Matrix Metalloproteinase-13 in Atherosclerotic Plaque Is Increased by Influenza A Virus Infection.

BACKGROUND: Influenza virus infection triggers acute cardiovascular events. Several studies have demonstrated that influenza A virus infection was associated with immune cell influx and increased production of inflammatory cytokines in the atherosclerotic plaque lesion, but the underlying mechanism for these findings is not clear. METHODS: We examined the expression levels of matrix metalloproteinases (MMPs) by influenza A virus infection in human cells using quantitative real-time polymerase chain reaction, Western blot, and human MMP-13 enzyme-linked immunosorbent assay. In an animal study, protein expression in the plaque lesions of apolipoprotein E (ApoE)-deficient mice were analyzed by immunohistochemistry and Western blot. RESULTS: We confirmed that MMP-13 was increased in influenza A virus-infected cells. In the aorta of infected ApoE-deficient mice, MMP-13 was increased at 3 days after infection. Immunohistochemical staining results suggested that collagen was degraded in the MMP-13 expression area and that macrophages were the main source of MMP-13 expression. Furthermore, the expression of MMP-13 was regulated by influenza A virus through activation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway. CONCLUSIONS: In this study, we demonstrated that p38 MAPK-mediated MMP-13 expression by influenza A virus infection led to destabilization of vulnerable atherosclerotic plaques in the artery.

Advances in Zika Virus⁻Host Cell Interaction: Current Knowledge and Future Perspectives.

Emerging mosquito-transmitted RNA viruses, such as Zika virus (ZIKV) and Chikungunya represent human pathogens of an immense global health problem. In particular, ZIKV has emerged explosively since 2007 to cause a series of epidemics in the South Pacific and most recently in the Americas. Although typical ZIKV infections are asymptomatic, ZIKV infection during pregnancy is increasingly associated with microcephaly and other fetal developmental abnormalities. In the last few years, genomic and molecular investigations have established a remarkable progress on the pathogenic mechanisms of ZIKV infection using in vitro and in vivo models. Here, we highlight recent advances in ZIKV-host cell interaction studies, including cellular targets of ZIKV, ZIKV-mediated cell death mechanisms, host cell restriction factors that limit ZIKV replication, and immune evasion mechanisms utilized by ZIKV. Understanding of the mechanisms of ZIKV⁻host interaction at the cellular level will contribute crucial insights into the development of ZIKV therapeutics and vaccines.

Advanced glycation end products impair NLRP3 inflammasome-mediated innate immune responses in macrophages.

Advanced glycation end products (AGEs) are adducts formed on proteins by glycation with reducing sugars, such as glucose, and tend to form and accumulate under hyperglycemic conditions. AGE accumulation alters protein function and has been implicated in the pathogenesis of many degenerative diseases such as diabetic complications. AGEs have also been shown to promote the production of pro-inflammatory cytokines, but the roles of AGEs in inflammasome signaling have not been explored in detail. Here, we present evidence that AGEs attenuate activation of the NLRP3 inflammasome in bone marrow-derived macrophages (BMDMs) as determined by caspase-1 processing and interleukin-1ß production. AGEs also dampened the assembly of the NLRP3 inflammasome, but did not affect the NLRC4 or AIM2 inflammasome activation. Moreover, our data indicated that AGE treatment inhibited Toll-like receptor (TLR)-dependent production of pro-inflammatory cytokines in BMDMs. This immunosuppressive effect of AGE was not associated with a receptor for AGEs (RAGE)-mediated signaling. Instead, AGE treatment markedly suppressed lipopolysaccharide-induced M1 polarization of macrophages. Furthermore, AGEs significantly dampened innate immune responses including NLRP3 inflammasome activation and type-I interferon production in macrophages upon influenza virus infection. These observations collectively suggest that AGEs could impair host NLRP3 inflammasome-mediated innate immune defenses against RNA virus infection leading to an increased susceptibility to infection.

Metformin alleviates ageing cellular phenotypes in Hutchinson-Gilford progeria syndrome dermal fibroblasts.

