NSUN2-mediated M5c methylation of IRF3 mRNA negatively regulates type I interferon responses during various viral infections.

5-Methylcytosine (m5C) is a widespread post-transcriptional RNA modification and is reported to be involved in manifold cellular responses and biological processes through regulating RNA metabolism. However, its regulatory role in antiviral innate immunity has not yet been elucidated. Here, we report that NSUN2, a typical m5C methyltransferase, negatively regulates type I interferon responses during various viral infections, including SARS-CoV-2. NSUN2 specifically mediates m5C methylation of IRF3 mRNA and accelerates its degradation, resulting in low levels of IRF3 and downstream IFN-ß production. Knockout or knockdown of NSUN2 enhanced type I interferon and downstream ISGs during various viral infection in vitro. And in vivo, the antiviral innate response is more dramatically enhanced in Nsun2+/- mice than in Nsun2+/+ mice. The highly m5C methylated cytosines in IRF3 mRNA were identified, and their mutation enhanced cellular IRF3 mRNA levels. Moreover, infection with Sendai virus (SeV), vesicular stomatitis virus (VSV), herpes simplex virus 1 (HSV-1), or Zika virus (ZIKV) resulted in a reduction of endogenous NSUN2 levels. Especially, SARS-CoV-2 infection (WT strain and BA.1 omicron variant) also decreased endogenous levels of NSUN2 in COVID-19 patients and K18-hACE2 KI mice, further increasing type I interferon and downstream ISGs. Together, our findings reveal that NSUN2 serves as a negative regulator of interferon response by accelerating the fast turnover of IRF3 mRNA, while endogenous NSUN2 levels decrease during SARS-CoV-2 and various viral infections to boost antiviral responses for effective elimination of viruses.

Human adenoviruses: A suspect behind the outbreak of acute hepatitis in children amid the COVID-19 pandemic.

As of 10 May 2022, at least 450 cases of pediatric patients with acute hepatitis of unknown cause have been reported worldwide. Human adenoviruses (HAdVs) have been detected in at least 74 cases, including the F type HAdV41 in 18 cases, which indicates that adenoviruses may be associated with this mysterious childhood hepatitis, although other infectious agents or environmental factors cannot be excluded. In this review, we provide a brief introduction of the basic features of HAdVs and describe diseases caused by different HAdVs in humans, aiming to help understand the biology and potential risk of HAdVs and cope with the outbreak of acute child hepatitis.

Minimizing the Impact of the COVID-19 Epidemic on Oncology Clinical Trials: Retrospective Study of Beijing Cancer Hospital.

BACKGROUND: In view of repeated COVID-19 outbreaks in most countries, clinical trials will continue to be conducted under outbreak prevention and control measures for the next few years. It is very significant to explore an optimal clinical trial management model during the outbreak period to provide reference and insight for other clinical trial centers worldwide. OBJECTIVE: The aim of this study was to explore the management strategies used to minimize the impact of the COVID-19 epidemic on oncology clinical trials. METHODS: We implemented a remote management model to maintain clinical trials conducted at Beijing Cancer Hospital, which realized remote project approval, remote initiation, remote visits, remote administration and remote monitoring to get through two COVID-19 outbreaks in the capital city from February to April and June to July 2020. The effectiveness of measures was evaluated as differences in rates of protocol compliance, participants lost to follow-up, participant withdrawal, disease progression, participant mortality, and detection of monitoring problems. RESULTS: During the late of the first outbreak, modifications were made in trial processing, participant management and quality control, which allowed the hospital to ensure the smooth conduct of 572 trials, with a protocol compliance rate of 85.24% for 3718 participants across both outbreaks. No COVID-19 infections were recorded among participants or trial staff, and no major procedural errors occurred between February and July 2020. These measures led to significantly higher rates of protocol compliance and significantly lower rates of loss to follow-up or withdrawal after the second outbreak than after the first, without affecting rates of disease progression or mortality. The hospital provided trial sponsors with a remote monitoring system in a timely manner, and 3820 trial issues were identified. CONCLUSIONS: When public health emergencies occur, an optimal clinical trial model combining on-site and remote management could guarantee the health care and treatment needs of clinical trial participants, in which remote management plays a key role.