Pseudorabies virus UL38 attenuates the cGAS-STING signaling pathway by recruiting Tollip to promote STING for autophagy degradation.

Natural immunity is the first defense line of the host immune system, which plays a significant role in combating foreign pathogenic microorganisms. The IFN-ß (interferon-beta) signaling pathway, being a typical example of innate immunity, plays a vital function. This study aimed to elucidate the function of pseudorabies virus (PRV) UL38 protein (unique long region 38) in suppressing the activation of the IFN-ß signaling pathway. The findings from our study indicate that the PRV UL38 protein effectively hampers the activation of IFN-ß by poly (dA: dT) (poly(deoxyadenylic-deoxythymidylic)) and 2'3'-cGAMP (2'-3'-cyclic GMP-AMP). Furthermore, UL38 exhibits spatial co-localization with STING (stimulator of interferon genes) and effectively hinders STING dimerization. Subsequently, STING was downgraded to suppress the production of IFN-ß and ISGs (interferon stimulated genes). Immunoprecipitation analysis revealed that the interaction between UL38 and STING, which subsequently initiated the degradation of STING via selective autophagy mediated by TOLLIP (toll interacting protein). To summarize, this research elucidates the function of UL38 in counteracting the cGAS (cGAMP synthase)-STING-induced IFN-ß pathway. The PRV UL38 protein may attenuate the activation of IFN-ß as a means of regulating the virus's persistence in the host.

Attitudes, knowledge and practices concerning delirium among paediatric intensive care unit nurses: a multisite cross-sectional study in Sichuan, China.

BACKGROUND: Delirium is an acute mental state associated with poor outcomes. The incidence of delirium is high, especially in the paediatric intensive care unit (PICU). It is important for staff, particularly nurses, to understand delirium and implement interventions to prevent it. We performed a survey with the aim of evaluating and analysing the factors influencing the knowledge, attitudes and behaviour of PICU nurses towards delirium. METHODS: This cross-sectional descriptive study included 215 PICU nurses in 6 PICUs from five teaching hospitals in Sichuan Province, China. An online survey about the knowledge, attitudes and practices related to delirium care was conducted among PICU nurses used a self-made and validated questionnaire. The data were analysed using descriptive statistics; differences between groups were compared using t tests, ANOVA and rank-sum tests. Variables with a significance level of 0.05 in the univariate analysis were entered into the multivariable regression analysis to identify predictors. RESULTS: Only 14.4% of the nurses had a good understanding of delirium, and 40.9% had received relevant training. The mean knowledge score was 9.01 ± 3.86, and the overall passing rate of knowledge was 49.8%. The mean attitude and behaviour scores were 40.95 ± 5.62 and 40.33 ± 8.01, respectively. Among the hospitals, different delirium assessments for children and specific training were performed, explaining approximately 10% of the variability in knowledge scores (F = 6.152), approximately 10% of the variability in attitude/belief scores (F = 5.908), and approximately 17% of the variability in practice scores (F = 10.767). CONCLUSIONS: PICU nurses have poor knowledge of delirium, particularly regarding its clinical manifestations, influencing factors and medications used, and they have adequate attitudes and confidence and good behaviour regarding delirium in children. To better prevent delirium, we suggest that PICU departments routinely assess delirium and conduct delirium training for nurses. TRIAL REGISTRATION: Not applicable.

Tailoring the p-Band Center of NS Pair for Accelerating High-Performance Lithium-Oxygen Battery.

The local coordination environment of catalytical moieties directly determines the performance of electrochemical energy storage and conversion devices, such as Li-O2 batteries (LOBs) cathode. However, understanding how the coordinative structure affects the performance, especially for non-metal system, is still insufficient. Herein, a strategy that introduces S-anion to tailor the electronic structure of nitrogen-carbon catalyst (SNC) is proposed to improve the LOBs performance. This study unveils that the introduced S-anion effectively manipulates the p-band center of pyridinic-N moiety, substantially reducing the battery overpotential by accelerating the generation and decomposition of intermediate products Li1-3 O4 . The lower adsorption energy of discharging product Li2 O2 on NS pair accounts for the long-term cyclic stability by exposing the high active area under operation condition. This work demonstrates an encouraging strategy to enhance LOBs performance by modulating the p-band center on non-metal active sites.

