Hui Hui

Significance N 6 -methylation of adenosine (m 6 A) RNA modification plays important roles in development and tumorigenesis. The functions and mechanisms of m 6 A demethylases during cancer immunotherapy is still unclear. Here we employed melanoma and colon syngeneic mouse models to study the roles of m 6 A demethylases ALKBH5 and FTO during anti–PD-1 antibody and GVAX vaccination therapy. We found that ALKBH5 knockout in tumor cells enhances efficacy of immunotherapy and prolonged mouse survival. ALKBH5 modulates target gene expression and gene splicing, leading to changes of metabolite contents, such as lactate in tumor microenvironment, which regulates suppressive lymphocytes Treg and myeloid-derived suppressor cell accumulations. Importantly, by using ALKBH5-specific inhibitor, we observed the similar phenotype, indicating future translational application of our findings.

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is spreading rapidly around the world, resulting in a massive death toll. Lung infection or pneumonia is the common complication of COVID-19, and imaging techniques, especially computed tomography (CT), have played an important role in diagnosis and treatment assessment of the disease. Herein, we review the imaging characteristics and computing models that have been applied for the management of COVID-19. CT, positron emission tomography - CT (PET/CT), lung ultrasound, and magnetic resonance imaging (MRI) have been used for detection, treatment, and follow-up. The quantitative analysis of imaging data using artificial intelligence (AI) is also explored. Our findings indicate that typical imaging characteristics and their changes can play crucial roles in the detection and management of COVID-19. In addition, AI or other quantitative image analysis methods are urgently needed to maximize the value of imaging in the management of COVID-19.

Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2 and has spread across the globe. SARS-CoV-2 is a highly infectious virus with no vaccine or antiviral therapy available to control the pandemic; therefore, it is crucial to understand the mechanisms of viral pathogenesis and the host immune responses to SARS-CoV-2. SARS-CoV-2 is a new member of the betacoronavirus genus like other closely related viruses including SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). Both SARS-CoV and MERS-CoV have caused serious outbreaks and epidemics in the past eighteen years. Here, we report that one of the interferon-stimulated genes (ISGs), cholesterol 25-hydroxylase (CH25H), is induced by SARS-CoV-2 infection in vitro and in COVID-19-infected patients. CH25H converts cholesterol to 25-hydrocholesterol (25HC) and 25HC shows broad anti-coronavirus activity by blocking membrane fusion. Furthermore, 25HC inhibits USA-WA1/2020 SARS-CoV-2 infection in lung epithelial cells and viral entry in human lung organoids. Mechanistically, 25HC inhibits viral membrane fusion by activating the ER-localized acyl-CoA:cholesterol acyltransferase (ACAT) which leads to the depletion of accessible cholesterol from the plasma membrane. Altogether, our results shed light on a potentially broad antiviral mechanism by 25HC through depleting accessible cholesterol on the plasma membrane to suppress virus-cell fusion. Since 25HC is a natural product with no known toxicity at effective concentrations, it provides a potential therapeutic candidate for COVID-19 and emerging viral diseases in the future.

-methylation of adenosine (m6A) in RNA regulates many physiological and disease processes. Here, we investigate m6A modification of the SARS-CoV-2 gene in regulating the host cell innate immune response. Our data show that the SARS-CoV-2 virus has m6A modifications that are enriched in the 3' end of the viral genome. We find that depletion of the host cell m6A methyltransferase METTL3 decreases m6A levels in SARS-CoV-2 and host genes, and m6A reduction in viral RNA increases RIG-I binding and subsequently enhances the downstream innate immune signaling pathway and inflammatory gene expression. METTL3 expression is reduced and inflammatory genes are induced in patients with severe coronavirus disease 2019 (COVID-19). These findings will aid in the understanding of COVID-19 pathogenesis and the design of future studies regulating innate immunity for COVID-19 treatment.