Metformin is a popular antidiabetic biguanide, which has been considered as a candidate drug for cancer treatment and ageing prevention. Hutchinson-Gilford progeria syndrome (HGPS) is a devastating disease characterized by premature ageing and severe age-associated complications leading to death. The effects of metformin on HGPS dermal fibroblasts remain largely undefined. In this study, we investigated whether metformin could exert a beneficial effect on nuclear abnormalities and delay senescence in fibroblasts derived from HGPS patients. Metformin treatment partially restored normal nuclear phenotypes, delayed senescence, activated the phosphorylation of AMP-activated protein kinase and decreased reactive oxygen species formation in HGPS dermal fibroblasts. Interestingly, metformin reduced the number of phosphorylated histone variant H2AX-positive DNA damage foci and suppressed progerin protein expression, compared to the control. Furthermore, metformin-supplemented aged mice showed higher splenocyte proliferation and mRNA expression of the antioxidant enzyme, superoxide dismutase 2 than the control mice. Collectively, our results show that metformin treatment alleviates the nuclear defects and premature ageing phenotypes in HGPS fibroblasts. Thus, metformin can be considered a promising therapeutic approach for life extension in HGPS.

The herbal-derived honokiol and magnolol enhances immune response to infection with methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA).

The emergence of antibiotic resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA) reminds us an urgent need to develop a new immune-modulating agent for preventing S. aureus infection. In this study, we found that herbal medicines, honokiol and magnolol, caused a significant cellular immune modulatory effect during S. aureus infection. In mouse macrophages, these compounds drove upregulation of an antioxidant effect in response to S. aureus, resulting in a dampened total cellular reactive oxygen species (ROS) production and decreased production of inflammatory cytokines/chemokines, whereas honokiol induced increased types I and III interferon messenger RNA (mRNA) expression levels in response to MSSA infection. Moreover, the internalization of S. aureus by human alveolar epithelial cells was inhibited by these compounds. Furthermore, honokiol and magnolol treatment promoted a delay in killing during MSSA infection in Caenorhabditis elegans, suggesting antimicrobial function in vivo. In conclusion, honokiol and magnolol may be considered as attractive immune-modulating treatment for S. aureus infection.

In vitro and in vivo antimicrobial efficacy of natural plant-derived compounds against Vibrio cholerae of O1 El Tor Inaba serotype.

In this study, we investigated antibacterial activities of 20 plant-derived natural compounds against Gram-negative enteric pathogens. We found that both flavonoids and non-flavonoids, including honokiol and magnolol, possess specific antibacterial activities against V. cholerae, but not against other species of Gram-negative bacterium which we tested. Using various antibacterial assays, we determined that there was a dose-dependent bactericidal and biofilm inhibitory activity of honokiol and magnolol against Vibrio cholerae. In addition to antibacterial activities, these molecules also induced an attenuating effect on reactive oxygen species (ROS) production and pro-inflammatory responses generated by macrophages in response to lipopolysaccharides (LPS). Additionally, Caenorhabditis elegans lethality assay revealed that honokiol and magnolol have an ability to extend a lifespan of V. cholerae-infected worms, contributing to prolonged survival of worms after lethal infection. Altogether, our data show for the first time that honokiol and magnolol may be considered as attractive protective or preventive food adjuncts for cholera.

Enhanced protection of pathogenic Escherichia coli ingested by a soil nematode Caenorhabditis elegans against sanitizer treatments.

We employed Caenorhabditis elegans as a model to study the effectiveness of sanitizers in killing pathogenic Escherichia coli strains ingested by free-living nematodes. Adult worms that had fed on six pathogenic E. coli strains (highly persistent in the nematode intestine) were treated with three chemical solutions. In planktonic cells, none of the H2O2 and acetic acid treatments influenced the survival of the pathogenic E. coli strains, whereas sodium hypochlorite critically decreased the viability of the strains. Importantly, the survival of the E. coli strains was dramatically increased by persistence in the C. elegans gut under 0.1% sodium hypochlorite, and several strains could survive at a concentration of 0.5%. In addition, all pathogenic E. coli strains in the C. elegans gut survived on the lettuce for 5 days even though they were washed with 0.1% sodium hypochlorite. Taken together, our results indicate that pathogenic E. coli ingested by C. elegans may be protected against washing treatment with commercial sanitizers on raw food materials.