[Nomographic Model for Predicting Severe Foot Pain in Nurses from Tertiary Hospitals in China].

Objective: To investigate the prevalence and common sites of severe foot pain among nurses, to define the risk factors of severe foot pain in nurses in tertiary hospital in China, and to construct a nomograph model for predicting individuals' risks for severe foot pain. Methods: Between August 2019 and December 2019, a stratified global sampling method was used to select 10691 nurses from 351 tertiary hospitals in China to investigate the incidence of severe foot pain among them. The variables that may affect the occurrence of severe foot pain were analyzed by single factor analysis to identify the influencing factors of severe foot pain in nurses. Furthermore, the independent risk factors of severe foot pain were analyzed by stepwise logistic regression analysis. The statistically significant factors identified in the multivariate regression analysis were incorporated into the nomograph prediction model. The predictive performance of the nomograph was measured by the consistency index (C-index) and calibrated with 1000 Bootstrap samples. Results: A total of 3419 nurses out of the 10691 had foot pain, resulting in an incidence of 31.98%. The incidence of severe pain (VAS score 7-10) was 2.27% (243 of 10691). The locations of severe pain were more commonly found in the soles and heels of both feet. Six factors, including age, education, the material of the work shoes, comfortableness of the work shoes, number of complications, and foot injure history, were incorporated in the nomograph predicting model. The C-index value was 0.706 and the standard curve fitted well with the calibrated prediction curve. Conclusion: The risk prediction model constructed in this study showed sound performance in predicting the risk of severe foot pain in nurses, and all the indicators involved are simple and the relevant data are easily obtained. The model can provide reference for preventing severe foot pain in nurses.

Single-Atom Tailored Hierarchical Transition Metal Oxide Nanocages for Efficient Lithium Storage.

Mitigating the mechanical degradation and enhancing the ionic/electronic conductivity are critical but challengeable issues toward improving electrochemical performance of conversion-type anodes in rechargeable batteries. Herein, these challenges are addressed by constructing interconnected 3D hierarchically porous structure synergistic with Nb single atom modulation within a Co3 O4 nanocage (3DH-Co3 O4 @Nb). Such a hierarchical-structure nanocage affords several fantastic merits such as rapid ion migration and enough inner space for alleviating volume variation induced by intragrain stress and optimized stability of the solid-electrolyte interface. Particularly, experimental studies in combination with theoretical analysis verify that the introduction of Nb into the Co3 O4 lattice not only improves the electron conductivity, but also accelerates the surface/near-surface reactions defined as pesudocapacitance behavior. Dynamic behavior reveals that the ensemble design shows huge potential for fast and large lithium storage. These features endow 3DH-Co3 O4 @Nb with remarkable battery performance, delivering ≈740 mA h g-1 after ultra-long cycling of 1000 times under a high current density of 5 A g-1 . Importantly, the assembled 3DH-Co3 O4 @Nb//LiCoO2 pouch cell also presents a long-lived cycle performance with only ≈0.059% capacity decay per cycle, inspiring the design of electrode materials from both the nanostructure and atomic level toward practical applications.

Encephalomyocarditis Virus Abrogates the Interferon Beta Signaling Pathway via Its Structural Protein VP2.

Type I interferon (IFN)-mediated antiviral responses are critical for modulating host-virus responses, and indeed, viruses have evolved strategies to antagonize this pathway. Encephalomyocarditis virus (EMCV) is an important zoonotic pathogen, which causes myocarditis, encephalitis, neurological disease, reproductive disorders, and diabetes in pigs. This study aims to understand how EMCV interacts with the IFN pathway. EMCV circumvents the type I IFN response by expressing proteins that antagonize cellular innate immunity. Here, we show that EMCV VP2 is a negative regulator of the IFN-ß pathway. This occurs via the degradation of the MDA5-mediated cytoplasmic double-stranded RNA (dsRNA) antiviral sensing RIG-I-like receptor (RLR) pathway. We show that structural protein VP2 of EMCV interacts with MDA5, MAVS, and TBK1 through its C terminus. In addition, we found that EMCV VP2 could significantly degrade RLRs by the proteasomal and lysosomal pathways. For the first time, EMCV VP2 was shown to play an important role in EMCV evasion of the type I IFN signaling pathway. This study expands our understanding that EMCV utilizes its capsid protein VP2 to evade the host antiviral response.IMPORTANCE Encephalomyocarditis virus is an important pathogen that can cause encephalitis, myocarditis, neurological diseases, and reproductive disorders. It also causes huge economic losses for the swine industry worldwide. Innate immunity plays an important role in defending the host from pathogen infection. Understanding pathogen microorganisms evading the host immune system is of great importance. Currently, whether EMCV evades cytosolic RNA sensing and signaling is still poorly understood. In the present study, we found that viral protein VP2 antagonized the RLR signaling pathway by degrading MDA5, MAVS, and TBK1 protein expression to facilitate viral replication in HEK293 cells. The findings in this study identify a new mechanism for EMCV evading the host's innate immune response, which provide new insights into the virus-host interaction and help develop new antiviral approaches against EMCV.

