Editorial: Nucleic Acid-Associated Inflammation.

Editorial on the Research Topic Nucleic Acid-Associated Inflammation

Genetic Resistance to Rhabdovirus Infection in Teleost Fish Is Paralleled to the Derived Cell Resistance Status

Genetic factors of resistance and predisposition to viral diseases explain a significant part of the clinical variability observed within host populations. Predisposition to viral diseases has been associated to MHC haplotypes and T cell immunity, but a growing repertoire of innate/intrinsic factors are implicated in the genetic determinism of the host susceptibility to viruses. In a long-term study of the genetics of host resistance to fish rhabdoviruses, we produced a collection of double-haploid rainbow trout clones showing a wide range of susceptibility to Viral Hemorrhagic Septicemia Virus (VHSV) waterborne infection. The susceptibility of fibroblastic cell lines derived from these clonal fish was fully consistent with the susceptibility of the parental fish clones. The mechanisms determining the host resistance therefore did not associate with specific host immunity, but rather with innate or intrinsic factors. One cell line was resistant to rhabdovirus infection due to the combination of an early interferon IFN induction - that was not observed in the susceptible cells - and of yet unknown factors that hamper the first steps of the viral cycle. The implication of IFN was well consistent with the wide range of resistance of this genetic background to VSHV and IHNV, to the birnavirus IPNV and the orthomyxovirus ISAV. Another cell line was even more refractory to the VHSV infection through different antiviral mechanisms. This collection of clonal fish and isogenic cell lines provides an interesting model to analyze the relative contribution of antiviral pathways to the resistance to different viruses

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Études des propriétés de reformage de catalyseurs à base de cérium (analyse des sites actifs et des mécanismes de réaction)

CAEN-BU Sciences et STAPS (141182103) / SudocSudocFranceF

Cyclic Guanosine Monophosphate–Adenosine Monophosphate Synthase (cGAS), a Multifaceted Platform of Intracellular DNA Sensing

International audienceInnate immune pathways are the first line of cellular defense against pathogen infections ranging from bacteria to Metazoa. These pathways are activated following the recognition of pathogen associated molecular patterns (PAMPs) by membrane and cytosolic pattern recognition receptors. In addition, some of these cellular sensors can also recognize endogenous danger-associated molecular patterns (DAMPs) arising from damaged or dying cells and triggering innate immune responses. Among the cytosolic nucleic acid sensors, the cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) synthase (cGAS) plays an essential role in the activation of the type I interferon (IFNs) response and the production of pro-inflammatory cytokines. Indeed, upon nucleic acid binding, cGAS synthesizes cGAMP, a second messenger mediating the activation of the STING signaling pathway. The functional conservation of the cGAS-STING pathway during evolution highlights its importance in host cellular surveillance against pathogen infections. Apart from their functions in immunity, cGAS and STING also play major roles in nuclear functions and tumor development. Therefore, cGAS-STING is now considered as an attractive target to identify novel biomarkers and design therapeutics for auto-inflammatory and autoimmune disorders as well as infectious diseases and cancer. Here, we review the current knowledge about the structure of cGAS and the evolution from bacteria to Metazoa and present its main functions in defense against pathogens and cancer, in connection with STING. The advantages and limitations of in vivo models relevant for studying the cGAS-STING pathway will be discussed for the notion of species specificity and in the context of their integration into therapeutic screening assays targeting cGAG and/or STING

Early antiviral response and virus-induced genes in fish

Chantier qualité GAIn fish as in mammals, virus infections induce changes in the expression of many host genes. Studies conducted during the last fifteen years revealed a major contribution of the interferon system in fish antiviral response. This review describes the screening methods applied to compare the impact of virus infections on the transcriptome in different fish species. These approaches identified a "core" set of genes that are strongly induced in most viral infections. The "core" interferon-induced genes (ISGs) are generally conserved in vertebrates, some of them inhibiting a wide range of viruses in mammals. A selection of ISGs - PKR, vig-1/viperin, Mx, ISG15 and finTRIMs - is further analyzed here to illustrate the diversity and complexity of the mechanisms involved in establishing an antiviral state. Most of the ISG-based pathways remain to be directly determined in fish. Fish ISGs are often duplicated and the functional specialization of multigenic families will be of particular interest for future studies

Impact du déploiement de variétés de Nicotiana tabacum portant le gène récessif de résistance va sur la virulence de populations du virus Y de la pomme de terre

