Activation of retinoic acid-inducible gene-I-like receptors (RLRs) is important for type I interferon (IFN-I) production and antiviral innate immunity initiation. However, the epigenetic mechanisms that regulate RLR signaling remain poorly understood and require further investigation. Here, we demonstrate that Fizzy-related protein 1 (FZR1), which is essential for mitotic exit and G1/S transition, potentiates antiviral innate immune responses against RNA viruses. Mechanistically, vesicular stomatitis virus infection increases N6-methyladenosine (m6A) modification of FZR1 mRNA, which enhances FZR1 translation and elevates intracellular FZR1 protein levels. Upregulated FZR1 attenuates mitochondrial antiviral-signaling protein (MAVS) binding to 6-Phosphofructo-2-Kinase/Fructose-2, 6-Biphosphatase 3, a glycolytic rate-limiting enzyme, thereby promoting MAVS aggregation. Furthermore, FZR1 facilitates tumor necrosis factor receptor-associated factor 3/6 (TRAF3/6) autoubiquitination independently of the anaphase-promoting complex/cyclosome, subsequently activating interferon regulatory factor 3 and P65 of nuclear factor κB to drive the production of IFN-I and proinflammatory cytokines. Consequently, FZR1 deficiency impairs antiviral responses and increases viral titer in vitro and in vivo. Pharmacological inhibition of FZR1 significantly attenuates MAVS activation and TRAF3/6 ubiquitination, thereby abolishing FZR1-mediated antiviral immunity both in vitro and in vivo. Collectively, these findings reveal a molecular mechanism by which m6A modification of FZR1 activates the MAVS-TRAF3/6 signaling axis to potentiate IFN-I-dependent antiviral innate immunity.

Gout is a disease caused by the deposition of sodium urate (MSU) crystals in the joints and tissues. Colchicine (COL) has become the first-line drug for the treatment of acute gout due to its low price and efficacy. However, colchicine is highly cytotoxic and oral administration is prone to cause severe adverse effects on the gastrointestinal tract, liver and kidney. Therefore, this study aimed to develop a novel dermal delivery formulation for addressing the safety concerns of this drug. The researchers used ethosomes encapsulation technology to improve the skin permeability of COL. In addition, in order to improve the performance of the ethosomes, it was screened and determined that the addition of 1.0-1.5 mg of ceramide III (Cer3) per mL of ethosomes as a modifier could significantly enhance the stability of the ethosomes, Cer3/COL-ethosomes (CCE) were successfully constructed. The CCE was then mixed with a cataplasm matrix to produce a colchicine-carrying CCE cataplasm, which demonstrated the superimposed effect of the advantages of the two dosage forms, the ethosomes and the cataplasm. Compared with the traditional delivery method of COL, this topical formulation is an attractive alternative for the treatment of gout as it can achieve effective blood levels without causing fluctuations in blood levels, and has good efficacy and higher safety profile.

beta-amyloid protein (A(3) deposition and plaque formation are key pathological markers leading to Alzheimer's disease (AD), and effective detection of A beta can help in the diagnosis and treatment of AD. Near-infrared fluorescence (NIRF) imaging has emerged as an advanced technique for A beta detection due to its low cost and convenience. In this study, BPQD@PDA-F nanocomposite consisting of black phosphorus quantum dots (BPQD), polydopamine (PDA) and fluorescent probe F were designed for fluorescence detection and modulation of A beta 42 aggregates. BPQD@PDA-F nanocomposite had a good fluorescence response (emission wavelength > 650 nm, and the fluorescence intensity was significantly increased when combined with A beta 42 aggregates), selectivity, fluorescence stability, and could be used for specific fluorescence imaging of A beta plaques in AD mouse brain slices. Meanwhile, BPQD@PDA-F nanocomposite was a multifunctional nanoplatform that could inhibit A beta 42 aggregates and significantly disaggregate A beta 42 aggregates under near-infrared (NIR) irradiation, reduce the toxicity of A beta 42 aggregates to SH-SY5Y cells. In particular, it could better penetrate the blood-brain barrier (BBB) under NIR irradiation. Therefore, BPQD@PDA-F nanocomposite provided an effective strategy for the detection and modulation of A beta 42 aggregates, which was expected to be used for the diagnosis and treatment of AD.