Modified endometriosis fertility index is more accurate to predict the non-ART pregnancy rate following surgery: a cohort of Chinese women.

OBJECTIVE: To examine whether a modified endometriosis fertility index (EFI) can better predict the rate of pregnancy without assisted reproductive technologies (ART) after laparoscopic surgery in infertile Chinese women with endometriosis. METHODS: 564 infertile women undergoing laparoscopy for endometriosis were retrospectively collected from January 2014 to December 2018. 472 patients were used to modify the EFI based on new, optimal cutoffs for its predictor variables. The predictive accuracy of the modified EFI was examined in the other 92 patients. RESULTS: Among the patients for the EFI modification, the multivariable Cox regression results showed that historical factors made more contribution in predicting non-ART pregnancy rate than surgical factors both in modified EFI (C-index: historical factors 0.617 vs surgical factors 0.558) and original EFI (C-index: historical factors 0.600 vs surgical factors 0.549). No significant relationship between the prior pregnancy and post-operative non-ART pregnancy rates was detected by both modified EFI and original EFI (p = 0.530 and 0.802, respectively). To assess the predictive effect of modified EFI, the two versions of modified EFI not only had higher predictive accuracy (C-index: 0.627 and 0.632) for non-ART pregnancy rates than that of the original EFI (C-index: 0.602) in the patients undergoing surgery during 2014-2017, but also higher than that of the original EFI (C-index: 0.638 and 0.612 vs 0.560) in the externally validated population in 2018. CONCLUSIONS: A modified EFI based on population-specific optimal cutoffs and weights might be more suitable for estimating the rate of non-ART pregnancy after laparoscopic surgery in infertile women with endometriosis.

Free-standing reduced graphene oxide/MnO2-reduced graphene oxide-carbon nanotube nanocomposite flexible membrane as an anode for improving lithium-ion batteries.

To solve the barriers of poor rate capability and inferior cycling stability for the MnO2 anode in lithium ion batteries, we present a highly flexible membrane anode employing two-dimensional (2D) reduced graphene oxide sheets (rGO) and a three-dimensional (3D) MnO2-reduced graphene oxide-carbon nanotube nanocomposite (MGC) by a vacuum filtration and thermal annealing approach. All the components in the 2D/3D thin film anode have a synergistic effect on the improved performance. The initial discharge specific capacity of the electrode with the MnO2 content of 56 wt% was 1656.8 mA h g-1 and remains 1172.5 mA h g-1 after 100 cycles at a density of 100 mA g-1. On enhancing the density to 200 mA g-1, the membrane-electrode still exhibits a large reversible discharging capacity of ∼948.9 mA h g-1 after 300 cycles. Moreover, the flexible Li-ion battery with a large area also shows excellent electrochemical performance in different bending positions, which provides the potential for wearable energy storage devices.

MicroRNA-144 mediates metabolic shift in ovarian cancer cells by directly targeting Glut1.

Warburg effect is characterized by an increased utilization of glucose via glycolysis in cancer cells, even when enough oxygen is present to properly respire. Recent studies demonstrate that deregulation of microRNAs contributes to the Warburg effect. In the present study, we show that miR-144 is downregulated while glucose transporter 1 (Glut1) is upregulated in ovarian cancers. In vitro studies further showed that miR-144 inhibits Glut1 expression through targeting its 3'-untranslated region. As a result, cells overexpressing miR-144 exhibited a metabolic shift, including enhanced glucose uptake and lactate production. The altered glucose metabolism induced by miR-144 also leads to a rapid growth of ovarian cancer cells. Taken together, our results indicate that miR-144 may serve as a molecular switch to regulate glycolysis in ovarian cancer by targeting the expression of Glut1.