Stimulator of Interferon Gene Agonists Induce an Innate Antiviral Response against Influenza Viruses.

The devastating effects of COVID-19 have highlighted the importance of prophylactic and therapeutic strategies to combat respiratory diseases. Stimulator of interferon gene (STING) is an essential component of the host defense mechanisms against respiratory viral infections. Although the role of the cGAS/STING signaling axis in the innate immune response to DNA viruses has been thoroughly characterized, mounting evidence shows that it also plays a key role in the prevention of RNA virus infections. In this study, we investigated the role of STING activation during Influenza virus (IFV) infection. In both mouse bone marrow-derived macrophages and monocytic cell line THP-1 differentiated with PMA, we found that dimeric amidobenzimidazole (diABZI), a STING agonist, had substantial anti-IFV activity against multiple strains of IFV, including A/H1N1, A/H3N2, B/Yamagata, and B/Victoria. On the other hand, a pharmacological antagonist of STING (H-151) or the loss of STING in human macrophages leads to enhanced viral replication but suppressed IFN expression. Furthermore, diABZI was antiviral against IFV in primary air-liquid interface cultures of nasal epithelial cells. Our data suggest that STING agonists may serve as promising therapeutic antiviral agents to combat IFV.

Varicella zoster virus glycoprotein E facilitates PINK1/Parkin-mediated mitophagy to evade STING and MAVS-mediated antiviral innate immunity.

Viruses have evolved to control mitochondrial quality and content to facilitate viral replication. Mitophagy is a selective autophagy, in which the damaged or unnecessary mitochondria are removed, and thus considered an essential mechanism for mitochondrial quality control. Although mitophagy manipulation by several RNA viruses has recently been reported, the effect of mitophagy regulation by varicella zoster virus (VZV) remains to be fully determined. In this study, we showed that dynamin-related protein-1 (DRP1)-mediated mitochondrial fission and subsequent PINK1/Parkin-dependent mitophagy were triggered during VZV infection, facilitating VZV replication. In addition, VZV glycoprotein E (gE) promoted PINK1/Parkin-mediated mitophagy by interacting with LC3 and upregulating mitochondrial reactive oxygen species. Importantly, VZV gE inhibited MAVS oligomerization and STING translocation to disrupt MAVS- and STING-mediated interferon (IFN) responses, and PINK1/Parkin-mediated mitophagy was required for VZV gE-mediated inhibition of IFN production. Similarly, carbonyl cyanide m-chlorophenyl hydrazone (CCCP)-mediated mitophagy induction led to increased VZV replication but attenuated IFN production in a three-dimensional human skin organ culture model. Our results provide new insights into the immune evasion mechanism of VZV gE via PINK1/Parkin-dependent mitophagy.

Stress Granules Inhibit Coxsackievirus B3-Mediated Cell Death via Reduction of Mitochondrial Reactive Oxygen Species and Viral Extracellular Release.

Stress granules (SGs) are cytoplasmic aggregates of RNA-protein complexes that form in response to various cellular stresses and are known to restrict viral access to host translational machinery. However, the underlying molecular mechanisms of SGs during viral infections require further exploration. In this study, we evaluated the effect of SG formation on cellular responses to coxsackievirus B3 (CVB3) infection. Sodium arsenite (AS)-mediated SG formation suppressed cell death induced by tumor necrosis factor-alpha (TNF-a)/cycloheximide (CHX) treatment in HeLa cells, during which G3BP1, an essential SG component, contributed to the modulation of apoptosis pathways. SG formation in response to AS treatment blocked CVB3-mediated cell death, possibly via the reduction of mitochondrial reactive oxygen species. Furthermore, we examined whether AS treatment would affect small extracellular vesicle (sEV) formation and secretion during CVB3 infection and modulate human monocytic cell (THP-1) response. CVB3-enriched sEVs isolated from HeLa cells were able to infect and replicate THP-1 cells without causing cytotoxicity. Interestingly, sEVs from AS-treated HeLa cells inhibited CVB3 replication in THP-1 cells. These findings suggest that SG formation during CVB3 infection modulates cellular response by inhibiting the release of CVB3-enriched sEVs.

