Glucocorticoid receptor dimers control intestinal STAT1 and TNF-induced inflammation in mice

TNF is an important mediator in numerous inflammatory diseases, e.g., in inflammatory bowel diseases (IBDs). In IBD, acute increases in TNF production can lead to disease flares. Glucocorticoids (GCs), which are steroids that bind and activate the glucocorticoid receptor (GR), are able to protect animals and humans against acute TNF-induced inflammatory symptoms. Mice with a poor transcriptional response of GR dimer-dependent target genes were studied in a model of TNF-induced lethal inflammation. In contrast to the GRWT/WT mice, these GRdim/dim mice displayed a substantial increase in TNF sensitivity and a lack of protection by the GC dexamethasone (DEX). Unchallenged GRdim/dim mice had a strong IFN-stimulated gene (ISG) signature, along with STAT1 upregulation and phosphorylation. This ISG signature was gut specific and, based on our studies with antibiotics, depended on the gut microbiota. GR dimers directly bound to short DNA sequences in the STAT1 promoter known as inverted repeat negative GRE (IR-nGRE) elements. Poor control of STAT1 in GRdim/dim mice led to failure to repress ISG genes, resulting in excessive necroptosis induction by TNF. Our findings support a critical interplay among gut microbiota, IFNs, necroptosis, and GR in both the basal response to acute inflammatory challenges and pharmacological intervention by GCs

MVA-CoV2-S Vaccine Candidate Neutralizes Distinct Variants of Concern and Protects Against SARS-CoV-2 Infection in Hamsters

To control the coronavirus disease 2019 (COVID-19) pandemic and the emergence of different variants of concern (VoCs), novel vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are needed. In this study, we report the potent immunogenicity and efficacy induced in hamsters by a vaccine candidate based on a modified vaccinia virus Ankara (MVA) vector expressing a human codon optimized full-length SARS-CoV-2 spike (S) protein (MVA-S). Immunization with one or two doses of MVA-S elicited high titers of S- and receptor-binding domain (RBD)-binding IgG antibodies and neutralizing antibodies against parental SARS-CoV-2 and VoC alpha, beta, gamma, delta, and omicron. After SARS-CoV-2 challenge, MVA-S-vaccinated hamsters showed a significantly strong reduction of viral RNA and infectious virus in the lungs compared to the MVA-WT control group. Moreover, a marked reduction in lung histopathology was also observed in MVA-S-vaccinated hamsters. These results favor the use of MVA-S as a potential vaccine candidate for SARS-CoV-2 in clinical trials.The authors declare that this study received funding from Fondo COVID-19 grant COV20/00151 [Spanish Health Ministry, Instituto de Salud Carlos III (ISCIII)], Fondo Supera COVID-19 grant (Crue Universidades-Banco Santander) and Spanish Research Council (CSIC) grant 202120E079 (to JG-A), CSIC grant 2020E84, La CaixaImpulse grant CF01-00008, Ferrovial and MAPFRE donations (to ME), a Spanish Ministry of Science and Innovation (MCIN)/Spanish Research Agency (AEI)/10.13039/501100011033 grant (PID2020-114481RB-I00 to JGA and ME), and internal funding from KU Leuven. This research work was also funded by the European Commission-NextGeneration EU through CSIC’s Global Health Platform (PTI Salud Global) (to JG-A and ME). The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.Peer reviewe

STAT2 signaling restricts viral dissemination but drives severe pneumonia in SARS-CoV-2 infected hamsters

Emergence of SARS-CoV-2 causing COVID-19 has resulted in hundreds of thousands of deaths. In search for key targets of effective therapeutics, robust animal models mimicking COVID-19 in humans are urgently needed. Here, we show that Syrian hamsters, in contrast to mice, are highly permissive to SARS-CoV-2 and develop bronchopneumonia and strong inflammatory responses in the lungs with neutrophil infiltration and edema, further confirmed as consolidations visualized by micro-CT alike in clinical practice. Moreover, we identify an exuberant innate immune response as key player in pathogenesis, in which STAT2 signaling plays a dual role, driving severe lung injury on the one hand, yet restricting systemic virus dissemination on the other. Our results reveal the importance of STAT2-dependent interferon responses in the pathogenesis and virus control during SARS-CoV-2 infection and may help rationalizing new strategies for the treatment of COVID-19 patients. SARS-CoV-2 infection can result in severe lung inflammation and pathology, but host response remains incompletely understood. Here the authors show in Syrian hamsters that STAT2 signaling restricts systemic virus dissemination but also drives severe lung injury, playing a dual role in SARS-CoV-2 infection

Inhibition of the Oxygen Sensor PHD2 Enhances Tissue-Engineered Endochondral Bone Formation

Tissue engineering holds great promise for bone regenerative medicine, but clinical translation remains challenging. An important factor is the low cell survival after implantation, primarily caused by the lack of functional vasculature at the bone defect. Interestingly, bone development and repair initiate predominantly via an avascular cartilage template, indicating that chondrocytes are adapted to limited vascularization. Given these advantageous properties of chondrocytes, we questioned whether tissue-engineered cartilage intermediates implanted ectopically in mice are able to form bone, even when the volume size increases. Here, we show that endochondral ossification proceeds efficiently when implant size is limited (≤30 mm3 ), but chondrogenesis and matrix synthesis are impaired in the center of larger implants, leading to a fibrotic core. Increasing the level of angiogenic growth factors does not improve this outcome, because this strategy enhances peripheral bone formation, but disrupts the conversion of cartilage into bone in the center, resulting in a fibrotic core, even in small implants. On the other hand, activation of hypoxia signaling in cells before implantation stimulates chondrogenesis and matrix production, which culminates in enhanced bone formation throughout the entire implant. Together, our results show that induction of angiogenesis alone may lead to adverse effects during endochondral bone repair, whereas activation of hypoxia signaling represents a superior therapeutic strategy to improve endochondral bone regeneration in large tissue-engineered implants. © 2018 American Society for Bone and Mineral Research.status: publishe