First molecular survey and identification of Anaplasma spp. in white yaks (Bos grunniens) in China.

Anaplasmosis is caused by a group of obligate intracellular bacteria in the genus Anaplasma, which are transmitted by ticks and infect humans, domestic animals and wildlife. This study was conducted to determine the prevalence and molecular characterization of Anaplasma spp. in semi-wild white yaks sampled in Tianzhu Tibetan Autonomous County, northwest China. Out of 332 samples tested, 35 (10·9%) were positive for Anaplasma spp. The positive rates were 6·2% (20/322) and 5·3% (17/322) for Anaplasma bovis and Anaplasma phagocytophilum in white yaks, respectively. None of the sample was positive for Anaplasma marginale. Two (0·6%) samples were simultaneously positive to A. bovis and A. phagocytophilum. Sequence analysis of the 16S rRNA gene revealed two genotypes (ApG1 and ApG2) of A. phagocytophilum and two sequence types (ST1 and ST2) of A. bovis in white yaks. This study is the first to document the presence of Anaplasma in white yaks. Our findings extend the host range for Anaplasma species and provide more valuable information for the control and management of anaplasmosis in white yaks.

Evaluation of different nested PCRs for detection of Anaplasma phagocytophilum in ruminants and ticks.

BACKGROUND: Anaplasma phagocytophilum is a causative agent of granulocytic anaplasmosis in mammals, which has a broad geographical distribution and a high degree of clinical diversity. Currently, numerous PCR assays have been developed and used for the detection of A. phagocytophilum in various specimens. However, their performance varies. The aim of this study was to evaluate the performance of five nested PCR assays by detection of 363 ruminant and tick samples, and to select the most appropriate methods for the sensitive detection of A. phagocytophilum in environmental or clinical samples. RESULTS: Positive PCR results for A. phagocytophilum were obtained in 75 (20.7%), 42 (11.6%) and 19 (5.2%) specimens with primer sets EC (EC9/EC12a and SSAP2f/SSAP2r), EE (EE1/EE2 and EE3/EE4) and ge (ge3a/ge10r, ge9f/ge2), respectively. The amplification of template DNA with the primer set MSP (MAP4AP5/MSP4AP3, msp4f/msp4r) could not be obtained in both ruminants and ticks, and a low specificity of the EL primers [EL(569)F/EL(1193)R, EL(569)F/EL(1142)R] in tick samples was observed. Our results revealed that the nested PCR with primer set EC complementary to the 16S rRNA gene was the most sensitive assay for detection of A. phagocytophilum in ruminant and tick specimens. A. phagocytophilum was detected in 47 (35.1%) sheep, 12 (10.4%) cattle, and 17 (14.9%) ticks. Two A. phagocytophilum genotypes were identified, that varied between sheep and cattle in sample collection sites. CONCLUSIONS: This report provides more valuable information for the diagnosis and management of granulocytic anaplasmosis in China.

Successful Laparoscopic Management of Type I Cesarean Scar Pregnancy A Case Series.

OBJECTIVE: To explore the efficacy of laparoscopic surgery without auxiliary treatment for type II cesarean scar pregnancy (CSP-II). STUDY DESIGN: This was a case series of 7 patients with CSP-II who underwent laparoscopic surgery without auxiliary treatment between April 2014 and April 2015. All cases were diagnosed by ultrasound, confirmed by laparoscopy, and managed by laparoscopic resection of scar and gestational tissue and wound repair. RESULTS: All 7 patients had successful surgeries without complication. Uterine scar and gestational tissues were resected, while also preserving the uterus. The operation time was 70.1 ± 16.3 min and blood loss was 65.7 ± 32.1 mL. Serum ß-hCG levels 24 hours after surgery declined by 84.8 ± 9.4%. Serum ß-hCG levels went back to <5 IU/L in all 7 patients by 14.4 ± 4.3 days after surgery. The time interval between surgery and first menstruation was 35.3 ± 4.5 days. CONCLUSION: These results suggest the possibility that skilled surgeons could use laparoscopy without auxiliary pretreatment to remove gestational tissues and uterine scar defect and to repair the wound in patients with CSP-II.

