Torque teno virus (TTV) DNA load in plasma is suggested as a marker for immunosuppression post-transplantation. Crohn's disease (CD) arises from genetic susceptibility, environmental factors, and dysbiosis, causing immune responses. This study examines TTV DNA load in CD patients in remission and its correlation with relapse. Using quantitative real-time polymerase chain reaction (PCR) and metagenomic analysis, the dynamic of plasma TTV DNA load was analyzed from a cohort of CD patients (n = 39) over 1 year and compared with controls (n = 49). At inclusion, TTV DNA was significantly higher in CD patients compare to control (Median [IQR]: 3.27 [2.43-3.67] and 2.05 [1.28-2.80] Log copies/mL, p = 0.0004). Plasma TTV DNA load failed to predict disease relapse in CD patients. Augmented plasma TTV DNA levels in CD patients correlated with diminished circulating CD3 + T cells and especially CD4 + T cells. No preferential representation of TTV subspecies or Anelloviridae genera was detected in CD patients' plasma. This study revealed elevated TTV DNA levels in CD patients' plasma compared to healthy controls, underscoring the intriguing potential of TTV blood sampling as a biomarker in CD.

Viruses adapt and modulate cellular pathways to allow their replication in host cells. The catabolic pathway of macroautophagy, for simplicity referred to as autophagy, is no exception. In this review, we discuss anti-viral functions of both autophagy and select components of the autophagy machinery, and how viruses have evaded them. Some viruses use the membrane remodeling ability of the autophagy machinery to build their replication compartments in the cytosol or efficiently egress from cells in a non-lytic fashion. Some of the autophagy machinery components and their remodeled membranes can even be found in viral particles as envelopes or single membranes around virus packages that protect them during spreading and transmission. Therefore, studies on autophagy regulation by viral infections can reveal functions of the autophagy machinery beyond lysosomal degradation of cytosolic constituents. Furthermore, they can also pinpoint molecular interactions with which the autophagy machinery can most efficiently be manipulated, and this may be relevant to develop effective disease treatments based on autophagy modulation.

Inflammatory bowel diseases (IBDs) are chronic inflammatory conditions of the gastrointestinal tract that are multifactorial in nature. The pathophysiology involves interactions between the host immune system and environmental factors, including the gut microbiota, in genetically predisposed individuals. Advances in understanding these interactions have led to the development of novel therapeutic targets, ranging from anti-TNFα to more recent anti-interleukin 23 treatments. However, some patients still experience resistance to these therapies. Monogenic intestinal diseases (MIDs), which present with more severe symptoms than IBD and typically begin early in life, result from significant disruptions of intestinal homeostasis. MIDs are driven by mutations in a single gene, offering a unique opportunity to explore the mechanisms underlying intestinal homeostasis in health. In this review, we provide a comprehensive overview of the mechanisms of intestinal homeostasis by examining the cellular and molecular features of IBD and MID pathophysiologies.

Airborne RNA viruses of the Paramyxoviridae family are major human pathogens. These include measles virus (MeV) and Nipah virus (NiV), the latter being on the World Health Organization’s blueprint list due to its high case-fatality rate and critical risk of emergence. Although an effective vaccine is available for MeV, this is not the case for NiV. Moreover, there is no cure for MeV- or NiV-infected patients that prevents the acute respiratory syndrome or lethal encephalitis. To identify new host factors to target for inhibiting viral growth, a library of metabolic modulators was screened for activity against MeV using an in vitro infection model. Results showed that Molidustat, a pharmacological inhibitor of Prolyl-Hydroxylase Domain (PHD) enzymes, inhibits MeV infection in a Hypoxia-Inducible Factor (HIF)-dependent manner. We then tested the antiviral effect of Molidustat in organotypic cultures of hamster cerebellum. Molidustat induced the hypoxia-response pathway in this ex vivo model as assessed by transcriptomic analysis, and inhibited MeV infection. A similar antiviral effect was observed with Roxadustat and Daprodustat, two PHD enzyme inhibitors chemically unrelated to Molidustat. Finally, we showed that Molidustat inhibits NiV infection in organotypic cultures of hamster cerebellum and lung, thereby validating its effect in the two organs mainly targeted during infection. Taken together, our results provide evidence that pharmacological activation of the hypoxia-response pathway restricts MeV and NiV infections, highlighting HIF-inducing drugs as promising candidates to consider in the development of treatments.