Background Due to global climate change, high temperature and heatwaves have become critical issues that pose threat to human health. An effective early warning system is essential to mitigate the health risks associated with high temperature and heatwaves. However, most of the current heatwave early warning systems are not adequately developed based on the heat-health risk model, and the health impact of hot weather has not been well managed in most countries. Methods This study proposed a " full-season coverage and population health-oriented graded early-warning" concept and developed a heat-health surveillance, forecast and early warning (HHSEW) model. The exposure-response (E-R) relationship between temperature and mortality was analyzed through a two-stage approach using time-series analysis data from 323 counties across China for the period 2013-2018. The premature mortality curve at each temperature percentile was plotted and four temperature-percentile points on the curve were determined as the thresholds of the pre-warning and warning levels 1-3 based on the variations in the rates of the segmental slopes on the curve. The HHSEW model was evaluated by comparing the frequency, the mortality risk of all-cause and cause-specific diseases, the predicted numbers of premature deaths, and the heat-related health economic burden at each warning level with those of the current high temperature early warning systems. Findings The HHSEW model determined fi ve levels, including seasonal surveillance, pre-warning, and warning levels 1-3. There was a gradual increase in the mortality risks of all-cause and cause-specific diseases along with the increase of warning levels. The risk of all-cause mortality increased by 9.79% (95% CI: 8.59%-11.01%), 22.62% (95% CI: 19.49%-25.83%), 28.36% (95% CI: 24.72%-32.10%), and 33.87% (95% CI: 28.89%-39.06%) at the pre warning level, warning level 1, warning level 2, and warning level 3, respectively. Through our HHSEW model, 94,008 heat-related all-cause deaths were predicted annually in the 337 major cities of China, which was much larger than the number (14,858) of the China Meteorological Administration (CMA) heatwave early-warning system currently used in China. It was estimated that the proper implementation of the HHSEW-based early warning system would save 220 billion CNY in heat-related health burden compared to the current heatwave early-warning system. Interpretation The HHSEW model has been proven to surpass the current heatwave early warning system. With its full-season coverage and graded warning levels for heat-related health risks, the HHSEW model and system can provide timely early warnings to the public, leading to significant health benefits. This methodology, labeled " full season coverage and population health-oriented graded early-warning", should be implemented globally to mitigate the escalating health risks associated with high temperature.

Hantaan virus (HTNV) infection causes severe hemorrhagic fever with renal syndrome (HFRS) in humans and the infectious process can be regulated by autophagy. The phosphatase and tensin homolog (PTEN) protein has antiviral effects and plays a critical role in the autophagy pathway. However, the relationship between PTEN and HTNV infection is not clear and whether PTEN-regulated autophagy involves in HTNV replication is unknown. Here, we identified that HTNV infection inhibits PTEN expression in vitro and in vivo. The HTNV glycoprotein Gc promotes PTEN ubiquitination and degradation through 26S-proteasome pathway via the E3 ubiquitin ligase NEDD4. In addition, knockdown of PTEN prevents autophagy and increases HTNV production, while overexpression of PTEN induces autophagosome formation which can wrap HTNV particles, thus leading to restrain the production of progeny viruses. Altogether, our findings reveal the role of PTEN in HTNV infection by autophagy, highlighting the potential importance of PTEN and autophagy in the treatment of HFRS diseases.