National serosurvey of encephalomyocarditis virus in healthy people and pigs in China.

Encephalomyocarditis virus (EMCV) is a zoonotic pathogen that has a wide spectrum of host range. The virus has been discovered on swine farms worldwide and can cause acute fatal myocarditis in piglets and reproductive disorders in sows. Although EMCV infection has been documented in farmed pigs in China, seroprevalence in humans has not been reported. In this study, we conducted nationwide serological surveys for EMCV in humans and farmed pigs in China in 2013, by the use of a double antigen sandwich ELISA method. A total of 3305 serum samples from healthy people were obtained from seven geographical regions in China, of which 1010 samples (30.56%) were positive for EMCV antibodies. The overall seroprevalence for EMCV in the age groups of 0-20, 21-40, 41-60 and >60 years were 13.5%, 30.25%, 36.83% and 38.71% respectively, showing a tendency of increasing with age (P = 0.000). A total of 3470 serum samples from farmed pigs were collected and tested for antibodies to EMCV. A high seroprevalence of 77% was recorded, and significant regional differences were observed. It was concluded that people and pigs in China were commonly infected by EMCV. In addition, in order to characterize changes of seroprevalence during natural EMCV infection in pigs, 240 serial serum samples were collected from 30 pigs (at 0, 15, 30, 60, 75, 90, 120, and 150 days of age) in a farrow-to-finish farm in China. The data showed that there were two EMCV antibody peaks: the first peak appeared at day 30, followed by a decrease in EMCV antibody titer, and the second occurred after day 75. Thus, the most susceptible period of pigs for EMCV infection was between day 30 and day 75 of age.

Predictors Associated with Forgotten Knee in Patients with Total Knee Arthroplasty Based on Multivariable Linear Regression.

OBJECTIVE: Existing studies have conflicting results about the predictors of forgotten joints in patients with total knee arthroplasty (TKA), and the relationship between psychosocial factors and forgotten knees is unknown. The purpose of this study was to confirm predictors for the forgotten joint in TKA patients. METHODS: This was an observational, prospective longitudinal study. A total of 205 patients who underwent TKA and a 6-month follow-up were included between August 2020 and September 2021. Demographic characteristics, clinical characteristics, and psychosocial variables were collected before TKA surgery (T0). The forgotten joint score (FJS) was taken before TKA surgery (T0) and at 1 month (T1), 3 months (T3), and 6 months (T6) after TKA surgery. The psychosocial variables were also completed at T6. Bivariate and multivariable linear regressions (LR) were performed to screen the predictors associated with FJS (T6). RESULTS: Patients who underwent TKA in our study had a mean FJS of 20.3 ± 12.2 before surgery, 15.9 ± 10.3 at 1 month, 28.7 ± 12.6 at 3 months, and 40.3 ± 12.5 at 6 months. The predictors were sex, combined musculoskeletal disorders (MSD), operation time, FJS (T3), range of motion (ROM) (T6), pain score (T6), Groningen orthopaedic social support scale (GO-SSS) score (T6), and the generalized anxiety disorder scale (GAD) score (T6). The data satisfied the assumptions of multivariable linear regressions. The multiple R2 of LR was 0.71, and the adjusted R2 was 0.70. The F-statistic of the LR model was 59.5 (p < 0.000). CONCLUSION: Our study revealed the level of forgotten knee decreased slightly from preoperation to 1 month postoperatively and then increased from 1 month postoperatively to 6 months postoperatively in TKA patients. The main predictors associated with the FJS at 6 months after surgery were sex, combined MSD, operation time, FJS (T3), ROM (T6), pain score (T6), GO-SSS score (T6), and anxiety (T6).

New perspective of small-molecule antiviral drugs development for RNA viruses.

High variability and adaptability of RNA viruses allows them to spread between humans and animals, causing large-scale infectious diseases which seriously threat human and animal health and social development. At present, AIDS, viral hepatitis and other viral diseases with high incidence and low cure rate are still spreading around the world. The outbreaks of Ebola, Zika, dengue and in particular of the global pandemic of COVID-19 have presented serious challenges to the global public health system. The development of highly effective and broad-spectrum antiviral drugs is a substantial and urgent research subject to deal with the current RNA virus infection and the possible new viral infections in the future. In recent years, with the rapid development of modern disciplines such as artificial intelligence technology, bioinformatics, molecular biology, and structural biology, some new strategies and targets for antivirals development have emerged. Here we review the main strategies and new targets for developing small-molecule antiviral drugs against RNA viruses through the analysis of the new drug development progress against several highly pathogenic RNA viruses, to provide clues for development of future antivirals.

