Biology subjects

Obadia, T.

Publications and source records attributed to Obadia, T..

4 recordsLinked to original sources

bioRxiv2024

Hamsters with long Covid exhibits a neurodegenerative signature in the brainstem

After infection with SARS-CoV-2, patients may present with one or more symptoms that appear or persist over time, including fatigue, respiratory, cardiovascular and neurological disorders. Neurological symptoms include anxiety, depression and impaired short-term memory. However, the exact underlying mechanisms of long Covid are not yet decrypted. Using the golden hamster as a model, we provide further evidence that SARS-CoV-2 is neuroinvasive and can persist in the central nervous system, as we found viral RNA and replicative virus in the brainstem after 80 days of infection. Infected hamsters presented a neurodegenerative signature in the brainstem, with overexpression of innate immunity genes, impacted dopaminergic and glutamatergic synapses, altered energy metabolism. Finally, the infected hamsters manifested persistent signs of depression and impaired short-term memory, as well as late-onset signs of anxiety, as a valuable model to study long Covid. Conclusively, we provide evidence that virus-related and neurodegenerative and immunometabolic mechanisms coexist in the brainstem of infected hamsters and contribute to the manifestation of neuropsychiatric and cognitive symptoms. HighlightsO_LISARS-CoV-2 infects and persists in the brainstem of intranasally-inoculated hamsters C_LIO_LIPersistent neuropsychiatric and cognitive consequences are observed in SARS-CoV-2-infected hamsters C_LIO_LIThe brainstem present distinct transcriptome profiles in acute and in long Covid C_LIO_LIThe dopaminergic and glutamatergic systems are affected in long Covid C_LIO_LIThe SARS-CoV-2 infection affects the expression of genes related to neurodegenerative processes in acute and in long Covid C_LI

pathology↗

bioRxiv2022

Caveolae govern plasma membrane mechanics to protect cells against EDIN B-induced transcellular tunnel formation and lethality from S. aureus septicaemia

Large transcellular pores elicited by bacterial mono-ADP-ribosyltransferase (mART) exotoxins inhibiting the small RhoA GTPase compromise the endothelial barrier. Recent advances in biophysical modeling point towards membrane tension and bending rigidity as the minimal set of mechanical parameters determining the nucleation and maximal size of transendothelial cell macroaperture (TEM) tunnels induced by bacterial RhoA-targeting mART exotoxins. We report that cellular depletion of caveolin-1, the membrane-embedded building block of caveolae, and depletion of cavin-1, the master regulator of caveolae invaginations, increase the number of TEMs per cell. The enhanced occurrence of TEM nucleation events correlates with a reduction of cell height, due to the increase of cell spreading and decrease of cell volume, which, together with the disruption of RhoA-driven F-actin meshwork, favor membrane apposition for TEM nucleation. Strikingly, caveolin-1 specifically controls the opening speed of TEMs leading to their dramatic 5.4-fold larger widening. Consistent with the increase of TEM density and width in siCAV1 cells, we record a higher lethality in caveolin-1-deficient mice subjected to a catalytically active mART exotoxin targeting RhoA during staphylococcal bloodstream infection. Combined theoretical modeling with independent biophysical measurements of plasma membrane bending rigidity point toward a specific contribution of caveolin-1 to membrane stiffening in addition to the role of cavin-1/caveolin-1-dependent caveolae in the control of membrane tension homeostasis.

biophysics↗

bioRxiv2022

Carbapenem heteroresistance of KPC-producing Klebsiella pneumoniae results from tolerance, persistence and resistance.