CALCOCO2/NDP52 recognizes LGALS8 (galectin 8)-coated invading bacteria and initiates anti-bacterial autophagy by recruiting RB1CC1/FIP200 and TBKBP1/SINTBAD-AZI2/NAP1. Whether CALCOCO2 exerts similar functions against viral infection is unknown. In our recent study we show that CALCOCO2 targets envelope proteins of hepatitis B virus (HBV) to the lysosome for degradation, resulting in inhibition of viral replication. In contrast to anti-bacterial autophagy, lysosomal degradation of HBV does not require either LGALS8 or ATG5, and CALCOCO2 mutants abolishing the formation of the RB1CC1-CALCOCO2-TBKBP1-AZI2 complex maintain their inhibitory function on the virus. CALCOCO2-mediated inhibition depends on RAB9, which is a key factor in the alternative autophagy pathway. CALCOCO2 forms a complex with RAB9 only in the presence of viral envelope proteins and links HBV to the RAB9-dependent lysosomal degradation pathway. These findings reveal a new mechanism by which CALCOCO2 triggers antiviral responses against HBV infection and suggest direct roles for autophagy receptors in other lysosomal degradation pathways than canonical autophagy.

HIV-1 entry into CD4+ T lymphocytes relies on the viral and cellular membranes' fusion, leading to viral capsid delivery in the target cell cytoplasm. Atg8/LC3B conjugation to lipids, process named Atg8ylation mainly studied in the context of macroautophagy/autophagy, occurs transiently in the early stages of HIV-1 replication in CD4+ T lymphocytes. Despite numerous studies investigating the HIV-1-autophagy interplays, the Atg8ylation impact in these early stages of infection remains unknown. Here we found that HIV-1 exposure leads to the rapid LC3B enrichment toward the target cell plasma membrane, in close proximity with the incoming viral particles. Furthermore, we demonstrated that Atg8ylation is a key event facilitating HIV-1 entry in target CD4+ T cells. Interestingly, this effect is independent of canonical autophagy as ATG13 silencing does not prevent HIV-1 entry. Together, our results provide an unconventional role of LC3B conjugation subverted by HIV-1 to achieve a critical step of its replication cycle.

L'immunothérapie a révolutionné le pronostic des cancers thoraciques. Bloquant les points de contrôles immunitaires, elle favorise la levée de l'inhibition des cellules immunitaires: en découle des effets indésirables immuno-induits, dont les effets cardiovasculaires parmi lesquels les plus fréquents, les myocardites, représentant 0,01 à 1 % dans les études rétrospectives. Malgré leur faible incidence, elles sont de plus en plus souvent rapportées devant leur évolution fatale dans 30 à 50 %. Nous avons évalué de manière prospective l'incidence et l'intérêt d'un dépistage systématique des myocardites chez les patients atteints d'un cancer thoracique traités par immunothérapie. Étude prospective multicentrique, de mai 2020 à novembre 2022. Tout patient majeur, avec un diagnostic de carcinome bronchopulmonaire ou pleural confirmé, avec ECG, ETT et dosage de la troponine en amont de la première cure d'immunothérapie était inclus. La troponine était dosée avant chaque injection d'immunothérapie ainsi qu'une consultation médicale, l'ECG uniquement en cas de symptomatologie ou d'augmentation des troponines. Le diagnostic de myocardite était confirmé par une IRM myocardique selon les critères de Lake Louise et les recommandations de l'ESC. Le traitement de la myocardite suivait celles de l'ASCO avec arrêt de l'immunothérapie et mise sous corticothérapie. Entre mai 2020 et novembre 2022, 298 patients ont été analysés. La majorité des patients était des hommes. L'âge médian était de 63 ans. Les adénocarcinomes représentaient 68 % des cas. 198 patients avaient reçu l'immunothérapie en première ligne, dont 67 % du pembrolizumab en combinaison avec la chimiothérapie. Cent soixante-dix-huit patients avaient un pathologie cardiovasculaire pré-existante. Sur les ECG et ETT pré-thérapeutiques réalisés, 12 nouveaux diagnostics ont été réalisés: 4 valvulopathies, une hypertension pulmonaire, 5 insuffisances cardiaques, une cardiomyopathie dilatée et un trouble de la repolarisation. L'incidence de la myocardite est de 1,68 pour 100 patients, soit 5 cas, tous diagnostiqués sur une élévation des troponines, toutes asymptomatiques, sans décès imputable. Toutes ont été traitées par corticothérapie et arrêt de l'immunothérapie. Le délai moyen était de 117 jours. La PFS était plus élevée dans le groupe des myocardites. Quatre patients ont bénéficié d'un rechallenge avec 2 récurrences : une réascension des troponines et un trouble du rythme. D'autres événements cardio-vasculaires ont été relevés : 5 SCA, 1 embolie pulmonaire, 2 arythmies, 1 AVC dont 4 ont eu un arrêt de l'immunothérapie et 3 un changement de ligne. L'incidence des myocardites immuno-induites dans les cancers bronchiques métastatiques est discrètement plus élevée que celle rapportée dans les études rétrospectives. Un dépistage systématique ne semble pas justifié devant sa faible incidence. Aucun examen paraclinique de première intention (troponinémie, ECG, ETT) ne semble assez précis pour pallier à l'IRM. Néanmoins ces examens ont permis de dépister des pathologies cardio-vasculaires méconnues avec une implication thérapeutique. Une consultation onco-cardiologique en amont semble cependant justifiée face à une population comorbide.