Human umbilical cord-derived mesenchymal stem cells and auto-crosslinked hyaluronic acid gel complex for treatment of intrauterine adhesion.

OBJECTIVE: The purpose of this study was to explore the therapeutic characteristics of mesenchymal stem cells generated from human umbilical cord (hUC-MSCs) when utilized in conjunction with auto-crosslinked hyaluronic acid gel (HA-gel) for the management of intrauterine adhesion (IUA). The goal was to see how this novel therapy could enhance healing and improve outcomes for IUA patients. METHODS: In this study, models of intrauterine adhesion (IUA) were established in Sprague-Dawley (SD) rats, which were then organized and divided into hUC-MSCs groups. The groups involved: hUC-MSCs/HA-gel group, control group, and HA-gel group. Following treatment, the researchers examined the uterine cavities and performed detailed analyses of the endometrial tissues to determine the effectiveness of the interventions. RESULTS: The results indicated that in comparison with to the control group, both HA-gel, hUC-MSCs, and hUC-MSCs/HA-gel groups showed partial repair of IUA. However, in a more notable fashion transplantation of hUC-MSCs/HA-gel complex demonstrated significant dual repair effects. Significant outcomes were observed in the group treated with hUC-MSCs and HA-gel, they showed thicker endometrial layers, less fibrotic tissue, and a higher number of endometrial glands. This treatment strategy also resulted in a significant improvement in fertility restoration, indicating a profound therapeutic effect. CONCLUSIONS: The findings of this study suggest that both HA-gel, hUC-MSCs, and hUC-MSCs/HA-gel complexes have the potential for partial repair of IUA and fertility restoration caused by endometrium mechanical injury. Nonetheless, the transplantation of the hUC-MSCs/HA-gel complex displayed exceptional dual healing effects, combining effective anti-adhesive properties with endometrial regeneration stimuli.

Pseudorabies virus VHS protein abrogates interferon responses by blocking NF-κB and IRF3 nuclear translocation.

Herpesviruses antagonize host antiviral responses through a myriad of molecular strategies culminating in the death of the host cells. Pseudorabies virus (PRV) is a significant veterinary pathogen in pigs, causing neurological sequalae that ultimately lead to the animal's demise. PRV is known to trigger apoptotic cell death during the late stages of infection. The virion host shutdown protein (VHS) encoded by UL41 plays a crucial role in the PRV infection process. In this study, we demonstrate that UL41 inhibits PRV-induced activation of inflammatory cytokine and negatively regulates the cGAS-STING-mediated antiviral activity by targeting IRF3, thereby inhibiting the translocation and phosphorylation of IRF3. Notably, mutating the conserved amino acid sites (E192, D194, and D195) in the RNase domain of UL41 or knocking down UL41 inhibits the immune evasion of PRV, suggesting that UL41 may play a crucial role in PRV's evasion of the host immune response during infection. These results enhance our understanding of how PRV structural proteins assist the virus in evading the host immune response.

Histone H1.2 Inhibited EMCV Replication through Enhancing MDA5-Mediated IFN-ß Signaling Pathway.

Histone H1.2 is a member of the linker histone family, which plays extensive and crucial roles not only in the regulation of chromatin dynamics, cell cycle, and cell apoptosis, but also in viral diseases and innate immunity response. Recently, it was discovered that H1.2 regulates interferon-ß and inhibits influenza virus replication, whereas its role in other viral infections is poorly reported. Here, we first found the up-regulation of H1.2 during Encephalomyocarditis virus (EMCV) infection, implying that H1.2 was involved in EMCV infection. Overexpression of H1.2 inhibited EMCV proliferation, whereas knockdown of H1.2 showed a significant promotion of virus infection in HEK293T cells. Moreover, we demonstrated that overexpression of H1.2 remarkably enhanced the production of EMCV-induced type I interferon, which may be the crucial factor for H1.2 proliferation-inhibitory effects. We further found that H1.2 up-regulated the expression of the proteins of the MDA5 signaling pathway and interacted with MDA5 and IRF3 in EMCV infection. Further, we demonstrated that H1.2 facilitated EMCV-induced phosphorylation and nuclear translocation of IRF3. Briefly, our research uncovers the mechanism of H1.2 negatively regulating EMCV replication and provides new insight into antiviral targets for EMCV.