Zika virus modulates mitochondrial dynamics, mitophagy, and mitochondria-derived vesicles to facilitate viral replication in trophoblast cells.

Zika virus (ZIKV) remains a global public health threat with the potential risk of a future outbreak. Since viral infections are known to exploit mitochondria-mediated cellular processes, we investigated the effects of ZIKV infection in trophoblast cells in terms of the different mitochondrial quality control pathways that govern mitochondrial integrity and function. Here we demonstrate that ZIKV (PRVABC59) infection of JEG-3 trophoblast cells manipulates mitochondrial dynamics, mitophagy, and formation of mitochondria-derived vesicles (MDVs). Specifically, ZIKV nonstructural protein 4A (NS4A) translocates to the mitochondria, triggers mitochondrial fission and mitophagy, and suppresses mitochondrial associated antiviral protein (MAVS)-mediated type I interferon (IFN) response. Furthermore, proteomics profiling of small extracellular vesicles (sEVs) revealed an enrichment of mitochondrial proteins in sEVs secreted by ZIKV-infected JEG-3 cells, suggesting that MDV formation may also be another mitochondrial quality control mechanism manipulated during placental ZIKV infection. Altogether, our findings highlight the different mitochondrial quality control mechanisms manipulated by ZIKV during infection of placental cells as host immune evasion mechanisms utilized by ZIKV at the placenta to suppress the host antiviral response and facilitate viral infection.

Small RNA sequencing of small extracellular vesicles secreted by umbilical cord mesenchymal stem cells following replicative senescence.

BACKGROUND: Umbilical cord mesenchymal stem cells (UCMSC) are subsets of multipotent stem cells involved in immune modulation, tissue regeneration, and antimicrobial defense. Cellular senescence is associated with the onset of aging-related diseases and small extracellular vesicles (sEVs) are important mediators of senescence and aging. OBJECTIVE: However, little is known about the role and function of microRNAs (miRNAs) carried by UCMSC-derived sEVs. To analyze the expression profiles of miRNAs secreted by senescent UCMSC, small RNA sequencing of the miRNAs within the sEVs was performed in this study. METHODS: UCMSC cultures underwent serial passaging beyond passage number 20 to achieve replicative senescence, which was confirmed by various methods, including increased senescence-associated ß-gal staining and cytokine secretion levels. sEVs derived from non-senescent and senescent UCMSC were isolated and characterized by nanoparticle tracking analysis, transmission electron microscopy, and immunoblot analysis. RESULTS: Small RNA sequencing of the miRNAs within the sEVs revealed senescence-associated differences in the miRNA composition, as shown by the upregulation of miR-122-5p and miR-146a-5p, and downregulation of miR-125b-5p and miR-29-3p. In addition, total RNA sequencing analysis showed that PENK, ITGA8, and TSIX were upregulated, whereas AKR1B10, UNC13D, and IL21R were downregulated by replicative senescence in UCMSC. In sEVs, upregulated genes were linked to downregulated miRNAs, and vice versa. In the gene-concept network analysis, five gynecologic terms were retrieved. CONCLUSIONS: The study provides an insight into the cellular characteristics of UCMSC following replicative senescence and emphasizes the importance of monitoring passage numbers of UCMSC for further therapeutic use.

Varicella-Zoster Virus ORF39 Transmembrane Protein Suppresses Interferon-Beta Promoter Activation by Interacting with STING.