Crohn disease (CD) is an inflammatory bowel disease whose pathogenesis involves inappropriate immune responses toward gut microbiota on genetically predisposed backgrounds. Notably, CD is associated with single-nucleotide polymorphisms affecting several genes involved in macroautophagy/autophagy, the catabolic process that ensures the degradation and recycling of cytosolic components and microorganisms. In a clinical translation perspective, monitoring the autophagic activity of CD patients will require some knowledge on the intrinsic functional status of autophagy. Here, we focused on monocyte-derived dendritic cells (DCs) to characterize the intrinsic quantitative features of the autophagy flux. Starting with DCs from healthy donors, we documented a reprogramming of the steady state flux during the transition from the immature to mature status: both the autophagosome pool size and the flux were diminished at the mature stage while the autophagosome turnover remained stable. At the cohort level, DCs from CD patients were comparable to control in term of autophagy flux reprogramming capacity. However, the homozygous presence of ATG16L1 rs2241880 A>G (T300A) and ULK1 rs12303764 (G/T) polymorphisms abolished the capacity of CD patient DCs to reprogram their autophagy flux during maturation. This effect was not seen in the case of CD patients heterozygous for these polymorphisms, revealing a gene dose dependency effect. In contrast, the NOD2 rs2066844 c.2104C>T (R702W) polymorphism did not alter the flux reprogramming capacity of DCs. The data, opening new clinical translation perspectives, indicate that polymorphisms affecting autophagy-related genes can differentially influence the capacity of DCs to reprogram their steady state autophagy flux when exposed to proinflammatory challenges.Abbreviation: BAFA1: bafilomycin A1, CD: Crohn disease; DC: dendritic cells; HD: healthy donor; iDCs: immature DCs; IL: interleukin; J: autophagosome flux; LPS: lipopolysaccharide; MHC: major histocompatibility complex; nA: autophagosome pool size; SNPs: single-nucleotide polymorphisms; PCA: principal component analysis; TLR: toll like receptor; τ: transition time; TNF: tumor necrosis factor.

