Group-B enteroviruses (EV-B) are ubiquitous naked single-stranded positive RNA viral pathogens that are responsible for common acute or persistent human infections. Their genome is composed in the 5′ end by a non-coding region, which is crucial for the initiation of the viral replication and translation processes. RNA domain-I secondary structures can interact with viral or cellular proteins to form viral ribonucleoprotein (RNP) complexes regulating viral genomic replication, whereas RNA domains-II to -VII (internal ribosome entry site, IRES) are known to interact with cellular ribosomal subunits to initiate the viral translation process. Natural 5′ terminally deleted viral forms lacking some genomic RNA domain-I secondary structures have been described in EV-B induced murine or human infections. Recent in vitro studies have evidenced that the loss of some viral RNP complexes in the RNA domain-I can modulate the viral replication and infectivity levels in EV-B infections. Moreover, the disruption of secondary structures of RNA domain-I could impair viral RNA sensing by RIG-I (Retinoic acid inducible gene I) or MDA5 (melanoma differentiation-associated protein 5) receptors, a way to overcome antiviral innate immune response. Overall, natural 5′ terminally deleted viral genomes resulting in the loss of various structures in the RNA domain-I could be major key players of host–cell interactions driving the development of acute or persistent EV-B infections.

We assessed relationships between early peripheral blood type I interferons (IFN) levels, clinical new early warning scores (NEWS), and clinical outcomes in hospitalized coronavirus disease‐19 (COVID‐19) adult patients. Early IFN‐β levels were lower among patients who further required intensive care unit (ICU) admission than those measured in patients who did not require an ICU admission during severe acute respiratory syndrome coronavirus type 2 infection. IFN‐β levels were inversely correlated with NEWS only in the subgroup of patients who further required ICU admission. To assess whether peripheral blood IFN‐β levels could be a potential relevant biomarker to predict further need for ICU admission, we performed receiver operating characteristic (ROC) curve analyses that showed for all study patients an area under ROC curve of 0.77 growing to 0.86 ( p = 0.003) when the analysis was restricted to a subset of patients with NEWS ≥5 at the time of hospital admission. Overall, our findings indicated that early peripheral blood IFN‐β levels might be a relevant predictive marker of further need for an ICU admission in hospitalized COVID‐19 adult patients, specifically when clinical score (NEWS) was graded as upper than 5 at the time of hospital admission.

Group-B enteroviruses (EV-B) are ubiquitous naked single-stranded positive RNA viral pathogens that are responsible for common acute or persistent human infections. Their genome is composed in the 5'end by a non-coding region, which is crucial for the initiation of the viral replication and translation processes. RNA domain-I secondary structures can interact with viral or cellular proteins to form viral ribonucleoprotein (RNP) complexes regulating viral genomic replication, whereas RNA domains-II to -VII (IRES) are known to interact with cellular ribosomal subunits to initiate the viral translation process. Natural 5’ terminally deleted viral forms lacking some genomic RNA domain-I secondary structures have been described in EV-B induced murine or human infections. Recent in vitro studies have evidenced that the loss of some viral RNP complexes in the RNA domain-I can modulate the viral replication and infectivity levels in EV-B infections. Moreover, the disruption of secondary structures of RNA domain-I could impair viral RNA sensing by RIG-I or MDA5 receptors, a way to overcome antiviral innate immune response. Overall, natural 5′ terminally deleted viral genomes resulting in the loss of various structures in the RNA domain-I could be major key players of host-cell interactions driving the development of acute or persistent EV-B infections.