In diabetic wounds, the presence of hyperglycemia is often accompanied by a persistent inflammatory response, oxidative stress damage, impaired angiogenesis and bacterial infections around the wound, resulting in impaired proliferation of dermal and epidermal cells and impaired skin regeneration in diabetic wounds. To solve the above problems, this study designed a near-infrared (NIR) light-responsive multifunctional poloxamer hydrogel (EGF/PDA-MXene Gel). The Gel is composed of two-dimensional nanomaterials (2D NMs) MXene as the core, modified by polymer, further loaded with epidermal growth factor (EGF), and has antibacterial, antioxidant, photothermal properties. Meanwhile, EGF/PDA-MXene Gel can be used as a drug repository, alleviating the problem of short half-life, and realizing the sustained release of EGF. The NIR photothermal property induces protein denaturation leading to the death of pathogenic bacteria, avoiding the common clinical problem of antibiotic resistance. In addition, EGF/PDA-MXene Gel promotes diabetic chronic wound healing by promoting epidermal regeneration, collagen deposition, angiogenesis, and several other mechanisms. Therefore, the Gel preparation strategies that combine bioactive molecules with 2D NMs, which maintains the activity of EGF while exploiting the antimicrobial advantages of 2D NMs photothermally, provide a new and promising therapeutic approach for accelerating the repair of chronic infected wounds.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of coronavirus disease 2019 (COVID-19). Severe and fatal COVID-19 cases often display cytokine storm i.e. significant elevation of pro-inflammatory cytokines and acute respiratory distress syndrome (ARDS) with systemic hypoxia. Understanding the mechanisms of these pathogenic manifestations would be essential for the prevention and especially treatment of COVID-19 patients. Here, using a dual luciferase reporter assay for hypoxia-response element (HRE), we initially identified SARS-CoV-2 nonstructural protein 5 (NSP5), NSP16, and open reading frame 3a (ORF3a) to upregulate hypoxia-inducible factor-1α (HIF-1α) signaling. Further experiments showed NSP16 to have the most prominent effect on HIF-1α, thus contributing to the induction of COVID-19 associated pro-inflammatory response. We demonstrate that NSP16 interrupts von Hippel-Lindau (VHL) protein interaction with HIF-1α, thereby inhibiting ubiquitin-dependent degradation of HIF-1α and allowing it to bind HRE region in the IL-6 promoter region. Taken together, the findings imply that SARS-CoV-2 NSP16 induces HIF-1α expression, which in turn exacerbates the production of IL-6.

Background and aims: The transplacental vertical transfer of maternal antibodies was determined to be a crucial factor in conferring protective immunity to infants following delivery, and this study aimed to evaluate the protective effect of maternal preconception COVID-19 vaccination on infants. Methods: A prospective cohort study was conducted at the National Clinical Medical Research Center for Child Health and Diseases in Chongqing, China, spanning from July 2022 to April 2023. The study included infants from mothers with a preconception COVID-19 vaccination and (or) a SARS-CoV-2 infection during pregnancy. Titers of SARS-CoV-2 immunoglobulin G (IgG) and cross-neutralizing activity against SARS-CoV-2 variants were detected. Results: In this cohort study comprising 158 infants, it was observed that infants born to mothers who experienced a pregnancy-related breakthrough infection following a preconception vaccination had the highest titers of SARS-CoV-2 IgG and cross-neutralizing antibody activity against different variants compared to those with either of these factors alone. The transplacental vertical transmission of anti-SARS-CoV-2 antibodies decreased significantly with increasing age, from 3.16 ODs at birth to 2.29 ODs at two months, and persisted for approximately four months after birth. The predominant subclass of passively transmitted antibodies via the placenta was found to be IgG1, and a positive correlation was observed between the titers of SARS-CoV-2 IgG and IgG1 (R = 0.59, p < 0.001; Slope: 0.49 ± 0.070, p < 0.001). Conclusions: Maternal preconception COVID-19 vaccination represents a promising immunological strategy for conferring postnatal protection to infants, especially during the period of heightened risk of exposure to SARS-CoV-2 infection. It is imperative to underscore the significance of vaccination for women who are preparing to become pregnant or are pregnant, and concerted efforts must be made to promote vaccination among eligible women.

