RESUMEN
Medullary thymic epithelial cells (mTECs) are critical for self-tolerance induction in T cells via promiscuous expression of tissue-specific antigens (TSAs), which are controlled by the transcriptional regulator, AIRE. Whereas AIRE-expressing (Aire+) mTECs undergo constant turnover in the adult thymus, mechanisms underlying differentiation of postnatal mTECs remain to be discovered. Integrative analysis of single-cell assays for transposase-accessible chromatin (scATAC-seq) and single-cell RNA sequencing (scRNA-seq) suggested the presence of proliferating mTECs with a specific chromatin structure, which express high levels of Aire and co-stimulatory molecules, CD80 (Aire+CD80hi). Proliferating Aire+CD80hi mTECs detected using Fucci technology express a minimal number of Aire-dependent TSAs and are converted into quiescent Aire+CD80hi mTECs expressing high levels of TSAs after a transit amplification. These data provide evidence for the existence of transit-amplifying Aire+mTEC precursors during the Aire+mTEC differentiation process of the postnatal thymus.
Asunto(s)
Cromatina , Análisis de la Célula Individual , Animales , Diferenciación Celular/genética , Cromatina/metabolismo , Células Epiteliales/metabolismo , Ratones , Ratones Endogámicos C57BL , Timo , Transposasas/metabolismoRESUMEN
BACKGROUND: Prevention and control of methicillin-resistant Staphylococcus aureus (MRSA) infections remain challenging. In-depth surveillance integrating patient and isolate data can provide evidence to better inform infection control and public health practice. METHODS: We analyzed MRSA cases diagnosed in 2010 (nâ =â 212) and 2016 (nâ =â 214) by hospitals in Ontario, Canada. Case-level clinical and demographic data were integrated with isolate characteristics, including antimicrobial resistance (AMR), classic genotyping, and whole-genome sequencing results. RESULTS: Community-associated MRSA (epidemiologically defined) increased significantly from 23.6% in 2010 to 43.0% in 2016 (Pâ <â .001). The MRSA population structure changed over time, with a 1.5×â increase in clonal complex (CC)8 strains and a concomitant decrease in CC5. The clonal shift was reflected in AMR patterns, with a decrease in erythromycin (86.7% to 78.4%, Pâ =â .036) and clindamycin resistance (84.3% to 47.9%, Pâ <â .001) and aâ >2-fold increase in fusidic acid resistance (9.0% to 22.5%, Pâ <â .001). Isolates within both CC5 and CC8 were relatively genetically diverse. We identified 6 small genomic clusters-3 potentially related to transmission in healthcare settings. CONCLUSIONS: Community-associated MRSA is increasing among hospitalized individuals in Ontario. Clonal shifting from CC5 to CC8 has impacted AMR. We identified a relatively high genetic diversity and limited genomic clustering within these dominant CCs.