Data on the real long-term influences of in utero drug exposure in pregnant women on childhood development are scarce and remain not well determined and depend on the duration of in utero drug exposure and maternal drug levels. Therapeutic drug monitoring (TDM) during pregnancy may help limit fetal drug exposure while maintaining an effective dose for the treatment of the underlying inflammatory bowel disease (IBD) in women. Most antibody therapies used in patients with IBD are IgG molecules which are actively transported across the placenta, especially during the third trimester of the pregnancy. Here, we propose an up-to-date clinical review to summarize the available findings of serum drug levels in maternal blood during pregnancy, in the cord blood, infants at delivery and in breast milk of patients with IBD treated with biologics. Conversely, in comparison to adalimumab (ADA) levels, which are relatively stable during pregnancy, infliximab (IFX) drug clearance decreased significantly during the last two trimesters of the pregnancy, leading to increasing drug concentrations in the blood of the pregnant women. As most guidelines recommend using live vaccines in infants at the age of one or earlier in case of negative serum drug levels in newborns, statistical models could help clinicians in making a decision to adjust the last dose of the biologic during pregnancy and to determine the optimal date to vaccinate. Altogether, data from the literature offers strong reassurance in terms of safety for anti-TNFα therapies during pregnancy not only for IBD patients who intend to conceive, but also for pregnant women and for the physicians taking care of these patients. ADA and IFX levels in breast milk are detectable, but at very low levels, and therefore, it is recommended to pursue breast feeding under anti-TNFα therapy. Our knowledge on ustekinumab or vedolizumab levels in pregnant women remains unclear and scarce. These drugs are currently not recommended for patients with IBD in clinical practice. Therefore, TDM and proactive dose adjustment are not necessary during pregnancy since its impact on making a clinical decision have not yet been clearly demonstrated in routine practice. Overall, drug concentrations in the cord blood, an infant at birth and postpartum serum concentrations in infants, due to active placental drug transfer, may have a greater impact than the limited drug transfer in breast milk during lactation on the risk of infection and developmental outcomes. Ustekinumab and vedolizumab exposure during pregnancy and lactation are both considered low risk by the recent ECCO guidelines despite the limited data that are currently available.

Les indications des inhibiteurs de checkpoint immunitaires (ICI) se multiplient et concernent de nombreux cancers. Les ICI peuvent entraîner des effets indésirables immuno-induits (irAEs) parfois sévères (grade ≥ 3). Les algorithmes de prise en charge recommandent alors l’arrêt définitif de l’ICI et les données de rechallenge après toxicité excluent les grades 4 et les atteintes neurologiques. Notre objectif était d’évaluer la sécurité du rechallenge d’ICI après irAE sévère, en incluant des atteintes neurologiques. Les données de notre RCP immunoTOX ont été recueillies entre décembre 2019 et décembre 2021. Les critères d’inclusion étaient : tout cancer traité par ICI seul, irAE sévère (grade 3 ou 4) et accord de la RCP pour le rechallenge. Les caractéristiques et prise en charge des patients et de leurs toxicités initiales ainsi que l’évolution après rechallenge étaient recensées. Les 15 patients inclus étaient traités par anti-PD-1/anti-PD-L1 (n = 9), par anti-PD1 et anti-CTLA4 (n = 6), 14 d’entre eux pour un mélanome. L’ICI a été interrompu chez tous les patients pour un irAE de grade 3, dont 5 toxicités neurologiques (méningite aseptique, polyradiculonévrite et anomalie de la jonction neuromusculaire), traité par corticothérapie systémique dans 13/15 cas. Les autres thérapeutiques étaient : immunoglobulines polyvalentes (n = 2), méthotrexate (n = 2), anti-TNF (n = 1), hydroxychloroquine (n = 1), antibiothérapie (n = 3) et dermocorticoïdes d’activité très forte (n = 2). Au moment du rechallenge, tous les patients étaient en grade 0 ou 1 et 7 avaient une immunosuppression (corticoïdes > 20 mg/j et/ou immunosuppresseur). Le rechallenge a été réalisé par anti-PD-1 après association anti-PD1-anti-CTLA4 (n = 6), par un autre anti-PD-1 (n = 5), par le même anti-PD-1 (n = 3) et par association anti-PD1-anti-CTLA4 après anti-PD-1 (n = 1). Après rechallenge, le même irAE a récidivé chez 2/15 patients (méningite aseptique grade 3 et pneumopathie interstitielle grade 2) combiné à un nouvel et différent irAE (pneumopathie interstitielle et dermatose lichénoïde grade 1-2). Deux autres patients ont présenté un nouvel et différent irAE (thrombopénie et dermatose lichénoïde grade 1-2). Au total, 11 patients (73,4 %) n’ont pas présenté de récidive ou de nouvel irAE après rechallenge de l’ICI. Un seul des 5 patients avec irAE neurologique a récidivé de cette toxicité après rechallenge réalisé par double immunothérapie et malgré une forte dose de corticoïdes. Cette dernière a possiblement masqué une toxicité non résolutive. Le rechallenge de l’ICI après toxicité sévère nécessite d’être validé par une équipe multidisciplinaire experte de l’ICI et de ses toxicités. Il n’existe pas actuellement de facteur prédictif de récidive des IrAEs. En cas de balance bénéfice–risque favorable, nous suggérons de discuter un rechallenge si l’irAE est revenu en grade 0 ou 1, avec une corticosensibilité initiale, sevrage ou faible posologie de corticothérapie lors du rechallenge et sous surveillance rapprochée.