Hantaan virus (HTNV) infection in humans can cause hemorrhagic fever and renal syndrome (HFRS). Understanding host responses to HTNV infection is crucial for developing effective disease intervention strategies. Previous RNA-sequencing studies have investigated the role of microRNAs (miRNAs) in the post-transcriptional regulation of host genes in response to HTNV infection. In this study, we demonstrated that HTNV infection induces let-7a expression in human umbilical vein endothelial cells (HUVEC) and that HTNV G protein upregulates the expression of let-7a. miRNA let-7a mimics and inhibitors validated the predicted targets, including cell apoptosis genes (FAS, caspase-8, and caspase-3) and inflammatory factors (IL-6 and its related factors). Modulation of miRNA let-7a levels by miRNA mimics and inhibitors affected HTNV replication, indicating that HTNV modulates host miRNA expression to affect the outcome of the antiviral host response.

Background According to the histopathology, lung adenocarcinoma (LUAD) could be divided into five distinct pathological subtypes, categorized as high-risk (micropapillary and solid) group, intermediate-risk (acinar and papillary) group, and low-risk (lepidic) group. Despite this classification, there is limited knowledge regarding the role of transcription factors (TFs) in the molecular regulation of LUAD histology patterns. Methods Publish data was mined to explore the candidate TFs associated with high-risk histopathology in LUAD, which was validated in tissue samples. Colony formation, CCK8, EdU, transwell, and matrigel assays were performed to determine the biological function of FAM83A in vitro. Subcutaneous tumor-bearing in BALB/c nude mice and xenograft perivitelline injection in zebrafish were utilized to unreal the function of FAM83A in vivo. We also performed chromatin immunoprecipitation (ChIP), dual-luciferase reporter, and rescue assays to uncover the underline mechanism of FAM83A. Immunohistochemistry (IHC) was performed to confirm the oncogenic role of FAM83A in clinical LUAD tissues. Results Screening the transcriptional expression data from TCGA-LUAD, we focus on the differentially expressed TFs across the divergent pathological subtypes, and identified that the expression of FAM83A is higher in patients with high-risk groups compared with those with intermediate or low-risk groups. The FAM83A expression is positively correlated with worse overall survival, progression-free survival, and advanced stages. Gain- and loss-of-function assays revealed that FAM83A promoted cell proliferation, invasion, and migration of tumor cell lines both in vivo and in vitro. Pathway enrichment analysis shows that FAM83A expression is significantly enriched in cell cycle-related pathways. The ChIP and luciferase reporter assays revealed that FAM83A hijacks the promoter of FOXM1 to progress the malignant LUAD, and the rescue assay uncovered that the function of FAM83A is partly dependent on FOXM1 regulation. Additionally, patients with high FAM83A expression positively correlated with higher IHC scores of Ki-67 and FOXM1, and patients with active FAM83A/FOXM1 axis had poor prognoses in LUAD. Conclusions Taken together, our study revealed that the high-risk histological subtype-related FAM83A hijacks FOXM1 transcriptional regulation to promote malignant progression in lung adenocarcinoma, which implies targeting FAM83A/FOXM1 is the therapeutic vulnerability.

