The multifunction Coxiella effector Vice stimulates macropinocytosis and interferes with the ESCRT machinery.

Intracellular bacterial pathogens divert multiple cellular pathways to establish their niche and persist inside their host. Coxiella burnetii, the causative agent of Q fever, secretes bacterial effector proteins via its Type 4 secretion system to generate a Coxiella-containing vacuole (CCV). Manipulation of lipid and protein trafficking by these effectors is essential for bacterial replication and virulence. Here, we have characterized the lipid composition of CCVs and found that the effector Vice interacts with phosphoinositides and membranes enriched in phosphatidylserine and lysobisphosphatidic acid. Remarkably, eukaryotic cells ectopically expressing Vice present compartments that resemble early CCVs in both morphology and composition. We found that the biogenesis of these compartments relies on the double function of Vice. The effector protein initially localizes at the plasma membrane of eukaryotic cells where it triggers the internalization of large vacuoles by macropinocytosis. Then, Vice stabilizes these compartments by perturbing the ESCRT machinery. Collectively, our results reveal that Vice is an essential C. burnetii effector protein capable of hijacking two major cellular pathways to shape the bacterial replicative niche.

Efficacy of infliximab after loss of response of/intolerance to adalimumab in pediatric Crohn's disease: A retrospective multicenter cohort study of the "GETAID pédiatrique".

BACKGROUND: Infliximab (IFX) and adalimumab (ADA) are recommended for induction and maintenance of remission in pediatric Crohn's disease (CD). ADA is now often used in first line due to its efficacy and tolerability, but a loss of response (LOR) can occur over time. The aim was to assess the efficacy of IFX as second line therapy after LOR or intolerance to ADA in pediatric CD patients at 1 year. METHODS: We conducted a retrospective and multicenter study in France among the "GETAID pédiatrique" centers between April 2019 and April 2022. CD patients under 18 years old and treated with IFX after ADA failure or intolerance were included. We collected anthropometric, clinical, and biological data at baseline (start of IFX), at 6 and 12 months. Clinical remission was defined by a Weighted Pediatric CD Activity Index (wPCDAI) score less than 12.5 points. RESULTS: Of the 32 patients included in our study, 27 (84.4%) were still on IFX at 12 months of the switch. Among them, 13 had discontinued ADA because of a LOR, 12 for insufficient response and 2 due to primary nonresponse. At M12, 22 patients were in corticosteroid free clinical remission (68.7%). Under IFX, the wPCDAI decreased over time (47.5 ± 24.1, 16.6 ± 21.2 and 9.7 ± 19.0 at M0, M6 and M12 respectively). The only factor associated with clinical remission at 12 months was absence of perianal disease at the end of the IFX induction. CONCLUSIONS: IFX is effective in maintaining remission at 1 year in pediatric CD patients experiencing a LOR or intolerance with ADA, and IFX could be an interesting therapeutic choice instead of other biologics in this situation.

Emergency department CT examinations demonstrate no evidence of early viral circulation at the start of the COVID-19 pandemic-a multicentre epidemiological study.

BACKGROUND: Biological studies suggested that the COVID-19 outbreak in France occurred before the first official diagnosis on January 24, 2020. We investigated this controversial topic using a large collection of chest CTs performed throughout French emergency departments within 6 months before the 1st lockdown. RESULTS: Overall, 49,311 consecutive patients (median age: 60 years, 23,636/49,311 [47.9%] women) with available chest CT images and reports from 61 emergency departments between September 1, 2020, and March 16, 2020 (day before the 1st French lockdown), were retrospectively included in this multicentre study. In the macroscopic analysis of reports automatically (labelled for presence of ground glass opacities [GGOs], reticulations, and bilateral and subpleural abnormalities), we found a significant breakpoint on February 17, 2020, for the weekly time series with 1, 2 and ≥ 3 of these 4 radiological features, with 146/49,311 (0.3%) patients showing bilateral abnormalities and ground glass opacities (GGOs) from that day. According to radiologists, 22/146 (15.1%) CT images showed typical characteristics of COVID-19, including 4/146 (2.7%) before February 2020. According to hospital records, one patient remained without microbial diagnosis, two patients had proven influenza A and one patient had concomitant influenza A and mycoplasma infection. CONCLUSION: These results suggest that SARS-CoV-2 was not circulating in the areas covered by the 61 emergency departments involved in our study before the official beginning of the COVID-19 outbreak in France. In emergency patients, the strong resemblance among mycoplasma, influenza A and SARS-CoV-2 lung infections on chest CT and the nonspecificity of CT patterns in low prevalence periods is stressed. CRITICAL RELEVANCE STATEMENT: We proposed here an innovative approach to revisit a controversial 'real' start of the COVID-19 pandemic in France based on (1) a population-level approach combining text mining, time series analysis and an epidemiological dataset and (2) a patient-level approach with careful retrospective reading of chest CT scans complemented by analysis of samples performed contemporarily to the chest CT. We showed no evidence that SARS-CoV-2 was actively circulating in France before February 2020.

Nuclear speckle rejuvenation alleviates proteinopathies at the expense of YAP1.

Current treatments targeting individual protein quality control have limited efficacy in alleviating proteinopathies, highlighting the prerequisite for a common upstream druggable target capable of global proteostasis modulation. Building on our prior research establishing nuclear speckles as pivotal organelles responsible for global proteostasis transcriptional control, we aim to alleviate proteinopathies through nuclear speckle rejuvenation. We identified pyrvinium pamoate as a small-molecule nuclear speckle rejuvenator that enhances protein quality control while suppressing YAP1 signaling via decreasing the surface tension of nuclear speckle condensates through interaction with the intrinsically disordered region of nuclear speckle scaffold protein SON. In pre-clinical models, pyrvinium pamoate reduced tauopathy and alleviated retina degeneration by promoting autophagy and ubiquitin-proteasome system. Aberrant nuclear speckle morphology, reduced protein quality control and increased YAP1 activity were also observed in human tauopathies. Our study uncovers novel therapeutic targets for tackling protein misfolding disorders within an expanded proteostasis framework encompassing nuclear speckles and YAP1.