L'interaction Hsp90/co-chaperonnes : nouvelle cible pour le traitement des candidoses invasives

During the past decade systemic candidiasis incidence has increased placing the yeast Candida albicans at the fourth rank of pathogenic agent responsible for hospital- acquired infections. Emergence of antifungal resistance, host toxicity, drug interactions and paucity of target limit the current treatment strategies. To overcome these limitations as well as to improve our therapeutic armamentarium, original targets need to be identified to develop new antifungal alternatives. Hsp90, a chaperone well-studied in oncology, has been identified as an original target in medical mycology. Indeed, Hsp90 plays a key role in virulence and drug resistance to mains classes of antifungals. To our knowledge, the vast majority of inhibitors developed target the N-terminal domain of the protein. Our work focused on binding sites with a lower degree of interspecies homology. We hypothesised that the e-terminal domain of Hsp90 and its co- chaperones would be more selective targets because their protein sequences were less conserved. Thus, we described the anti-Candida activity of celastrol, a natural compound interacting with the co-chaperone Cdc37. Furthermore, at the end of this collaborative and multidisciplinary project, the modelling of the interaction of Hsp90 with Sba1 allowed the selection by high- throughput screening of other "hit" compounds that could serve as a basis for optimization towards "lead" compounds.L'incidence des candidoses invasives ne cesse d'augmenter ces dix dernières années plaçant la levure Candida albicans au quatrième rang des pathogènes responsables d'infections nosocomiales. L'émergence de résistances, les interactions médicamenteuses, la toxicité et la faible diversité de cibles, limitent les stratégies thérapeutiques. li apparaît donc nécessaire d'identifier de nouvelles cibles afin de développer des outils thérapeutiques innovants en mycologie médicale. La Heat-Shock-Protein 90kDa (Hsp90}, protéine chaperonne étudiée en cancérologie car impliquée dans la survie cellulaire, a également été identifiée comme une cible d'intérêt en mycologie médicale. Elle intervient dans plusieurs voies de signalisation intracellulaires, jouant un rôle dans la virulence et la résistance de la levure. Alors que la grande majorité des inhibiteurs développés à notre connaissance ciblent le domaine N-terminal de la protéine, nos travaux se sont concentrés sur des sites d'interaction avec un moindre degré d'homologie inter- espèces. Nous avons fait l'hypothèse que le domaine e-terminal d'Hsp90 et ses co- chaperonnes serraient des cibles plus sélectives car leurs séquences protéiques ont été moins conservées. Ainsi, nous avons décrit l'activité anti-Candida du célastrol, molécule naturelle interagissant avec la co-chaperonne Cdc37. D'autre part, à l'issue de ce projet collaboratif et multidisciplinaire la modélisation de l'interaction d'Hsp90 avec Sba 1 a permis la sélection par criblage à haut débit d'autres composés "hit" pouvant servir de socle à l'optimisation vers des chefs de file "lead"

Could PLATELIA Toxo IgM be the new gold standard for the serological diagnosis of congenital toxoplasmosis: a French multicenter study

International audienceTo assess the performance of PLATELIA Toxo IgM (Bio-Rad) and Toxo ISAGA (BioMérieux) to detect anti- IgM in infants at risk of congenital toxoplasmosis, a retrospective multicenter study was conducted comparing serological results obtained in the framework of routine diagnosis work-up for congenital toxoplasmosis. All infants born to mothers infected with during pregnancy from 2010 to 2020 with at least 6 months of serological follow-up were included ( = 1,010). One thousand ten cases were included, of which 250 infants (24.75%) had congenital toxoplasmosis. A total of 1039 sera were included. The concordance between the two techniques was 96%, with kappa coefficient of 0.87, showing an almost perfect agreement between ISAGA and PLATELIA. Cumulative sensitivity and specificity were 73.2% and 99.5.% and 74.8% and 100% for ISAGA and PLATELIA, respectively. The mean time to detect IgM using ISAGA and PLATELIA tests was 6.9 ± 20.1 days and 5.6 ± 14.7 days, respectively not significant (ns). Finally, the sensitivity of ISAGA and PLATELIA to detect IgM antibodies in infected neonates at 5 days of life was 62% and 64%, respectively. Performances of PLATELIA Toxo IgM assay were comparable to the gold standard ISAGA. This enzyme-linked immunosorbent assay is suitable for routine serology for the diagnosis of congenital toxoplasmosis in newborns. IMPORTANCE This study will help clinical microbiologists to chose an alternative serological method for the neonatal diagnosis of congenital toxoplasmosis, once the gold standard technique ISAGA will be withdrawn next year

