patients with recurrences. Data of 269 patients without evidence of HPV16/18 integration were subject to post-hoc analyses. Standard co-testing revealed a false positive rate of 15.7% (95% CI 11.7–20.7%) and predicted ten of fourteen recurrences at six months. Conclusions: Although highly specific on its own vcj-PCR could not detect all recurrent CIN2/3. Possible reasons for this unexpected result may be multifocal lesions, intratumoral heterogeneity with respect to HPV integration and/or incident CIN.
<i>Staphylococcus aureus</i> is an important pathogen causing various infections, including – as most frequently isolated bacterium – cutaneous infections. Keratinocytes as the first barrier cells of the skin respond to <i>S. aureus</i> by the release of defense molecules such as cytokines and antimicrobial peptides. Although several pattern recognition receptors expressed in keratinocytes such as Toll-like and NOD-like receptors have been reported to detect the presence of <i>S. aureus</i>, the mechanisms underlying the interplay between <i>S. aureus</i> and keratinocytes are still emerging. Here, we report that <i>S. aureus</i> induced gene expression of CYP1A1 and CYP1B1, responsive genes of the aryl hydrocarbon receptor (AhR). AhR activation by <i>S. aureus</i> was further confirmed by AhR gene reporter assays. AhR activation was mediated by factor(s) <2 kDa secreted by <i>S. aureus</i>. Whole transcriptome analyses and real-time PCR analyses identified IL-24, IL-6, and IL-1beta as cytokines induced in an AhR-dependent manner in <i>S. aureus</i>-treated keratinocytes. AhR inhibition in a 3D organotypic skin equivalent confirmed the crucial role of the AhR in mediating the induction of IL-24, IL-6, and IL-1beta upon stimulation with living <i>S. aureus</i>. Taken together, we further highlight the important role of the AhR in cutaneous innate defense and identified the AhR as a novel receptor mediating the sensing of the important skin pathogen <i>S. aureus</i> in keratinocytes.
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