Cross-sectional magnetic resonance enterography (MRE) and intestinal ultrasonography (IUS) provide valuable and noninvasive information to accurately assess disease activity, severity, and extent; detect complications; and monitor the response to treatment, as well as predict the postoperative recurrence of Crohn's disease and a negative disease course. Therefore, both imaging modalities are emerging as pivotal diagnostic tools to achieve the emerging therapeutic target of transmural healing associated with better disease outcomes. Despite its numerous potential advantages over endoscopy and even MRE and its good availability, IUS is still widely underused to monitor and manage inflammatory bowel disease (IBD) patients and help in making clinical decisions in routine practice. This situation is clearly due to the absence of validated, reliable, and responsive indices, as well as the lack of trained gastroenterologists and radiologists, as IUS is a component of radiologist expertise in several countries but not yet integrated into the training program of gastroenterologists. However, there is an increasing body of evidence in the literature that IUS and MRE are both becoming essential imaging resources to help clinicians in making reliable decisions. Here, we discuss the up-to-date evidence about the usefulness and performance of cross-sectional imaging, focusing on the ability of bowel US and MRE to aid clinical decision-making for the optimal management and monitoring of IBD.

Abstract Background The prevalence of nonadherence to major treatments and the subsequent adverse outcomes in IBD patients during the first wave of COVID-19 pandemic remain scarce. Aim to investigate the risk of early disease relapse in a cohort of IBD patients under immunosuppressants and/or biologics who decided themselves to discontinue their IBD-related major treatments without previous medical advice during the first wave of COVID-19 pandemic. Methods All consecutive patients with inactive IBD under immunosuppressants and/or biologics who acknowledged having withdrawn their major therapy for IBD without previous medical advice during the first wave of COVID-19 (from March 2020 to December 2020) were enrolled. The primary endpoint was the survival rate without disease relapse. Kaplan-Meier curves were plotted for time from inclusion to IBD relapse and a logistic regression model with uni- and multivariate analyses was performed to identify predictors of relapse after drug discontinuation. Results During the study period, among the 862 IBD patients followed as outpatients either treated with infliximab or vedolizumab (outpatient clinics n= 368) or treated with oral azathioprine, adalimumab, golimumab or ustekinumab alone or in combination (n= 494), 54 patients (6.2 %) (42 CD, 12 UC, 28 F, median age 36 years) who had discontinued themselves their IBD-related major therapy without previous medical advice were included. The median duration of drug withdrawal was 7.0 weeks (range 2-24) and the median time to relapse was 9.0 weeks (range 4-20). The most treatments withdrawn were adalimumab (n=19), ustekinumab (n=19), azathioprine (n= 12), golimumab (n=1) and a lesser degree infliximab (n=7) eand vedolizumab (n=6). During the median follow-up period of 24 weeks (range 5-42), 22 out of 54 patients (40.7 %) who discontinued their IBD treatment experienced a relapse in whom 6 requiring administration of oral steroids, 4 hospitalization and 2 IBD-related surgery. By univariate analysis, past IBD related surgery was identified as the only predictor of disease relapse after drug withdrawal (OR=3.3 CI 95 % [1.08-10.38]. Conclusion In IBD patients, major treatment discontinuation by the patients themselves without medical advices during the first wave of pandemic Covid-19 including the lockdown was associated with a substantial risk of disease relapse occurring in around 4 out of 10 patients and subsequent further risk of need for steroids, hospitalization and surgery. Strategies targeting the adherence to therapy and patient’s informations about the real risks leading to drug discontinuation are of paramount interest, especially during health crisis to minimize such issues.

