Enhanced Pathogenesis Caused by Influenza D Virus and Mycoplasma bovis Coinfection in Calves: a Disease Severity Linked with Overexpression of IFN-gamma as a Key Player of the Enhanced Innate Immune Response in Lungs

Bovine respiratory disease (BRD) is a major disease of young cattle whose etiology lies in complex interactions between pathogens and environmental and host factors. Despite a high frequency of codetection of respiratory pathogens in BRD, data on the molecular mechanisms and pathogenesis associated with viral and bacterial interactions are still limited. In this study, we investigated the effects of a coinfection with influenza D virus (IDV) and Mycoplasma bovis in cattle. Naive calves were infected by aerosol with a French IDV strain and an M. bovis strain. The combined infection shortened the incubation period, worsened the disease, and led to more severe macroscopic and microscopic lesions compared to these parameters in calves infected with only one pathogen. In addition, IDV promoted colonization of the lower respiratory tract (LRT) by M. bovis and increased white cell recruitment to the airway lumen. The transcriptomic analysis highlighted an upregulation of immune genes in the lungs of coinfected calves. The gamma interferon (IFN-gamma) gene was shown to be the gene most statistically overexpressed after coinfection at 2 days postinfection (dpi) and at least until 7 dpi, which correlated with the high level of lymphocytes in the LRT. Downregulation of the PACE4 and TMPRSS2 endoprotease genes was also highlighted, being a possible reason for the faster clearance of IDV in the lungs of coinfected animals. Taken together, our coinfection model with two respiratory pathogens that when present alone induce moderate clinical signs of disease was shown to increase the severity of the disease in young cattle and a strong transcriptomic innate immune response in the LRT, especially for IFN-gamma.IMPORTANCE Bovine respiratory disease (BRD) is among the most prevalent diseases in young cattle. BRD is due to complex interactions between viruses and/or bacteria, most of which have a moderate individual pathogenicity. In this study, we showed that coinfection with influenza D virus (IDV) and Mycoplasma bovis increased the severity of the respiratory disease in calves in comparison with IDV or M. bovis infection. IDV promoted M. bovis colonization of the lower respiratory tract and increased white cell recruitment to the airway lumen. The transcriptomic analysis highlighted an upregulation of immune genes in the lungs of coinfected calves. The IFN-gamma gene in particular was highly overexpressed after coinfection, correlated with the disease severity, immune response, and white cell recruitment in the lungs. In conclusion, we showed that IDV facilitates coinfections within the BRD complex by modulating the local innate immune response, providing new insights into the mechanisms involved in severe respiratory diseases

The role of type I interferons (IFNs) in the regulation of chicken macrophage inflammatory response to bacterial challenge

International audienceMammalian type I interferons (IFNα/β) are known to modulate inflammatory processes in addition to their antiviral properties. Indeed, virus-induced type I interferons regulate the mammalian phagocyte immune response to bacteria during superinfections. However, it remains unresolved whether type I IFNs similarly impact the chicken macrophage immune response. We first evidenced that IFNα and IFNβ act differently in terms of gene expression stimulation and activation of intracellular signaling pathways in chicken macrophages. Next, we showed that priming of chicken macrophages with IFNα increased bacteria uptake, boosted bacterial-induced ROS/NO production and led to an increased transcriptional expression or production of NOS2/NO, IL1B/IL-1β and notably IFNB/IFNβ. Neutralization of IFNβ during bacterial challenge limited IFNα-induced augmentation of the pro-inflammatory response. In conclusion, we demonstrated that type I IFNs differently regulate chicken macrophage functions and drive a pro-inflammatory response to bacterial challenge. These findings shed light on the diverse functions of type I IFNs in chicken macrophages

Overview of the current use of levosimendan in France: a prospective observational cohort study

Abstract Background Following the results of randomized controlled trials on levosimendan, French health authorities requested an update of the current use and side-effects of this medication on a national scale. Method The France-LEVO registry was a prospective observational cohort study reflecting the indications, dosing regimens, and side-effects of levosimendan, as well as patient outcomes over a year. Results The patients included ( n = 602) represented 29.6% of the national yearly use of levosimendan in France. They were treated for cardiogenic shock ( n = 250, 41.5%), decompensated heart failure ( n = 127, 21.1%), cardiac surgery-related low cardiac output prophylaxis and/or treatment ( n = 86, 14.3%), and weaning from veno-arterial extracorporeal membrane oxygenation ( n = 82, 13.6%). They received 0.18 ± 0.07 µg/kg/min levosimendan over 26 ± 8 h. An initial bolus was administered in 45 patients (7.5%), 103 (17.1%) received repeated infusions, and 461 (76.6%) received inotropes and or vasoactive agents concomitantly. Hypotension was reported in 218 patients (36.2%), atrial fibrillation in 85 (14.1%), and serious adverse events in 17 (2.8%). 136 patients (22.6%) died in hospital, and 26 (4.3%) during the 90-day follow-up. Conclusions We observed that levosimendan was used in accordance with recent recommendations by French physicians. Hypotension and atrial fibrillation remained the most frequent side-effects, while serious adverse event potentially attributable to levosimendan were infrequent. The results suggest that this medication was safe and potentially associated with some benefit in the population studied

