Cellular immune responses in porcine reproductive and respiratory syndrome virus (PRRSV) vaccinated weaned piglets challenged with a virulent strain of PRRSV

The porcine reproductive and respiratory syndrome (PRRS) is an important viral infection of swine that can persist in lymphoid organs of infected pigs despite the induction of specific immune responses, suggesting an immune evasion mechanism. Vaccination has been shown to prevent climcal signs but remains ineffective against viral persistence. Our objective was to investigate the immunological disorders related to vaccination and subsequent challenge by a virulent strain. Groups of piglets were vaccmated with RespPRRS vaccine (Boehringer-lngelheim) and challenged 4 weeks later with the virulent LHVA-93-3 strain of the PRRS virus

Pathogenic Mouse Hepatitis Virus or Poly(I:C) Induce IL-33 in Hepatocytes in Murine Models of Hepatitis.

International audienceThe IL-33/ST2 axis is known to be involved in liver pathologies. Although, the IL-33 levels increased in sera of viral hepatitis patients in human, the cellular sources of IL-33 in viral hepatitis remained obscure. Therefore, we aimed to investigate the expression of IL-33 in murine fulminant hepatitis induced by a Toll like receptor (TLR3) viral mimetic, poly(I:C) or by pathogenic mouse hepatitis virus (L2-MHV3). The administration of poly(I:C) plus D-galactosamine (D-GalN) in mice led to acute liver injury associated with the induction of IL-33 expression in liver sinusoidal endothelial cells (LSEC) and vascular endothelial cells (VEC), while the administration of poly(I:C) alone led to hepatocyte specific IL-33 expression in addition to vascular IL-33 expression. The hepatocyte-specific IL-33 expression was down-regulated in NK-depleted poly(I:C) treated mice suggesting a partial regulation of IL-33 by NK cells. The CD1d KO (NKT deficient) mice showed hepatoprotection against poly(I:C)-induced hepatitis in association with increased number of IL-33 expressing hepatocytes in CD1d KO mice than WT controls. These results suggest that hepatocyte-specific IL-33 expression in poly(I:C) induced liver injury was partially dependent of NK cells and with limited role of NKT cells. In parallel, the L2-MHV3 infection in mice induced fulminant hepatitis associated with up-regulated IL-33 expression as well as pro-inflammatory cytokine microenvironment in liver. The LSEC and VEC expressed inducible expression of IL-33 following L2-MHV3 infection but the hepatocyte-specific IL-33 expression was only evident between 24 to 32h of post infection. In conclusion, the alarmin cytokine IL-33 was over-expressed during fulminant hepatitis in mice with LSEC, VEC and hepatocytes as potential sources of IL-33

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

Persistent in Vitro Infection with Mouse Hepatitis Virus Type 3

Various mouse strains display different types of sensitivity to mouse hepatitis virus type 3 (MHV3) infection: resistance, full susceptibility (acute hepatitis leading to death), and semi-susceptibility characterized by occurrence of paralysis and viral persistence. In order to study the mechanisms of viral persistency, persistent infections were established -in -vitro in mouse lymphoid cell line cultures and were characterized in terms of virus production, occurrence of cytoplasmic viral antigens and cell lysis. Cell cloning and antibody treatment experiments showed that viral transmission was horizontal and not vertical. These data indicated that persistent infections induced by MHV 3 in lymphoid cell lines were characterized by a viral "carrier state" where production of infectious viral particles remained in equilibrium with cell permissivity. Biological and biochemical properties of MHV 3 variants derived from persistently infected YAC lymphoid cells were characterized. Similar heterogeneous thermosensitive properties were observed when YAC-derived cloned substrains (YAC-MHV 3) were compared to parental-derived cloned viruses, indicating that no selection of temperature- sensitive mutants was induced in persistently infected YAC cells. […]Le virus de l'hépatite murine de type 3 (MHV 3) se comporte selon différents modes évolutifs en fonction de la lignée des souris: soit une résistance à la maladie, soit une susceptibilité (hépatite aigue mortelle) soit une semi-susceptibilité caractérisée par le développement de paralysie et une persistance du virus dans l'organisme. Afin d'étudier les mécanismes impliqués dans la virose persistante, des infections persistantes, ont été induites dans des cultures de cellules lymphoïdes murines en lignée continue. L'infection persistante a été caractérisée par la production de virus, la présence d'antigènes viraux cellulaires et la lyse cellulaire. Le clonage cellulaire et le traitement des infections persistantes a l'aide d'anticorps spécifiques ont démontré que la transmission de l'infection se faisait par voie horizontale et non verticale au sein de la population cellulaire. Ces résultats indiquent que la virose persistante induite par le MHV 3 dans des cellules lymphoïdes en lignée continue est maintenue par une infection de type "porteur" ou la production de particules virales infectieuses se maintient en équilibre avec la permissivité des cellules. Les propriétés biologiques et biochimiques des virus variants provenant d'une infection persistante dans des cellules lymphoïdes YAC ont été analysées. Une hétérogénéité dans la propriété de thermosensibilité a été observée autant chez les virus clones provenant de cellules Y AC que ceux de la culture parentale. Ce résultat indique qu'aucune sélection de virus mutants thermosensibles n'est induite lors d'une virose persistante sur cellules lymphoïdes YAC. […

