RESUMO
Potential inhibitors of a target biomolecule, NAD-dependent deacetylase Sirtuin 1, were identified by a contest-based approach, in which participants were asked to propose a prioritized list of 400 compounds from a designated compound library containing 2.5 million compounds using in silico methods and scoring. Our aim was to identify target enzyme inhibitors and to benchmark computer-aided drug discovery methods under the same experimental conditions. Collecting compound lists derived from various methods is advantageous for aggregating compounds with structurally diversified properties compared with the use of a single method. The inhibitory action on Sirtuin 1 of approximately half of the proposed compounds was experimentally accessed. Ultimately, seven structurally diverse compounds were identified.
RESUMO
Virus infection is restricted by intracellular immune responses in host cells, and this is typically modulated by stimulation of cytokines. The cytokines and host factors that determine the host cell restriction against hepatitis B virus (HBV) infection are not well understood. We screened 36 cytokines and chemokines to determine which were able to reduce the susceptibility of HepaRG cells to HBV infection. Here, we found that pretreatment with IL-1ß and TNFα remarkably reduced the host cell susceptibility to HBV infection. This effect was mediated by activation of the NF-κB signaling pathway. A cytidine deaminase, activation-induced cytidine deaminase (AID), was up-regulated by both IL-1ß and TNFα in a variety of hepatocyte cell lines and primary human hepatocytes. Another deaminase APOBEC3G was not induced by these proinflammatory cytokines. Knockdown of AID expression impaired the anti-HBV effect of IL-1ß, and overexpression of AID antagonized HBV infection, suggesting that AID was one of the responsible factors for the anti-HBV activity of IL-1/TNFα. Although AID induced hypermutation of HBV DNA, this activity was dispensable for the anti-HBV activity. The antiviral effect of IL-1/TNFα was also observed on different HBV genotypes but not on hepatitis C virus. These results demonstrate that proinflammatory cytokines IL-1/TNFα trigger a novel antiviral mechanism involving AID to regulate host cell permissiveness to HBV infection.
Assuntos
Citidina Desaminase/biossíntese , Regulação Enzimológica da Expressão Gênica , Vírus da Hepatite B/metabolismo , Hepatite B/metabolismo , Interleucina-1beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Citidina Desaminase/genética , Citidina Desaminase/imunologia , DNA Viral/biossíntese , DNA Viral/genética , DNA Viral/imunologia , Células Hep G2 , Hepacivirus/genética , Hepacivirus/imunologia , Hepacivirus/metabolismo , Hepatite B/genética , Hepatite B/imunologia , Vírus da Hepatite B/genética , Vírus da Hepatite B/imunologia , Humanos , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Mutação , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Regulação para Cima/genéticaRESUMO
A 19-year-old man consulted a doctor for swelling of his neck and shortness of breath. The day before, he woke up with a slight cough and upper chest pain early in the morning. He went to school and spent the day as usual. He did not have a history of asthma or violent cough. The next day, chest radiography showed subcutaneous emphysema and pneumomediastinum. Computed tomography not only confirmed the presence of mediastinal and subcutaneous air, but also demonstrated a linear radiolucent stripe in the spinal canal corresponding to epidural emphysema. The patient did not have any neurologic findings. His general condition remained good except that his arterial blood oxygen saturation slightly decreased to 95%. Laboratory data were normal, except for serum IgE, which was elevated (2072 IU/ml). He stayed at rest and was treated conservatively and his symptoms improved within a few days. Seven days later, the intraspinal air and pneumomediastinum had resolved spontaneously on follow-up chest computed tomography (CT).
