Hepatic Interferon Regulatory Factor 6 Alleviates Liver Steatosis and Metabolic Disorder by Transcriptionally Suppressing Peroxisome Proliferator-Activated Receptor γ in Mice.

Nonalcoholic fatty liver disease (NAFLD) has become a worldwide epidemic. A large and growing unmet therapeutic need has inspired numerous studies in the field. Integrating the published genomic data available in the Gene Expression Omnibus (GEO) with NAFLD samples from rodents, we discovered that interferon regulatory factor 6 (IRF6) is significantly downregulated in high-fat diet (HFD)-induced fatty liver. In the current study, we identified IRF6 in hepatocytes as a protective factor in liver steatosis (LS). During HFD challenge, hepatic Irf6 was suppressed by promoter hypermethylation. Severity of HFD-induced LS was exacerbated in hepatocyte-specific Irf6 knockout mice, whereas hepatocyte-specific transgenic mice overexpressing Irf6 (IRF6-HTG) exhibited alleviated steatosis and metabolic disorder in response to HFD feeding. Mechanistic studies in vitro demonstrated that hepatocyte IRF6 directly binds to the promoter of the peroxisome proliferator-activated receptor γ (PPARγ) gene and subsequently halts the transcription of Pparγ and its target genes (e.g., genes that regulate lipogenesis and lipid acid uptake) under physiological conditions. Conclusion: Irf6 is downregulated by promoter hypermethylation upon metabolic stimulus exposure, which fail to inhibit Pparγ and its targets, driving abnormalities of lipid metabolism.

Measles Virus-Based Vaccine Expressing Membrane-Anchored Spike of SARS-CoV-2 Inducing Efficacious Systemic and Mucosal Humoral Immunity in Hamsters.

As SARS-CoV-2 continues to evolve and COVID-19 cases rapidly increase among children and adults, there is an urgent need for a safe and effective vaccine that can elicit systemic and mucosal humoral immunity to limit the emergence of new variants. Using the Chinese Hu191 measles virus (MeV-hu191) vaccine strain as a backbone, we developed MeV chimeras stably expressing the prefusion forms of either membrane-anchored, full-length spike (rMeV-preFS), or its soluble secreted spike trimers with the help of the SP-D trimerization tag (rMeV-S+SPD) of SARS-CoV-2 Omicron BA.2. The two vaccine candidates were administrated in golden Syrian hamsters through the intranasal or subcutaneous routes to determine the optimal immunization route for challenge. The intranasal delivery of rMeV-S+SPD induced a more robust mucosal IgA antibody response than the subcutaneous route. The mucosal IgA antibody induced by rMeV-preFS through the intranasal routine was slightly higher than the subcutaneous route, but there was no significant difference. The rMeV-preFS vaccine stimulated higher mucosal IgA than the rMeV-S+SPD vaccine through intranasal or subcutaneous administration. In hamsters, intranasal administration of the rMeV-preFS vaccine elicited high levels of NAbs, protecting against the SARS-CoV-2 Omicron BA.2 variant challenge by reducing virus loads and diminishing pathological changes in vaccinated animals. Encouragingly, sera collected from the rMeV-preFS group consistently showed robust and significantly high neutralizing titers against the latest variant XBB.1.16. These data suggest that rMeV-preFS is a highly promising COVID-19 candidate vaccine that has great potential to be developed into bivalent vaccines (MeV/SARS-CoV-2).