Influenza A virus (IAV) is a highly transmissible respiratory pathogen and a major cause of morbidity and mortality around the world. Nucleoprotein (NP) is an abundant IAV protein essential for multiple steps of the viral life cycle. Our recent proteomic study of the IAV-host interaction network found that TRIM41 (tripartite motif-containing 41), a ubiquitin E3 ligase, interacted with NP. However, the role of TRIM41 in IAV infection is unknown. Here, we report that TRIM41 interacts with NP through its SPRY domain. Furthermore, TRIM41 is constitutively expressed in lung epithelial cells, and overexpression of TRIM41 inhibits IAV infection. Conversely, RNA interference (RNAi) and knockout of TRIM41 increase host susceptibility to IAV infection. As a ubiquitin E3 ligase, TRIM41 ubiquitinates NP and in cells. The TRIM41 mutant lacking E3 ligase activity fails to inhibit IAV infection, suggesting that the E3 ligase activity is indispensable for TRIM41 antiviral function. Mechanistic analysis further revealed that the polyubiquitination leads to NP protein degradation and viral inhibition. Taking these observations together, TRIM41 is a constitutively expressed intrinsic IAV restriction factor that targets NP for ubiquitination and protein degradation. Influenza control strategies rely on annual immunization and require frequent updates of the vaccine, which is not always a foolproof process. Furthermore, the current antivirals are also losing effectiveness as new viral strains are often refractory to conventional treatments. Thus, there is an urgent need to find new antiviral mechanisms and develop therapeutic drugs based on these mechanisms. Targeting the virus-host interface is an emerging new strategy because host factors controlling viral replication activity will be ideal candidates, and cellular proteins are less likely to mutate under drug-mediated selective pressure. Here, we show that the ubiquitin E3 ligase TRIM41 is an intrinsic host restriction factor to IAV. TRIM41 directly binds the viral nucleoprotein and targets it for ubiquitination and proteasomal degradation, thereby limiting viral infection. Exploitation of this natural defense pathway may open new avenues to develop antiviral drugs targeting the influenza virus.
IntroductionTo understand better the risk of tuberculosis transmission with increasing delay in tuberculosis treatment, we undertook a retrospective cohort study in Shenzhen, China.MethodsAll pulmonary tuberculosis cases in the Shenzhen tuberculosis surveillance database from 1993–2010 were included. Sputum smear positivity and presence of pulmonary cavity were used as proxies for risk of tuberculosis transmission.ResultsAmong 48,441pulmonary tuberculosis cases, 70% presented with symptoms of pulmonary TB, 62% were sputum smear positive, and 21% had a pulmonary cavity on chest x-ray. 95.3% of patients self-presented for evaluation of illness after a median 58 days of delay after symptoms began. The proportion presenting sputum smear positive (p<0.001) and with a pulmonary cavity (p<0.001) increased significantly with increasing duration of delay.ConclusionsDelayed diagnosis and treatment of tuberculosis is associated with a significantly increased risk of pulmonary sputum smear positivity and pulmonary cavity. To decrease risk of transmission, treatment delay needs to be reduced further.
BackgroundNon-adherence to tuberculosis (TB) treatment threatens the success of treatment, increases the risk of TB spread, and leads to the development of drug resistance. The present study assessed non-adherence to anti-TB treatment among internal migrants with pulmonary TB living in Shenzhen, China, and examined risk factors for non-adherence in order to identify targets for intervention.MethodsA total of 794 internal migrants with TB treated at Bao’an Hospital for Chronic Disease Prevention and Cure, Shenzhen, were recruited. Structured questionnaires were used to collect data on these patients’ history and experiences with TB treatment. Ordinal logistic regression model were used to identify risk factors for non-adherence.ResultsThe proportion of patients who had missed one dose of medication within two weeks was 93/794 (11.71%), and those who missed at least two doses of medication within two weeks was 167/794 (21.03%), with a total of 33.74% of patients not adhering to TB treatment. Lack of knowledge about TB treatment and longer travel time to the nearest community health centers are significant predictors for non-adherence.ConclusionsThe present study shows that non-adherence is common among internal migrants with TB. Patients who lack knowledge about TB treatment or have to travel far to get treated are prone to miss one or more doses of medication. Interventions to improve health education and healthcare access are essential to reduce non-adherence to TB treatment among internal migrants.
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