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The recognition of viral nucleic acids by host pattern recognition receptors (PRRs) is critical for initiating innate immune responses against viral infections. These innate immune responses are mediated by the induction of interferons (IFNs), IFN-stimulated genes (ISGs) and pro-inflammatory cytokines. However, regulatory mechanisms are critical to avoid excessive or long-lasting innate immune responses that may cause detrimental hyperinflammation. Here, we identified a novel regulatory function of the ISG, IFN alpha inducible protein 27 (IFI27) in counteracting the innate immune responses triggered by cytoplasmic RNA recognition and binding. Our model systems included three unrelated viral infections caused by Influenza A virus (IAV), Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), and Sendai virus (SeV), and transfection with an analog of double-stranded (ds) RNA. Furthermore, we found that IFI27 has a positive effect on IAV and SARS-CoV-2 replication, most likely due to its ability to counteract host-induced antiviral responses, including in vivo. We also show that IFI27 interacts with nucleic acids and PRR retinoic acid-inducible gene I (RIG-I), being the interaction of IFI27 with RIG-I most likely mediated through RNA binding. Interestingly, our results indicate that interaction of IFI27 with RIG-I impairs RIG-I activation, providing a molecular mechanism for the effect of IFI27 on modulating innate immune responses. Our study identifies a molecular mechanism that may explain the effect of IFI27 in counterbalancing innate immune responses to RNA viral infections and preventing excessive innate immune responses. Therefore, this study will have important implications in drug design to control viral infections and viral-induced pathology.

[EN] Coronaviridae viruses usually cause mild respiratory disease in humans, nevertheless, a new infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally since December 2019, resulting in the ongoing 2019-2021 coronavirus pandemic. The present invention discloses the use of coated iron oxyhydroxide nanoparticles (lOHNPs) for use in the treatment and/or prevention of viral infections caused by Coronaviridae, especially those caused by respiratory syndrome-related coronaviruses such as SARS-CoV and SARS-CoV-2 and MERS-CoV. The iron oxyhydroxide nanoparticles are coated with biocompatible molecules and polymers which bind to the nanoparticle core via oxygen (e.g. sorbitol and sucrose). The lOHNPs were found stable, non-cytotoxic in vitro and can efficiently impair virus replication and transcription. Furthermore, the lOHNPs are suitable for oral, intranasal or parenteral administration in combination with a pharmaceutical carrier., [FR] Les virus Coronaviridae provoquent généralement une maladie respiratoire légère chez l'homme, cependant, une nouvelle maladie infectieuse provoquée par le coronavirus 2 du syndrome respiratoire aigu sévère (SARS-CoV-2) se propage dans le monde depuis décembre 2019, conduisant à la pandémie actuelle de coronavirus de 2019-2021. La présente invention divulgue l'utilisation de nanoparticules d'oxyhydroxyde de fer (lOHNP) enrobées destinées à être utilisées dans le traitement et/ou la prévention d'infections virales provoquées par des Coronaviridae, notamment celles provoquées par des coronavirus associés à des syndromes respiratoires tels que le SARS-CoV, le SARS-CoV-2 et le MERS-CoV. Les nanoparticules d'oxyhydroxyde de fer sont revêtues de molécules et de polymères biocompatibles qui se lient au noyau de nanoparticule via l'oxygène (par exemple, le sorbitol et le saccharose). Les lOHNP se sont révélées stables, non cytotoxiques in vitro et peuvent altérer efficacement la réplication et la transcription du virus. En outre, les lOHNP sont appropriées pour une administration orale, intranasale ou parentérale en combinaison avec un support pharmaceutique.

Background Coronaviruses usually cause mild respiratory disease in humans but as seen recently, some human coronaviruses can cause more severe diseases, such as the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the global spread of which has resulted in the ongoing coronavirus pandemic. Results In this study we analyzed the potential of using iron oxide nanoparticles (IONPs) coated with biocompatible molecules like dimercaptosuccinic acid (DMSA), 3-aminopropyl triethoxysilane (APS) or carboxydextran (FeraSpin™ R), as well as iron oxyhydroxide nanoparticles (IOHNPs) coated with sucrose (Venofer®), or iron salts (ferric ammonium citrate -FAC), to treat and/or prevent SARS-CoV-2 infection. At non-cytotoxic doses, IONPs and IOHNPs impaired virus replication and transcription, and the production of infectious viruses in vitro, either when the cells were treated prior to or after infection, although with different efficiencies. Moreover, our data suggest that SARS-CoV-2 infection affects the expression of genes involved in cellular iron metabolism. Furthermore, the treatment of cells with IONPs and IOHNPs affects oxidative stress and iron metabolism to different extents, likely influencing virus replication and production. Interestingly, some of the nanoparticles used in this work have already been approved for their use in humans as anti-anemic treatments, such as the IOHNP Venofer®, and as contrast agents for magnetic resonance imaging in small animals like mice, such as the FeraSpin™ R IONP. Conclusions Therefore, our results suggest that IONPs and IOHNPs may be repurposed to be used as prophylactic or therapeutic treatments in order to combat SARS-CoV-2 infection.

Influenza A viruses (IAV) can infect a broad range of mammalian and avian species. However, the host innate immune system provides defenses that restrict IAV replication and infection. Likewise, IAV have evolved to develop efficient mechanisms to counteract host antiviral responses to efficiently replicate in their hosts. The IAV PA-X and NS1 non-structural proteins are key virulence factors that modulate innate immune responses and virus pathogenicity during infection. To study the determinants of IAV pathogenicity and their functional co-evolution, we evaluated amino acid differences in the PA-X and NS1 proteins of early (1996–1997) and more recent (since 2016) H5N1 IAV. H5N1 IAV have zoonotic and pandemic potential and represent an important challenge both in poultry farming and human health. The results indicate that amino acid changes occurred over time, affecting the ability of these two non-structural H5N1 IAV proteins to inhibit gene expression and affecting virus pathogenicity. These results highlight the importance to monitor the evolution of these two virulence factors of IAV, which could result in enhanced viral replication and virulence.

Pancreatic heterotopia is defined as pancreatic tissue outside its normal location in the body and anatomically separated from the pancreas. In this work we have analyzed the stomach glandular epithelium of Gata4 flox/flox; Pdx1‐Cre mice (Gata4KO mice). We found that Gata4KO glandular epithelium displays an atypical morphology similar to the cornified squamous epithelium and exhibits upregulation of forestomach markers. The developing gastric units fail to form properly, and the glandular epithelial cells do not express markers of gastric gland in the absence of GATA4. Of interest, the developing glands of the Gata4KO stomach express pancreatic cell markers. Furthermore, a mass of pancreatic tissue located in the subserosa of the Gata4KO stomach is observed at adult stages. Heterotopic pancreas found in Gata4‐deficient mice contains all three pancreatic cell lineages: ductal, acinar, and endocrine. Moreover, Gata4 expression is downregulated in ectopic pancreatic tissue of some human biopsy samples.