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Study of innate immune response induced by avian influenza viruses in chicken lung epithelial cells and chicken endothelial cells

Les virus influenza aviaires faiblement pathogènes (IAFP) ciblent principalement les épithéliums des voies respiratoires et intestinales chez les poulets (Gallus gallus) infectés. Cependant, les virus influenza aviaires hautement pathogènes (IAHP) mènent à une maladie systémique fatale avec une localisation particulière aux endothéliums. L’objectif de cette thèse a été d’explorer les relations entre la réplication des virus influenza aviaires (IA) et la réponse antivirale de l’hôte dans deux modèles cellulaires originaux obtenus chez le poulet : des cellules épithéliales pulmonaires (CLEC213) et des cellules endothéliales d’aortes (chAEC). Les résultats clés sont les suivants : (i) la réplication productive des virus IA dans les chAEC dépend du clivage de l’hémagglutinine et de l’échappement viral à la réponse immunitaire innée ; (ii) les CLEC213 sont très permissives aux virus IA et présentent une faible réponse antivirale médiée par la signalisation TLR3 et MDA5 ; (iii) les fonctions régulatrices de SOCS1 et SOCS3, sur le signal des interférons et des cytokines, sont conservées chez le poulet. Nous proposons que certains virus IA peuvent exploiter les fonctions pro-virales de SOCS1 et SOCS3 à leur avantage de manière spécifique au type cellulaire.Low pathogenic avian influenza (LPAI) viruses essentially target the epithelia of the respiratory and intestinal tract in the infected chicken host (Gallus gallus). However, highly pathogenic avian influenza (HPAI) viruses induce a peracute fatal systemic disease and exhibit a striking endothelial cell tropism. The objective of the present thesis was to explore the interdependencies of AI virus replication and the antiviral host response in two novel avian cell culture models: chicken lung epithelial cells (CLEC213) and chicken aortic endothelial cells (chAEC). The salient findings from this study are that (i) productive AI virus replication in chAEC is dependent on hemagglutinin cleavability and appears to be related to innate immune escape; (ii) CLEC213 are highly permissive to AI virus infection, due to a cell type-specific diminished TLR3- and/or MDA5-mediated antiviral signaling response; (iii) the interferon and cytokine regulatory functions of SOCS1 and SOCS3 are conserved in the chicken. Based on our data, we propose a model that predicts that certain AI viruses may exploit the proviral functions of SOCS1 and SOCS3 in a cell type-specific manner

Susceptibility and permissiveness of chicken endothelial cells to avian influenza virus infections

National audienc

Interferon regulatory functions of chicken suppressor of cytokine signaling proteins 1 (chSOCS1) and 3 (chSOCS3) and their exploitation by avian influenza viruses

National audienc

Samovar: An evaluation framework for real time applications deployment over WSANs

Wireless Sensor and Actuator Networks (WSANs) combine sensors and actuators interconnected by wireless networks in order to perform distributed sensing and acting tasks. Closed-loop controllers can therefore be deployed on WSANs; such systems have to meet specific requirements in terms of performance, dependability, energy and cost which raises great challenges due to the unreliability of wireless communications. A way to ensure that a system meets the required properties is to model it and go through its analysis. Building a model requires both deep knowledge on the system as well as on the used framework. Therefore there is a need for frameworks well-suited to the targeted systems and to the properties to verify. We propose an approach meeting these conditions and a simulation framework, Samovar, based on Matlab / Simulink, allowing the modeling of the network protocols (Mac and routing services) and the resources sharing policy thanks to the TrueTime toolbox. Several classes of components (application, nodes, networks and middleware) and a clear semantics for their composition are identified. Furthermore, the design of Samovar was also driven by the need to transfer easily software components model between the concrete systems and its simulated model. The modeling and simulation method as well as the Samovar framework are illustrated on a Pursuit Evasion Game.