TRIM18 is a critical regulator of viral myocarditis and organ inflammation.

BACKGROUND: Infections by viruses including severe acute respiratory syndrome coronavirus 2 could cause organ inflammations such as myocarditis, pneumonia and encephalitis. Innate immunity to viral nucleic acids mediates antiviral immunity as well as inflammatory organ injury. However, the innate immune mechanisms that control viral induced organ inflammations are unclear. METHODS: To understand the role of the E3 ligase TRIM18 in controlling viral myocarditis and organ inflammation, wild-type and Trim18 knockout mice were infected with coxsackievirus B3 for inducing viral myocarditis, influenza A virus PR8 strain and human adenovirus for inducing viral pneumonia, and herpes simplex virus type I for inducing herpes simplex encephalitis. Mice survivals were monitored, and heart, lung and brain were harvested for histology and immunohistochemistry analysis. Real-time PCR, co-immunoprecipitation, immunoblot, enzyme-linked immunosorbent assay, luciferase assay, flow cytometry, over-expression and knockdown techniques were used to understand the molecular mechanisms of TRIM18 in regulating type I interferon (IFN) production after virus infection in this study. RESULTS: We find that knockdown or deletion of TRIM18 in human or mouse macrophages enhances production of type I IFN in response to double strand (ds) RNA and dsDNA or RNA and DNA virus infection. Importantly, deletion of TRIM18 protects mice from viral myocarditis, viral pneumonia, and herpes simplex encephalitis due to enhanced type I IFN production in vivo. Mechanistically, we show that TRIM18 recruits protein phosphatase 1A (PPM1A) to dephosphorylate TANK binding kinase 1 (TBK1), which inactivates TBK1 to block TBK1 from interacting with its upstream adaptors, mitochondrial antiviral signaling (MAVS) and stimulator of interferon genes (STING), thereby dampening antiviral signaling during viral infections. Moreover, TRIM18 stabilizes PPM1A by inducing K63-linked ubiquitination of PPM1A. CONCLUSIONS: Our results indicate that TRIM18 serves as a negative regulator of viral myocarditis, lung inflammation and brain damage by downregulating innate immune activation induced by both RNA and DNA viruses. Our data reveal that TRIM18 is a critical regulator of innate immunity in viral induced diseases, thereby identifying a potential therapeutic target for treatment.

Toll-Like Receptor Signaling in Severe Acute Respiratory Syndrome Coronavirus 2-Induced Innate Immune Responses and the Potential Application Value of Toll-Like Receptor Immunomodulators in Patients With Coronavirus Disease 2019.

Toll-like receptors (TLRs) are key sensors that recognize the pathogen-associated molecular patterns (PAMPs) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to activate innate immune response to clear the invading virus. However, dysregulated immune responses may elicit the overproduction of proinflammatory cytokines and chemokines, resulting in the enhancement of immune-mediated pathology. Therefore, a proper understanding of the interaction between SARS-CoV-2 and TLR-induced immune responses is very important for the development of effective preventive and therapeutic strategies. In this review, we discuss the recognition of SARS-CoV-2 components by TLRs and the downstream signaling pathways that are activated, as well as the dual role of TLRs in regulating antiviral effects and excessive inflammatory responses in patients with coronavirus disease 2019 (COVID-19). In addition, this article describes recent progress in the development of TLR immunomodulators including the agonists and antagonists, as vaccine adjuvants or agents used to treat hyperinflammatory responses during SARS-CoV-2 infection.

Mechanisms involved in controlling RNA virus-induced intestinal inflammation.

Gastroenteritis is inflammation of the lining of stomach and intestines and causes significant morbidity and mortality worldwide. Many viruses, especially RNA viruses are the most common cause of enteritis. Innate immunity is the first line of host defense against enteric RNA viruses and virus-induced intestinal inflammation. The first layer of defense against enteric RNA viruses in the intestinal tract is intestinal epithelial cells (IECs), dendritic cells and macrophages under the intestinal epithelium. These innate immune cells express pathogen-recognition receptors (PRRs) for recognizing enteric RNA viruses through sensing viral pathogen-associated molecular patterns (PAMPs). As a result of this recognition type I interferon (IFN), type III IFN and inflammasome activation occurs, which function cooperatively to clear infection and reduce viral-induced intestinal inflammation. In this review, we summarize recent findings about mechanisms involved in enteric RNA virus-induced intestinal inflammation. We will provide an overview of the enteric RNA viruses, their RNA sensing mechanisms by host PRRs, and signaling pathways triggered by host PRRs, which shape the intestinal immune response to maintain intestinal homeostasis.

How to think about severe acute respiratory syndrome coronavirus 2 vaccination for pregnant and lactating women in China. / å¦‚ä½•çœ‹å¾ ä¸­å›½å¦Šå¨ æœŸåŠå“ºä¹³æœŸå¥³æ€§æ–°åž‹å† çŠ¶ç— æ¯’ç–«è‹—æŽ¥ç§ï¼Ÿ.

The coronavirus disease 2019 (COVID-19) continues to spread around the world, and how to build an immune barrier against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the population is the work we need to do for a long time in the future. The vaccination is an important strategy to construct and improve the herd immunity barrier. Therefore, our country is currently actively and extensively implementing the anti-epidemic policy of SARS-CoV-2 vaccination. However, because of insufficient data on the safety of the SARS-CoV-2 vaccine in the population, especially the lack of clinical research in pregnant and lactating women, China has adopted a conservative approach on whether women in this special physiological period receive SARS-CoV-2 vaccine based on the safe consideration. However, with the widespread application of the SARS-CoV-2 vaccine in the prevention and control of the global epidemic, and the emergence of a large number of clinical research evidences at home and abroad, if we still exclude pregnant and lactating women from the vaccinated population, this part of the population will be fully exposed to the SARS-CoV-2 threat, which will weak the national prevention and control policy. Therefore, it is necessary to reconsider the vaccination of people in this special physiological period based on the experience of vaccination at home and abroad.