Mammalian reovirus µ1 protein attenuates RIG-I and MDA5-mediated signaling transduction by blocking IRF3 phosphorylation and nuclear translocation.

Mammalian reovirus (MRV) is a non-enveloped, gene segmented double-stranded RNA (dsRNA) virus. It is an important zoonotic pathogen that infects many mammals and vertebrates that act as natural hosts and causes respiratory and digestive tract diseases. Studies have reported that RIG-I and MDA5 in the innate immune cytoplasmic RNA-sensing RIG-like receptor (RLR) signaling pathway can recognize dsRNA from MRV and promote antiviral type I interferon (IFN) responses. However, the mechanism by which many MRV-encoded proteins evade the host innate immune response remains unclear. Here, we show that exogenous µ1 protein promoted the proliferation of MRV in vitro, while knockdown of MRV µ1 protein expression by shRNA could impair MRV proliferation. Specifically, µ1 protein inhibited MRV or poly(I:C)-induced IFN-ß expression, and attenuated RIG-I/MDA5-mediated signaling axis transduction during MRV infection. Importantly, we found that µ1 protein significantly decreased IFN-ß mRNA expression induced by MDA5, RIG-I, MAVS, TBK1, IRF3(5D), and degraded the protein expression of exogenous MDA5, RIG-I, MAVS, TBK1 and IRF3 via the proteasomal and lysosomal pathways. Additionally, we show that µ1 protein can physically interact with MDA5, RIG-I, MAVS, TBK1, and IRF3 and attenuate the RIG-I/MDA5-mediated signaling cascades by blocking the phosphorylation and nuclear translocation of IRF3. In conclusion, our findings reveal that MRV outer capsid protein µ1 is a key factor in antagonizing RLRs signaling cascades and provide new strategies for effective prevention and treatment of MRV infection.

Mammalian orthoreovirus capsid protein σ3 antagonizes RLR-mediated antiviral responses by degrading MAVS.

Mammalian orthoreovirus (MRV) outer capsid protein σ3 is a multifunctional protein containing a double-stranded RNA-binding domain, which facilitates viral entry and assembly. We reasoned that σ3 has an innate immune evasion function. Here, we show that σ3 protein localizes in the mitochondria and interacts with mitochondrial antiviral signaling protein (MAVS) to activate the intrinsic mitochondria-mediated apoptotic pathway. Consequently, σ3 protein promotes the degradation of MAVS through the intrinsic caspase-9/caspase-3 apoptotic pathway. Moreover, σ3 protein can also inhibit the expression of the components of the RNA-sensing retinoic acid-inducible gene (RIG)-like receptor (RLR) signaling pathway to block antiviral type I interferon responses. Mechanistically, σ3 inhibits RIG-I and melanoma differentiation-associated gene 5 expression is independent of its inhibitory effect on MAVS. Overall, we demonstrate that the MRV σ3 protein plays a vital role in negatively regulating the RLR signaling pathway to inhibit antiviral responses. This enables MRV to evade host defenses to facilitate its own replication providing a target for the development of effective antiviral drugs against MRV. IMPORTANCE: Mammalian orthoreovirus (MRV) is an important zoonotic pathogen, but the regulatory role of its viral proteins in retinoic acid-inducible gene-like receptor (RLR)-mediated antiviral responses is still poorly understood. Herein, we show that MRV σ3 protein co-localizes with mitochondrial antiviral signaling protein (MAVS) in the mitochondria and promotes the mitochondria-mediated intrinsic apoptotic pathway to cleave and consequently degrade MAVS. Furthermore, tryptophan at position 133 of σ3 protein plays a key role in the degradation of MAVS. Importantly, we show that MRV outer capsid protein σ3 is a key factor in antagonizing RLR-mediated antiviral responses, providing evidence to better unravel the infection and transmission mechanisms of MRV.