Biology subjects

Mirceta, M.

Publications and source records attributed to Mirceta, M..

3 recordsLinked to original sources

bioRxiv2024

C9orf72 expansion creates the unstable folate-sensitive fragile site FRA9A

The hyper-unstable Chr9p21 locus, harbouring the interferon gene cluster, oncogenes and C9orf72, is linked to multiple diseases. C9orf72 (GGGGCC)n expansions (C9orf72Exp) are associated with incompletely penetrant amyotrophic lateral sclerosis, frontotemporal dementia and autoimmune disorders. C9orf72Exp patients display hyperactive cGAS-STING-linked interferon immune and DNA damage responses, but the source of immuno-stimulatory or damaged DNA is unknown. Here, we show C9orf72Exp in pre-symptomatic and ALS-FTD patient cells and brains cause the folate- sensitive chromosomal fragile site, FRA9A. FRA9A centers on >33kb of C9orf72 as highly-compacted chromatin embedded in an 8.2Mb fragility zone spanning 9p21, encompassing 46 genes, making FRA9A one of the largest fragile sites. C9orf72Exp cells show chromosomal instability, heightened global- and Chr9p-enriched sister-chromatid exchanges, truncated-Chr9s, acentric-Chr9s and Chr9-containing micronuclei, providing endogenous sources of damaged and immunostimulatory DNA. Cells from one C9orf72Exp patient contained highly-rearranged FRA9A-expressing Chr9 with Chr9-wide dysregulated gene expression. Somatic C9orf72Exp repeat instability and chromosomal fragility are sensitive to folate-deficiency. Age-dependent repeat instability, chromosomal fragility, and chromosomal instability can be transferred to CNS and peripheral tissues of transgenic C9orf72Exp mice, implicating C9orf72Exp as the source. Our results highlight unappreciated effects of C9orf72 expansions that trigger vitamin-sensitive chromosome fragility, adding structural variations to the disease-enriched 9p21 locus, and likely elsewhere. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=94 SRC="FIGDIR/small/620312v2_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@154b23borg.highwire.dtl.DTLVardef@1814a6dorg.highwire.dtl.DTLVardef@13d713eorg.highwire.dtl.DTLVardef@d5d994_HPS_FORMAT_FIGEXP M_FIG C_FIG

genetics↗

bioRxiv2017

Antimicrobial resistant Klebsiella pneumoniae carriage and infection in specialized geriatric care wards linked to acquisition in the referring hospital

BackgroundKlebsiella pneumoniae is a leading cause of extended-spectrum beta-lactamase (ESBL) producing hospital-associated infections, for which elderly patients are at increased risk.\n\nMethodsWe conducted a 1-year prospective cohort study, in which a third of patients admitted to two geriatric wards in a specialized hospital were recruited and screened for carriage of K. pneumoniae by microbiological culture. Clinical isolates were monitored via the hospital laboratory. Colonizing and clinical isolates were subjected to whole genome sequencing and antimicrobial susceptibility testing.\n\nResultsK. pneumoniae throat carriage prevalence was 4.1%, rectal carriage 10.8% and ESBL carriage 1.7%. K. pneumoniae infection incidence was 1.2%. The isolates were diverse, and most patients were colonized or infected with a unique phylogenetic lineage, with no evidence of transmission in the wards. ESBL strains carried blaCTX-M-15 and belonged to clones associated with hospital-acquired ESBL infections in other countries (ST29, ST323, ST340).\n\nOne also carried the carbapenemase blaIMP-26. Genomic and epidemiological data provided evidence that ESBL strains were acquired in the referring hospital. Nanopore sequencing also identified strain-to-strain transmission of a blaCTX-M-15 FIBK/FIIK plasmid in the referring hospital.\n\nConclusionsThe data suggest the major source of K. pneumoniae was the patients own gut microbiome, but ESBL strains were acquired in the referring hospital. This highlights the importance of the wider hospital network to understanding K. pneumoniae risk and infection control. Rectal screening for ESBL organisms upon admission to geriatric wards could help inform patient management and infection control in such facilities.\n\nSummaryPatients own gut microbiota were the major source of K. pneumoniae, but extended-spectrum beta-lactamase strains were acquired in the referring hospital. This highlights the potential for rectal screening, and the importance of the wider hospital network, for local risk management.

microbiology↗

bioRxiv2016

Gastrointestinal carriage is a major reservoir of K. pneumoniae infection in intensive care patients

BackgroundKlebsiella pneumoniae is an opportunistic pathogen and a leading cause of hospital-associated (HA) infections. Patients in intensive care units (ICUs) are particularly at risk, and outbreaks are frequently reported in ICUs. K. pneumoniae is also part of the healthy human microbiome, providing a potential reservoir for HA infection. However, the frequency of K. pneumoniae gut colonization and its contribution to HA infections are not well characterized.\n\nMethodsWe conducted one-year prospective cohort study of ICU patients. Participants (n=498) were screened for rectal and throat carriage of K. pneumoniae shortly after admission, and clinical information was extracted from hospital records.K. pneumoniae isolated from screening swabs and clinical diagnostic samples were characterized using whole genome sequencing. Genomic and epidemiological data were combined to identify likely transmission events.\n\nResults and ConclusionsK. pneumoniae carriage frequencies were estimated at 6% (95% CI, 3%-8%) amongst ICU patients admitted direct from the community, and 19% (95% CI, 14% - 51%) amongst those who had recent contact with healthcare. Gut colonisation on admission was significantly associated with subsequent K. pneumoniae infection (infection risk 16% vs 3%, OR=6.9, p<0.001), and genome data indicated a match between carriage and infection isolates in most patients. Five likely transmission chains were identified, resulting in six infections (12% of K. pneumoniae infections in ICU). In contrast, 49% of K. pneumoniae infections were caused by a strain that was unique to the patient, and 48% of patients with K. pneumoniae infections who participated in screening were positive for prior colonisation. These data confirm K. pneumoniae colonisation is a significant risk factor for subsequent infection in ICU, and indicate that half of all K. pneumoniae infections result from patients own microbiota. Screening for colonisation on admission could limit risk of infection in the colonised patient and others.

microbiology↗