L identification des causes et des conséquences de la diversification de populations virales permet de déterminer l impact de différents filtres sélectifs sur leur évolution. Différents allèles du gène récessif de résistance va, qui constitue la source de résistance la plus utilisée au niveau mondial pour contrôler les épidémies du virus Y de la pomme de terre (PVY, Potyvirus) en cultures de tabac, ont été introgressés dans le fond génétique de plusieurs variétés de tabac sans informations précises sur leur impact dans le processus évolutif du PVY. L objectif de ce travail de thèse est de déterminer l impact de la pression de sélection imposée par le gène va sur la structure et l évolution de populations virales de PVY. Pour cela, la diversité de caractéristiques biologiques et sérologiques d isolats viraux de PVY collectés au sein de deux environnements culturaux contrastés (France et Brésil) a été analysée. Les populations virales collectées en France sont caractérisées par une forte fréquence d isolats virulents et par une hétérogénéité de la distribution des différents pathotypes au sein de variétés de tabac sensibles et résistantes. La structure de populations virales collectées au Brésil est similaire à celle décrite en France, suggérant que l émergence de variants virulents sous la pression de sélection imposée par le gène va n est pas influencée par des paramètres environnementaux. Le suivi du processus évolutif d isolats viraux de PVY inoculés en conditions contrôlées au sein de plantes de lignées quasi-isogéniques sauf au locus du gène va a permis de montrer qu un cycle d infection sur des plantes portant l allèle 2 du gène va génère des populations virales adaptées, dont la virulence vis-à-vis des deux allèles 0 et 2 est plus élevée que celle des isolats viraux initiaux. Enfin, l acquisition de la virulence vis-à-vis de l allèle 2 du gène va est associée à l apparition d une mutation ponctuelle dans la partie centrale de la séquence codant pour la protéine VPg. Les conséquences possibles de l adaptation du PVY au gène va sur l interaction entre ce virus et différents partenaires du pathosystème sont discutées dans le cadre du développement d une stratégie durable d utilisation de cette source de résistance et d une compréhension globale de l épidémiologie du PVY.The analysis of the causes and consequences of the diversification of viral populations reveals the impact of different selective pressures on their evolution. Different alleles of the recessive resistance gene va, which constitutes the most commonly used genetic resistance source worldwide to control Potato virus Y (PVY, Potyvirus) epidemics in tobacco crops, have been introduced into tobacco cultivars without precise information on their impact on PVY evolution. The objective of this research program was to analyse the impact of the selective pressure imposed by the va gene on the structure and evolution of PVY populations. Thus, the diversity of biological and serological properties of PVY isolates collected in two contrasting environments (France and Brazil) was analyzed. Viral populations collected in France were characterized by a high frequency of virulent isolates and by a heterogeneous distribution of pathotypes in susceptible and resistant tobacco cultivars. The structure of PVY populations collected in Brazil and in France was similar, suggesting that the emergence of virulent isolates under the va selection pressure did not depend on environmental parameters. The evolutionary process of PVY isolates inoculated in controlled conditions to quasi-isogenic tobacco plants for the allele 0 and 2 of the va gene was monitored. A single passage on plants carrying the allele 2 of the va gene led to the selection of virulent viral populations, able to overcome both the allele 0 and 2 of the va gene. The acquisition of the capacity to overcome the allele 2 of the va gene was associated with a single point mutation in the central part of the sequence of the VPg protein. The possible consequences of the adaptation process of PVY to the va gene for the interaction between this virus and different vector agents and hosts are discussed in the context of the development of a durable strategy to use the different va alleles and of a global understanding of PVY epidemiology.RENNES-Agrocampus-CRD (352382323) / SudocSudocFranceF

Effect of passage of a Potato virus Y isolate on a line of tobacco containing the recessive resistance gene va(2) on the development of isolates capable of overcoming alleles 0 and 2

International audienceControl strategies developed for plant viral diseases through breeding programs can be impaired by adaptive response of pathogens. A few years after the deployment in France of improved tobacco genotypes introgressed with alleles of the Potato virus Y (PVY) recessive resistance gene va, necrotic symptoms associated with PVY infection have been reported on these cultivars. Due to the lack of efficient alternative methods to control PVY, the va resistance sources have to be managed according to viral parameters, such as the dynamic of emergence of virulent variants. The effects of va alleles on the evolution of PVY was tested in experimental conditions using a PVY infectious clone and two couples of resistant tobacco near isogenic lines BVA/Bva (0) and FVA/Fva (2) both allelic for the va gene. Infection efficiencies data showed that a single passage on Fva (2) line led to the selection of virulent viral populations able to overcome both va (0) and va (2) alleles. Sequence analyses of va (2) derived PVY variants revealed that the acquisition of the capacity to overcome va (2) resistance is associated with single point mutations at two different nucleotide positions in the central part of the VPg. The described PVY adaptation process to overcome resistance mediated by different va alleles should be considered for the future development of durable and integrated strategies of management of PVY infections in tobacco crops

Analyse génétique de la résistance aux rhabdovirus chez la truite arc-en-ciel (Oncorhynchus mykiss)

DOI ne fonctionne pas. Chantier qualité GALa truite arc-en-ciel ( Oncorhynchus mykiss) est une espèce d'intérêt aquacole majeur en Europe et notamment en France. Le système immunitaire de cette espèce est également l'un des mieux connus au sein des poissons téléostéens. Différentes maladies virales affectent la truite arc-en-ciel, en particulier deux rhabdoviroses, causées par le virus de la septicémie hémorragique virale (VSHV) et par le virus de la nécrose hématopoïétique infectieuse (VNHI), qui sont à l'origine de pertes importantes dans les élevages. Une variabilité significative de la résistance naturelle à ces infections a été décrite chez la truite arc-en-ciel, entre et au sein des populations. L'étude de cette variabilité génétique est à la fois pertinente pour améliorer les approches de sélection d'individus naturellement résistants à ces virus, et pour progresser dans la dissection des mécanismes sous-jacents. Les méthodes employées, et les premiers résultats de l'analyse des bases génétiques de la résistance de la truite arc-en-ciel à la septicémie hémorragique virale sont présentés ici, de l'identification d'un QTL majeur à l'étude du rôle des interférons