Background: Hantaan virus (HTNV, Orthohantavirus hantanensae species, Hantaviridae family) is the main etiological agent responsible for hemorrhagic fever with renal syndrome (HFRS). The novel HTNV may pose a potential danger to the control and prevention of HFRS in China, which highlights the importance of vaccine development in public health management. In previous studies, our laboratory discovered and successfully isolated a new HTNV strain, HV004 strain, from Apodemus agrarius captured in an epidemic area in Hubei, China.Methods: An initial biological and pathogenicity characterization of HTNV 76-118 (standard train), HV114 strain (a clinical isolate from Hubei province in 1986), and the novel isolate HV004 strain from the epidemic areas of Hubei province were performed in susceptible cells and in vivo. An experimental HV004 strain inactivated vaccine was prepared, and its corresponding immunogenicity was analyzed in BALB/c mice.Results: HV004 strain had a similar but higher pathogenicity than HTNV 76-118 and HV114 in suckling mice. A subcutaneous vaccination (s.c.) with the inactivated HTNV vaccine adjuvanted with aluminum, followed by a challenge intraperitoneally with 106 FFU/ml HTNV, afforded full protection against an HTNV challenge. All immunized mice in every group elicited serum neutralizing antibodies with increasing dosages, which may protect mice from HTNV infection. A dose-dependent stimulation index of splenocytes was also observed in immunized mice. The percentage of IFN-gamma-producing CD3+CD8+ T cells was significantly higher in the spleens of immunized mice than in those of control mice.Conclusions: These findings suggest that the inactivated HTNV vaccine may stimulate mice to produce high levels of antibodies with neutralization activity and elicit specific anti-HTNV humoral and cellular immune responses in BALB/c mice against the prevalent strain of HTNV in south central China.

OBJECTIVEOrthohantaviruses (genus Orthohantavirus, family Hantaviridae of order Bunyavirales) are rodent-borne viruses causing 2 human diseases: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), which are mainly prevalent in Eurasia and the Americas, respectively. We initiated this study to investigate and analyze the Orthohantaviruses infection in rodent reservoirs and humans in the Hubei Province of China from 1984 to 2010.SAMPLEThe study included 10,314 mouse and 43,753 human serum samples.PROCEDURESIn this study, we analyzed the incidence of Orthohantavirus infection in humans and observed changes in rodent reservoirs in Hubei Province.RESULTSThe results indicated that although the incidence of HFRS declined from the 1990s, the human inapparent infection did not decrease dramatically. Although elements of the disease ecology have changed over the study period, Apodemus agrarius and Rattus norvegicus remain the major species and a constituent ratio of Rattus norvegicus increased. Rodent population density fluctuated between 16.65% and 2.14%, and decreased quinquennially, showing an obvious downward trend in recent years. The average orthohantaviruses-carrying rate was 6.36%, of which the lowest rate was 2.92% from 2006 to 2010. The analysis of rodent species composition showed that Rattus norvegicus and Apodemus agrarius were the dominant species over time (68.6% [1984 to 1987] and 90.4% [2000 to 2011]), while the composition and variety of other species decreased. The density of rodents was closely related to the incidence of HFRS (r = 0.910, P = .032).CLINICAL RELEVANCEOur long-term investigation demonstrated that the occurrence of HFRS is closely related to rodent demographic patterns. Therefore, rodent monitoring and rodent control measures for prevention against HFRS in Hubei are warranted.

目的 观察小儿宝泰康颗粒对呼吸道合胞病毒和腺病毒感染细胞的抑制作用,以便为呼吸道病毒感染的治疗提供新的药物.方法 通过细胞培养技术观察不同浓度的小儿宝泰康颗粒对HEp-2细胞的细胞毒作用,采用MTT法并结合细胞病变效应(CPE)法检测病毒感染细胞存活率和病毒抑制率,以利巴韦林作为阳性药物对照,评价该药物对呼吸道合胞病毒和腺病毒感染细胞的抗病毒活性.结果 小儿宝泰康颗粒对HEp-2细胞的半数细胞毒性浓度(TC50)为4.4 mg·mL-1,对呼吸道合胞病毒的半数有效浓度(EC50)为2.03 mg·mL-1,而腺病毒的EC50为0.65 mg·mL-1,抗病毒指数分别为2.17和6.75,在对两种病毒的直接灭活作用中,EC50分别为4.13和8.99 mg·mL-1.阳性对照药物利巴韦林在128 g·mL-1时,对呼吸道合胞病毒和腺病毒的抑制率分别为92.7％和80.16％.结论 小儿宝泰康颗粒是一种对呼吸道合胞病毒和腺病毒感染有抗病毒作用的药物,有临床应用前景和进一步研究的价值.