Major EV-B populations characterized by 5′ terminal deletions (5′TD) have been shown to be associated with the development of myocarditis and type 1 diabetes in mice or humans. To date, the dynamics of EV-B 5′TD-RNA forms’ emergence during the course of infection and their impact on cellular functions remain unclear. Using a RACE-PCR approach in CVB3/28-infected mouse organs, we showed an early (3 days post infection, DPI) emergence of major 5′TD populations associated with minor full-length RNA forms. Viral replication activities with infectious particle production were associated with heart, liver, and pancreas acute inflammatory lesions, whereas clearance of viral RNA without organ lesions was observed in the brain, lung, intestines, and muscles from 3 to 7 DPI. At 28 DPI, low viral RNA levels, +/-RNA ratios < 5 associated with viral protein 1 expression revealed a persistent infection in the heart and pancreas. This persistent infection was characterized by molecular detection of only 5′TD RNA forms that were associated with dystrophin cleavage in the heart and insulin production impairment in beta-pancreatic cells. These results demonstrated that major EV-B 5′TD RNA forms can be early selected during systemic infection and that their maintenance may drive EV-induced acute and persistent infections with target cell dysfunctions.

Emergence of 5′ terminally deleted coxsackievirus-B RNA forms (CVB-TD) have been associated with the development of human diseases. These CVB-TD RNA forms have been detected in mouse pancreas during acute or persistent experimental infections. To date, the impact of the replication activities of CVB-TD RNA forms on insulin metabolism remains unexplored. Using an immunocompetent mouse model of CVB3/28 infection, acute and persistent infections of major CVB-TD populations were evidenced in the pancreas. The inoculation of mice with homogenized pancreases containing major CVB-TD populations induced acute and chronic pancreatic infections with pancreatitis. In the mouse pancreas, viral capsid protein 1 (VP1) expression colocalized with a decrease in beta cells insulin content. Moreover, in infected mouse pancreases, we showed a decrease in pro-hormone convertase 2 (PCSK2) mRNA, associated with a decrease in insulin plasmatic concentration. Finally, transfection of synthetic CVB-TD50 RNA forms into cultured rodent pancreatic beta cells demonstrated that viral replication with protein synthesis activities decreased the PCSK2 mRNA expression levels, impairing insulin secretion. In conclusion, our results show that the emergence and maintenance of major CVB-TD RNA replicative forms in pancreatic beta cells can play a direct, key role in the pathophysiological mechanisms leading to the development of type 1 diabetes.

La grippe est une maladie respiratoire aigüe, due à une infection par des virus influenza et qui représente un problème important de santé publique. Une meilleure compréhension des interactions entre le virus influenza et son hôte nous permettra de mieux comprendre la physiopathologie de l'infection grippale, et donc, à terme, de mieux se protéger contre la maladie. La morbidité et la mortalité, causées par les infections grippales sévères, sont associées à une dérégulation de la réponse immunitaire, au niveau pulmonaire. Cette inflammation délétère serait à l'origine de dommages collatéraux du poumon, entrainant une diminution de la capacité respiratoire du patient. Bien que les mécanismes impliqués ne soient pas totalement élucidés, de récents travaux mettent en évidence un rôle central des cellules endothéliales dans la dérégulation de la réponse de l'hôte face à l'infection grippale. Lors d'une agression de l'endothélium, le processus physiologique de l'hémostase (activation plaquettaire, coagulation et fibrinolyse) s'active afin de permettre la cicatrisation de la plaie et de maintenir l'intégrité des vaisseaux sanguins. Dans de nombreuses maladies inflammatoires, la seule dérégulation de l'hémostase est directement liée à une réponse inflammatoire délétère. Lors de ma thèse, nous avons émis l'hypothèse que l'hémostase pouvait être à l'origine de la dérégulation inflammatoire durant les infections grippales. Nos données montrent le rôle de deux facteurs fortement impliqués dans l'hémostase : le récepteur activé par la thrombine, PAR-1 (Protease Activated Receptor J) ainsi que le plasminogène, dans l'inflammation délétère des poumons et dans la pathogénicité des virus influenza. Outre le rôle de l'hémostase, nous avons également pu mettre en évidence que le virus influenza incorpore des protéines cellulaires dans l'enveloppe virale, lui permettant d'échapper au système immunitaire, ce qui pourrait aussi contribuer à la dérégulation de la réponse de l'hôte. L'ensemble des résultats obtenus ont permis de mieux comprendre les mécanismes à l'origine d'une réponse immunitaire dérégulée dans les infections grippales et de proposer de nouvelles cibles thérapeutiques pour lutter contre la maladie