Biology subjects

Torresi, M.

Publications and source records attributed to Torresi, M..

3 recordsLinked to original sources

bioRxiv2026

Targeting hypoxia-responsive miR-155-5p and miR-210-3p restores alveolar regeneration and reverses pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is an age-associated degenerative disease largely driven by failure of alveolar epithelial regeneration, yet current therapies slow fibrosis progression without restoring epithelial repair. Building on our previous unbiased microRNA screen in primary murine alveolar type II (ATII) cells, we identified miR-155-5p and miR-210-3p as previously unrecognized mediators of alveolar epithelial regenerative failure. Both microRNAs were markedly upregulated in ATII cells from patients with IPF and enriched within KRT17+/KRT5- aberrant transitional epithelial cells. Their expression also increased spontaneously with ageing in ATII cells from uninjured mice, linking these microRNAs to the age-dependent loss of ATII to ATI transdifferentiation capacity. Furthermore, we found that hypoxia-induced HIF signalling drives the expression of these microRNAs in ATII cells, locking them in a dysfunctional transitional state characterized by a profibrotic secretome that promotes paracrine myofibroblasts activation. Antisense oligonucleotide (ASO) inhibition of selected miRNAs restored ATII-to-ATI differentiation, eliminated aberrant transitional states, normalized epithelial-mesenchymal communication, promoted de novo alveolar regeneration and reversed fibrosis, including in both young and aged mice. Together, these findings identify the hypoxia-responsive miRNAs miR-155-5p and miR-210-3p as therapeutically actionable regulators of alveolar regenerative failure and establish their inhibition as a strategy to restore endogenous lung repair while disrupting pathological epithelial-mesenchymal crosstalk in pulmonary fibrosis.

cell biology↗

bioRxiv2026

AAV-miR-124 enhances endogenous alveolar epithelial regenerative plasticity and reverses bleomycin-induced pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by irreversible destruction of the alveolar epithelium and impaired regeneration. Although current therapies slow disease progression, they do not restore functional alveoli, highlighting the need for regenerative approaches that promote endogenous lung repair. Here, we performed the first unbiased functional screen of 2,042 human microRNA mimics in primary mouse alveolar type II (ATII) cells to identify regulators of ATII-to-alveolar type I (ATI) cell transdifferentiation. The screen identified miR-124-3p as the most effective promoter of ATI differentiation. In vitro, miR-124-3p promoted ATII-to-ATI transdifferentiation in healthy and bleomycin-injured ATII cells while also increasing the ATII cell pool, consistent with activity on epithelial progenitors. Using the engineered AAV6.2FF capsid, we generated a vector encoding miR-124-3p, which efficiently transduced ATII cells, MHC-II club distal progenitor cells, and injury-induced KRT8 epithelial intermediates. Therapeutic administration after fibrosis establishment reduced lung fibrosis, restored alveolar architecture, and showed greater efficacy than nintedanib in the bleomycin mouse model. Mechanistically, we propose a context-dependent model whereby miR-124-3p regulates epithelial cell states through the EZH2-C/EBP axis while attenuating epithelial transcriptional programs associated with IPF. Together, these findings support AAV-mediated delivery of miR-124 to promote alveolar repair in pulmonary fibrosis.

cell biology↗

bioRxiv2023

Large-scale phenotypic and genomic characterization of Listeria monocytogenes susceptibility to quaternary ammonium compounds

Listeria monocytogenes is a significant concern for the food industry due to its ability to persist in the food processing environment. Decreased susceptibility to disinfectants is one of the factors that contribute to the persistence of L. monocytogenes. The objective of this study was to explore the diversity of L. monocytogenes susceptibility to quaternary ammonium compounds (QACs) using 1,671 L. monocytogenes isolates. This was used to determine the phenotype-genotype concordance and characterize genomes of the QAC sensitive and tolerant isolates for stress resistance, virulence and plasmid replicon genes. Distribution of QAC tolerance genes among 37,897 publicly available L. monocytogenes genomes were also examined. The minimum inhibitory concentration to QACs was determined by the broth microdilution method and non-sequenced isolates (n=1,244) were whole genome sequenced. Genotype-phenotype concordance was 99% for benzalkonium chloride, DDAC and a commercial QAC based sanitizer. Prevalence of QAC tolerance genes was 23% and 28% in our L. monocytogenes collection and in the global dataset, respectively. qacH was the most prevalent gene in our collection (61%), with 19% prevalence in the global dataset. Notably, bcrABC was most common (72%) globally, while 25% in our collection. Prevalence of emrC and emrE was comparable in both datasets, 7% and 2%, respectively. Replicon genes, indicative of plasmid harborage, were detected in 44% of the isolates and associated with the QAC tolerant phenotype. The presented analysis is based on the biggest L. monocytogenes collection in diversity and quantity for characterization of the L. monocytogenes QAC tolerance at both phenotypic and genomic levels. IMPORTANCEContamination of Listeria monocytogenes within the food processing environment is of concern to the food industry due to challenges in eradicating the pathogen once it becomes persistent in the environment. Genetic markers associated with increased tolerance to disinfectants have been identified, which alongside factors favor the persistence of L. monocytogenes in the production environment. By employing a comprehensive large-scale phenotypic testing and genomic analysis our study significantly enhances the understanding of the prevalence of quaternary ammonium compound (QAC) tolerant L. monocytogenes and the genetic determinants associated with the increased tolerance. Furthermore, we report on the prevalence of QAC tolerance genes among 37,897 publicly available L. monocytogenes sequences and their distribution within clonal complexes, isolation sources and geographical locations. As the propagation of QAC tolerance showed not be evenly distributed globally this highlights that understanding the development of L. monocytogenes disinfectant tolerance can be monitored using publicly available WGS data.

microbiology↗