Neurocysticercosis Diagnosis in a Non-Endemic Country: France

International audienceDiagnosing neurocysticercosis (NCC) is difficult due to its variable clinical presentations and the different imaging techniques used to detect brain damage. This study aimed to evaluate the use of cerebrospinal fluid serology and PCR for diagnosing biological neurocysticercosis in a non-endemic country. We tested samples from patients living in France with suspected NCC and confirmed that 45 of the patients presented with the disease. A total of 89% of patients had previously traveled to countries where the disease was endemic. The sensitivity of Western blots compared to ELISA was not significantly different (80% vs. 60%) (p > 0.05), and neither was the sensitivity of Western blots vs. PCR (78% vs. 56%) (p > 0.05). The PCR sensitivity was 78% and 47% in definitive NCC and in probable NCC. PCR tests using cerebrospinal fluid should be considered as a diagnostic criterion for identifying NCC

Cryptococcus neoformans Infections Differ Among Human Immunodeficiency Virus (HIV)–Seropositive and HIV-Seronegative Individuals: Results From a Nationwide Surveillance Program in France

International audienceAmong 1107 cryptococcosis cases from the French surveillance network (2005–2020), the proportion of HIV-seronegative individuals has recently surpassed that of HIV-seropositive individuals. We observed marked differences in patient characteristics, disease presentations, cryptococcal antigen results, infecting species, and mortality according to HIV serostatus

Features of cryptococcosis among 652 HIV-seronegative individuals in France: a cross-sectional observational study (2005-2020)

International audienceObjectives: We aimed to describe features and outcomes of cryptococcosis among HIV-seronegative individuals in a large surveillance network for cryptococcosis in France.Methods: We included incident cases of cryptococcosis in HIV-seronegative individuals from 2005 to 2020. We compared patient characteristics, disease presentations, cryptococcal antigen (CrAg) results, and induction antifungal treatments according to underlying disease. We examined factors associated with 90-day mortality. Among patients with disseminated infections, we investigated whether receipt of flucytosine and polyene combination was associated with lower mortality.Results: Among 652 individuals, 209 (32.1%) had malignancy, 130 (19.9%) were solid-organ transplant (SOT) recipients, 204 (31.3%) had other immunocompromising conditions, and 109 (16.7%) had no reported underlying factor. The commonest presentations were disseminated infections (63.3%, 413/652) and isolated pulmonary infections (25.3%, 165/652). SOT patients were most likely to have disseminated infections and a positive serum CrAg result. Patients with malignancy were older and less likely to receive a flucytosine-containing regimen for disseminated infections than others (58.7%, 78/133 vs. 73.2%, 194/265, p=0.029). The crude 90-day case-fatality ratio was 27.2% (95%CI: 23.5%-31.1%). Age ≥60 years (aOR: 2.75 [1.78-4.26], p<0.001), meningitis/fungaemia (aOR: 4.79 [1.80-12.7], p=0.002), and malignancy (aOR: 2.4 [1.14-5.07], p=0.02) were associated with higher 90-day mortality. Receipt of flucytosine and polyene combination was associated with lower 90-day mortality (aOR: 0.40 [0.23-0.71], p=0.002) in multivariable analysis and inverse probability of treatment weighted analysis (aOR: 0.45 [0.25-0.80], p=0.006).Conclusions: HIV-seronegative individuals with cryptococcosis comprise a wide range of underlying conditions with different presentations and outcomes, requiring a tailored approach to diagnosis and management