Introduction: Rapidly emerging diseases, such as viral infections, cancer, and autoimmune disorders are becoming an increasing global health concern. Natural products, including plant extracts and compounds, possess an enormous spectrum of pharmacological activities, including antiviral, anticancer, immunomodulatory, antiasthma, anti-diabetic, anti-hypertension, and anti-rheumatism activities. Among them, the genus Uncaria (Rubiaceae family), rich in alkaloids and triterpenes, is believed to have vast therapeutic potential. This genus is mostly found in tropical regions, such as Africa, Southeast Asia, and Southeast America. In this review, we aim to summarize the studies on plant substances of genus Uncaria showing promising antimicrobial, anticancer, and immunomodulatory activities. Methodology: A total of 814 studies were identified through database searches, of which 681 studies were excluded due to duplication and irrelevance to antimicrobial, immunomodulatory, and pharmacology activity. 133 studies were included, out of which 16 studies were related to antimicrobial and 117 studies related to the pharmacology of Uncaria. Conclusion: According to the collected data Uncaria species proved to have a broad range of pharmacological activities, which makes it more interesting for further studies, to explore more about its antimicrobial, immunomodulatory, and other potential pharmacological properties.

Objective: The present study aimed to screen the differentially expressed (DE) circular RNAs (circ-RNAs) between lumbar intervertebral disc degeneration (IVDD) and normal tissues. Material and Methods: In this experimental study, microarray hybridization was performed to evaluate circ-RNA expression, and the DE circ-RNAs were confirmed by quantitative real-time polymerase chain reaction (qRT-PCR). Host genes of DE circ-RNAs were predicted, and their functions were evaluated. Further, a competitive endogenesis (ce) RNA network among 4 DE circ-RNAs-miRNA-mRNA was constructed by Cytoscape. Results: A total of 2636 circ-RNAs were detected in all samples; among them, 89.23% were exonic circ-RNAs. There were 138 DE circ-RNAs, including 134 up-regulated circ-RNAs and 4 downregulated circ-RNAs in IVDD samples. qRT-PCR validation experiments showed that expression trends of hsa_circ_0003239, hsa_circ_0003162, hsa_circ_0005918, and hsa_circ_0005556 were in line with the microarray analysis results. Functional enrichment analysis showed that host genes of DE circ-RNAs significantly disturbed pathways of regulation of actin cytoskeleton, propanoate metabolism, and ErbB signaling pathway. The four DE circ-RNAs related ceRNA network was constructed. Conclusions: Our results revealed that circ-RNAs can function as miRNA sponges and regulate parent gene expression to affect IVDD.

目的:观察小儿宝泰康颗粒对流感病毒感染细胞的抑制作用.方法:通过细胞培养技术观察不同浓度的小儿宝泰康颗粒对Madin-Darby犬肾(MDCK)细胞的细胞毒性作用,采用MTT法并结合CPE法检测细胞成活率和病毒抑制率,计算药物的抗病毒指数TI,以利巴韦林作为阳性对照药物,评价该药物对甲、乙型流感病毒的抗病毒活性.结果:小儿宝泰康颗粒对MDCK细胞的半数细胞毒性浓度(CC50)为5.6 mg/mL,对甲型H1 N1流感病毒感染MDCK细胞的半数有效浓度(EC50)为2.1 mg/mL,而对乙型流感病毒的EC50为1.44 mg/mL,抗病毒指数分别为2.64和3.89.在阳性对照药物实验中,利巴韦林在200μg/mL时,对甲、乙型流感病毒的抑制率均达到70％以上.结论:小儿宝泰康颗粒是一种对不同型流感病毒感染有抗病毒作用的药物,有临床应用前景和进一步研究的价值.