L’évaluation de l’éthique médicale des résidents

Contexte : L'évaluation est réputée représenter la prochaine étape pédagogique à franchir pour l'éducation en éthique médicale. But : Élaborer une stratégie d'évaluation de l'éthique médicale des résidents cohérente avec leur apprentissage. Modèle : L'approche dialogique de l'éthique comme compétence clinique fournit un modèle intégrateur pour évaluer l'éthique professionnelle des résidents durant leur formation : la sensibilité éthique identifie les enjeux en présence ; la délibération précise le noeud du dilemme entre deux valeurs en conflit ; l'action témoigne de la décision dans le contexte ; le dialogue révèle les raisons d'agir dans une argumentation convaincante dans les circonstances ; l'environnement donne le contexte et les circonstances qui colorent le cas précis du dilemme et influencent le comportement professionnel adopté. Application et exemple : Compétence complexe, transversale, dialogique se construisant tout au long de la formation clinique, l'éthique s'intègre à la formation clinique dans l'exemple fourni. Son évaluation doit être interactive, de médiation humaine, et doit suivre toute la formation. L'évaluation de l'éthique doit être variée : le carnet de stage, les séances d'apprentissage au raisonnement éthique (ARE) et l'observation directe couvrent l'éventail de la réalité clinique dont l'éthique est indissociab le. Conclusion : Le modèle de l'approche dialogique de l'éthique comme compétence clinique peut guider l'évaluation de l'éthique professionnelle des résidents

Le consentement éclairé ; à propos de la controverse sur les produits de contraste en radiologie au Québec

Le consentement éclairé fait partie intégrante des standards d'excellence recherchée dans la pratique médicale contemporaine. Depuis 1971, il est exigé explicitement dans la loi québécoise, au code civil'. Pour en arriver là, c'est au cours de la première moitié du XXe siècle qu'on l'a vu émergé comme une précision nécessaire à apporter lors d'une relation professionnelle médicale. Auparavant, on présumait du consentement du patient du seul fait de la bienfaisance du médecin qu'on considérait aller de soi. De nos jours, on ne nie peut-être pas la bienfaisance professionnelle médicale, mais on tient à mettre l'accent sur le caractère autonome de la personne du patient. Culturellement, cela revient à glisser peu à peu d'un modèle paternaliste vers un modèle autonomiste

Herpes simplex virus type 1 pathogenicity in mice expressed by lytic infection in pre-B and B cells

NRC publication: Ye

Impaired T and B cell subpopulations involved in a chronic disease induced by mouse hepatitis virus type 3

NRC publication: Ye

BRAIN INVASION BY MOUSE HEPATITIS VIRUS DEPENDS ON IMPAIRMENT OF TIGHT JUNCTIONS AND INTERFERON-β PRODUCTION IN BRAIN MICROVASCULAR ENDOTHELIAL CELLS

International audienceUnlabelled - Coronaviruses (CoVs) have shown neuroinvasive properties in humans and animals secondary to replication in peripheral organs, but the mechanism of neuroinvasion is unknown. The major aim of our work was to evaluate the ability of CoVs to enter the central nervous system (CNS) through the blood-brain barrier (BBB). Using the highly hepatotropic mouse hepatitis virus type 3 (MHV3), its attenuated variant, 51.6-MHV3, which shows low tropism for endothelial cells, and the weakly hepatotropic MHV-A59 strain from the murine coronavirus group, we investigated the virus-induced dysfunctions of BBB in vivo and in brain microvascular endothelial cells (BMECs) in vitro. We report here a MHV strain-specific ability to cross the BBB during acute infection according to their virulence for liver. Brain invasion was observed only in MHV3-infected mice and correlated with enhanced BBB permeability associated with decreased expression of zona occludens protein 1 (ZO-1), VE-cadherin, and occludin, but not claudin-5, in the brain or in cultured BMECs. BBB breakdown in MHV3 infection was not related to production of barrier-dysregulating inflammatory cytokines or chemokines by infected BMECs but rather to a downregulation of barrier protective beta interferon (IFN-β) production. Our findings highlight the importance of IFN-β production by infected BMECs in preserving BBB function and preventing access of blood-borne infectious viruses to the brain. Importance - Coronaviruses (CoVs) infect several mammals, including humans, and are associated with respiratory, gastrointestinal, and/or neurological diseases. There is some evidence that suggest that human respiratory CoVs may show neuroinvasive properties. Indeed, the severe acute respiratory syndrome coronavirus (SARS-CoV), causing severe acute respiratory syndrome, and the CoVs OC43 and 229E were found in the brains of SARS patients and multiple sclerosis patients, respectively. These findings suggest that hematogenously spread CoVs may gain access to the CNS at the BBB level. Herein we report for the first time that CoVs exhibit the ability to cross the BBB according to strain virulence. BBB invasion by CoVs correlates with virus-induced disruption of tight junctions on BMECs, leading to BBB dysfunction and enhanced permeability. We provide evidence that production of IFN-β by BMECs during CoV infection may prevent BBB breakdown and brain viral invasion