Autophagy receptor NDP52 triggers bacterial autophagy against infection. However, the ability of NDP52 to protect against viral infection has not been established. We show that NDP52 binds to envelope proteins of hepatitis B virus (HBV) and triggers a degradation process that promotes HBV clearance. Inactivating NDP52 in hepatocytes results in decreased targeting of viral envelopes in the lysosome and increased levels of viral replication. NDP52 inhibits HBV at both viral entry and late replication stages. In contrast to NDP52-mediated bacterial autophagy, lysosomal degradation of HBV envelopes is independent of galectin 8 and ATG5. NDP52 forms complex with Rab9 and viral envelope proteins and links HBV to Rab9-dependent lysosomal degradation pathway. These findings reveal that NDP52 acts as a sensor for HBV infection, which mediates a unique antiviral response to eliminate the virus. This work also suggests direct roles for autophagy receptors in other lysosomal degradation pathways than canonical autophagy.

La mucormycose est la 4ème infection fongique invasive en France. La mortalité globale est lourde, autour de 50 à 60%, malgré des améliorations diagnostiques et thérapeutiques récentes. Le pronostic est conditionné par l'instauration rapide d'un antifongique efficace nécessitant un diagnostic précoce. Bien qu'encore non intégrée dans les critères EORTC/MSGERC, la PCR Mucorales sérique a montré d'excellentes performances diagnostiques. Compte tenu du portage possible dans les voies aériennes, son exactitude diagnostique dans les prélèvements respiratoires profonds doit être évaluée, et ce en fonction des populations à risque. L'objectif était donc d'estimer les performances de la PCR Mucorales dans les prélèvements respiratoires profonds. Cette étude rétrospective a inclus tous les patients de plus 18 ans ayant bénéficié d'un prélèvement respiratoire profond avec PCR Mucorales entre Janvier 2021 et Mai 2022. Le diagnostic de mucormycose était porté après analyse du dossier clinico-biologique par un comité d'adjudication (technique de référence), à partir des données PMSI, de la base du système d'information hospitalier, de la base pharmacologique puis classé selon les critères EORTC/MSGERC 2019. La PCR Mucorales à l'étude était le kit multiplex de PCR MycoGENIE® (Ademtech, France). Les critères d'hôte ont été recueillis pour chaque patient à partir des données du PMSI. Les statistiques ont été réalisées avec EpiInfo. De Janvier 2021 et mai 2022, le diagnostic de mucormycose a été suspecté pour 26 patients et confirmé pour 11. Pendant cette période, 942 patients ont bénéficié d'une PCR Mucorales dans les prélèvements respiratoires profonds. Cette dernière était positive pour 21/942 patients (2.2%). A noter que 4 patients avaient une PCR Mucorales positive dans le sérum mais négative dans le LBA parmi lesquels 3 avaient un diagnostic de mucormycose pulmonaire. Parmi les cas avérés (n=11), 2 (18.2%) étaient des mucormycoses prouvées, 2 (18.2%) probables, 7 possibles (63.6%) selon les critères EORTC/MSGERC 2019. L'âge médian des patients était de 57ans. Le principal critère d'hôte était une hémopathie maligne pour 10/11 (90,9%) dont 2 allogreffés. La PCR sang était positive dans 72,7% des cas (n = 8). Le Ct moyen était respectivement de 32,2 dans le sérum et 34,3 dans les prélèvements respiratoires. Trois patients avaient une PCR positive dans le LBA mais négative dans le sang. Les espèces ont été identifiées par séquençage pour 8 patients (72,7%) et par culture pour 2 (18,3%). La taux mortalité à J90 était de 45.5%. La sensibilité de la PCR Mucorales a été estimée à 72.7 % (IC95 43.4 – 90.3) et la spécificité à 98.6% (IC95 97.6 – 99.2%). La VPP était de 38.1 % (IC95 20.8 – 59.1%) et la VPN de 99.7% (IC95 99.1 – 99.9%). L'intérêt de la PCR Mucorales dans les prélèvements respiratoires profonds a été confirmé dans cette étude. La faible VPP confirme qu'un résultat positif doit être interprété avec prudence compte tenu d'un portage possible de Mucorales dans les voies aériennes. Cependant, sa VPN et sa spécificité élevées en font un outil pertinent dans la stratégie diagnostique des mucormycoses pulmonaires. Aucun lien d'intérêt