Hantaan virus (HTNV), a Hantavirus serotype that is prevalent in Asia, causes hemorrhagic fever with renal syndrome (HFRS) with high mortality in human race. However, the pathogenesis of HTNV infection remains elusive. Circular RNAs (circRNAs), a new type of non-coding RNAs, play a crucial role in various pathogenic processes. Nevertheless, circRNA expression profiles and their effects on pathogenesis of HTNV infection are still completely unknown. In the present study, RNA sequencing was performed to analyze the circRNA, microRNA (miRNA), and mRNA expression profiles in HTNV-infected and mock-infected human umbilical vein endothelial cells (HUVECs). A total of 70 circRNAs, 66 miRNAs, and 788 mRNAs were differently expressed. Several differentially expressed RNAs were validated by RT-qPCR. Moreover, we verified that some differentially expressed RNAs, such as circ_0000479, miR-149-5p, miR-330-5p, miR-411-3p, RIG-I, CMPK2, PARP10, and GBP1, promoted or inhibited HTNV replication. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis demonstrated that the host genes of differentially expressed circRNAs were principally involved in the innate immune response, the type I interferon (IFN) signaling pathway, and the cytokine-mediated signaling pathway. Additionally, the circRNA-miRNA-mRNA regulatory network was integrally analyzed. The data showed that there were many circRNA-miRNA-mRNA interactions in HTNV infection. By dual-luciferase reporter assay, we confirmed that circ_0000479 indirectly regulated RIG-I expression by sponging miR-149-5p, hampering viral replication. This study for the first time presents a comprehensive overview of circRNAs induced by HTNV and reveals that a network of enriched circRNAs and circRNA-associated competitive endogenous RNAs (ceRNAs) is involved in the regulation of HTNV infection, thus offering new insight into the mechanisms underlying HTNV-host interaction.

The resistance of drugs to the new influenza A virus (IAV) strains and the limited efficiency of vaccines to prevent seasonal flu epidemics underscore the urgency in finding novel strategies to block IAV infection, which is required to gain insights into the mechanism of the initial step of IAV adhesion. While it is well established that IAVs bind to respiratory tract cells by recognizing sialylated glycans on host cell membranes through a multivalency effect, how IAVs dynamically respond to multiple glycan receptors via distinct valencies has not been fully understood, limiting the discovery of novel anti-flu strategies. Using single-particle tracking to record the 2D mobilities and surface residence times of highly pathogenic H5N1 avian IAVs adhered to fluidic membranes containing alpha 2-3 sialylated GM3 glycolipids, we quantified the univalent and multivalent IAV adhesion channels, which provide insights into the mechanism of IAV binding; IAV can guide the clustering of dynamic glycolipids to statistically match the multivalent binding affinities for IAV adhesion. This mechanism can be inhibited by disrupting the dynamic glycan clustering on membranes of varying fluidities, like the gel phase membrane. This work facilitates a deeper fundamental understanding of IAV infection as well as the development of novel anti-flu strategies.

Human infection of orthohantavirus can cause potentially fatal diseases, such as hemorrhagic fever with renal syndrome (HFRS) caused by Hantaan virus (HTNV) in Eurasia. Exosomes are new carriers for information exchange between cells. Cumulative findings suggest that exosomes released from parental infected cells can block or promote viral infection in recipient cells, but the role of exosomes in hantavirus infection is poorly understood. In our study, we identified the exosomes derived from HTNV-infected human vascular endothelial cells (HUVECs) (Exo-HV) and found the antiviral properties of Exo-HV in the uninfected recipient cells. High-throughput sequencing revealed the distinctly expressed miRNAs transcriptomes in Exo-HV. MiR-145-5p, one of the abundant miRNAs packaged into Exo-HV, was found to be able to transferred to recipient cells and functioned by directly targeting M RNA of HTNV 76-118 and inducing type I interferon (IFN-I) response, thus, blocking the viral replication. Concluding, this study indicated that exosomes released by HTNV-infected HUVECs were able to transfer active molecules, miR-145-5p as a proving sample, to mediate novel anti-HTNV activity in the neighboring uninfected cells, which will help us to explore new strategies for the treatment of infectious disease utilizing exosomes with miRNA.