Carbapenemase-producing Klebsiella pneumoniae (CPKp) have disseminated globally and represent a major threat in hospitals with few therapeutic options and high mortality rates. Isolates producing the carbapenemase KPC (KPC-Kp) might be classified as susceptible according to clinical breakpoints by antibiotic susceptibility testing (AST), allowing the use of imipenem or meropenem for treatment of infections. However, some KPC-Kp show heteroresistance (HR) to carbapenems, with colonies growing in the inhibition halo of agar-based AST. HR KPC-Kp have been associated with a higher risk of treatment failure. Here, we characterized the diversity of mechanisms behind HR to imipenem of these isolates. By analyzing a diverse collection of CPKp, we showed that HR is frequent among KPC-Kp. By monitoring single HR colony appearance using the ScanLag setup, we discriminated surviving cells in two subpopulations leading to a Gaussian-like distribution of early-appearing colonies, with a delayed emergence compared to colonies arising in the absence of antibiotics, and a long tail of late-appearing colonies. A subset of colonies showed a reduced growth rate. Characterization of surviving populations by AST and whole-genome sequencing of 333 colonies revealed a majority of parental genotypes and a broad landscape of genetic alterations in 28% of the colonies, including gene loss, DNA amplification and point mutations. This unveils the complexity of imipenem HR among KPC-Kp isolates, which involves tolerant and persistent cells, but also resistant bacteria. These observations contribute to a better understanding of reasons behind carbapenem treatment failure of KPC-Kp isolates. IMPORTANCEThe ability of a bacterium to defeat antibiotics not only depends upon resistance, but also on tolerance and persistence, which allow a bacterial population to temporarily survive high drug doses. Carbapenems are antibiotics of last resort and Klebsiella pneumoniae isolates producing the carbapenemase KPC are a threat to hospitals, although they might remain susceptible to carbapenems. However, seemingly homogeneous populations of KPC-K. pneumoniae isolates frequently show varying degrees of susceptibility to carbapenem, i.e., a phenomenon called heteroresistance. We characterized bacteria surviving a high dose of imipenem, progressively degraded by the released carbapenemase, by monitoring the growth of the resulting colonies using the ScanLag system, their genome sequence and carbapenem susceptibility. We show that the observed phenotypic diversity combines tolerance, persistence and resistance making the treatment with high doses of carbapenems frequently inefficient.

microbiology↗

bioRxiv2018

Close proximity interactions support transmission of ESBL-K. pneumoniae but not ESBL-E. coli in healthcare settings

Antibiotic-resistance of hospital-acquired infections is a major public health issue. The worldwide emergence and diffusion of extended-spectrum {beta}-lactamase (ESBL)-producing Enterobacteriaceae, including Escherichia coli (ESBL-EC) and Klebsiella pneumoniae (ESBL-KP), is of particular concern. Preventing their nosocomial spread requires understanding their transmission. Using Close Proximity Interactions (CPIs), measured by wearable sensors, and weekly ESBL-EC- and ESBL-KP-carriage data, we traced their possible transmission paths among 329 patients in a 200-bed long-term care facility over 4 months. Based on phenotypically defined resistance profiles to 12 antibiotics, new bacterial acquisitions were tracked. Extending a previously proposed statistical method, the CPI networks ability to support observed incident colonization episodes of ESBL-EC and ESBL-KP was tested. Finally, mathematical modeling based on our findings assessed the effect of several infection-control measures. A potential infector was identified in the CPI network for 80% (16/20) of ESBL-KP acquisition episodes. The lengths of CPI paths between ESBL-KP incident cases and their potential infectors were shorter than predicted by chance (P = 0.02), indicating that CPI-network relationships were consistent with dissemination. Potential ESBL-EC infectors were identified for 54% (19/35) of the acquisitions, with longer-than-expected lengths of CPI paths. These contrasting results yielded differing impacts of infection control scenarios, with contact reduction interventions proving less effective for ESBL-EC than for ESBL-KP. These results highlight the widely variable transmission patterns among ESBL-producing Enterobacteriaceae species CPI networks supported ESBL-KP, but not ESBL-EC spread. These outcomes could help design more specific surveillance and control strategies to prevent in-hospital Enterobacteriaceae dissemination.\n\nAuthor summaryTracing extended-spectrum {beta}-lactamase (ESBL) dissemination in hospitals is an important step in the fight against the spread of multi-drug resistant bacteria. Indeed, understanding ESBL spreading dynamics will help identify efficient control interventions. In the i-Bird study, patients and hospital staff from a French long-term care facility in France carried a wearable sensor to capture their interactions at less than 1.5 meters, every 30 seconds over a 4-month period. Every week, patients were also swabbed to detect carriage of ESBL-producing Enterobacteriaceae. Based on the analysis of these longitudinal data, this study shows that ESBL-producing Klebsiella pneumoniae (ESBL-KP) mostly spreads during close-proximity interactions between individuals, while this is not the case for ESBL-producing Escherichia coli (ESBL-EC), suggesting that ESBL-KP but not ESBL-EC may be controlled by contact reduction interventions.

epidemiology↗