Varicella-Zoster virus (VZV) causes varicella in primary infection of children and zoster during reactivation in adults. Type I interferon (IFN) signaling suppresses VZV growth, and stimulator of interferon genes (STING) plays an important role in anti-VZV responses by regulating type I IFN signaling. VZV-encoded proteins are shown to inhibit STING-mediated activation of the IFN-ß promoter. However, the mechanisms by which VZV regulates STING-mediated signaling pathways are largely unknown. In this study, we demonstrate that the transmembrane protein encoded by VZV open reading frame (ORF) 39 suppresses STING-mediated IFN-ß production by interacting with STING. In IFN-ß promoter reporter assays, ORF39 protein (ORF39p) inhibited STING-mediated activation of the IFN-ß promoter. ORF39p interacted with STING in co-transfection assays, and this interaction was comparable to that of STING dimerization. The cytoplasmic N-terminal 73 amino acids region of ORF39P was not necessary for ORF39 binding and suppression of STING-mediated IFN-ß activation. ORF39p also formed a complex containing both STING and TBK1. A recombinant VZV expressing HA-tagged ORF39 was produced using bacmid mutagenesis and showed similar growth to its parent virus. During HA-ORF39 virus infection, the expression level of STING was markedly reduced, and HA-ORF39 interacted with STING. Moreover, HA-ORF39 also colocalized with glycoprotein K (encoded by ORF5) and STING at the Golgi during virus infection. Our results demonstrate that the transmembrane protein ORF39p of VZV plays a role in evading the type I IFN responses by suppressing STING-mediated activation of the IFN-ß promoter.

Cross-reactive humoral immunity of clade 2 Oka and MAV/06 strain-based varicella vaccines against different clades of varicella-zoster virus.

The currently used Japanese Oka and Korean MAV/06-attenuated varicella vaccine strains belong to clade 2 genotype varicella-zoster viruses (VZV). More than seven clades of VZV exist worldwide. In this study, we investigated the cross-reactivity of antibodies induced by clade 2 genotype vaccines against VZV strains belonging to clades 1, 2, 3, and 5 using a fluorescent antibody to membrane antigen (FAMA) test. Among 59 donors, 29 were vaccinated with the MAV/06 strain MG1111 (GC Biopharma, South Korea) and the other 30 were vaccinated with the Oka strain VARIVAX (Merck, USA). The sera were titrated using FAMA tests prepared with six different VZV strains (two vaccine strains, one wild-type clade 2 strain, and one each of clade 1, 3, and 5 strains). The ranges of geometric mean titers (GMTs) of FAMA against six different strains were 158.7-206.5 and 157.6-238.9 in MG1111 and VARIVAX groups, respectively. GMTs of the MG1111 group against all six strains were similar; however, GMTs of the VARIVAX group showed differences of approximately 1.5-fold depending on the strains. Nevertheless, the GMTs of the two vaccinated groups for the same strain were not significantly different. These results suggest that both MG1111 and VARIVAX vaccinations induce cross-reactive humoral immunity against other clades of VZV.

Identification of a Complex Karyotype Signature with Clinical Implications in AML and MDS-EB Using Gene Expression Profiling.

Complex karyotype (CK) is associated with a poor prognosis in both acute myeloid leukemia (AML) and myelodysplastic syndrome with excess blasts (MDS-EB). Transcriptomic analyses have improved our understanding of the disease and risk stratification of myeloid neoplasms; however, CK-specific gene expression signatures have been rarely investigated. In this study, we developed and validated a CK-specific gene expression signature. Differential gene expression analysis between the CK and non-CK groups using data from 348 patients with AML and MDS-EB from four cohorts revealed enrichment of the downregulated genes localized on chromosome 5q or 7q, suggesting that haploinsufficiency due to the deletion of these chromosomes possibly underlies CK pathogenesis. We built a robust transcriptional model for CK prediction using LASSO regression for gene subset selection and validated it using the leave-one-out cross-validation method for fitting the logistic regression model. We established a 10-gene CK signature (CKS) predictive of CK with high predictive accuracy (accuracy 94.22%; AUC 0.977). CKS was significantly associated with shorter overall survival in three independent cohorts, and was comparable to that of previously established risk stratification models for AML. Furthermore, we explored of therapeutic targets among the genes comprising CKS and identified the dysregulated expression of superoxide dismutase 1 (SOD1) gene, which is potentially amenable to SOD1 inhibitors.

Coronavirus disease 2019 (COVID-19) vaccine platforms: how novel platforms can prepare us for future pandemics: a narrative review.

More than 2 years after the explosion of the coronavirus disease 2019 (COVID-19) pandemic, extensive efforts have been made to develop safe and efficacious vaccines against infections with severe acute respiratory syndrome coronavirus 2. The pandemic has opened a new era of vaccine development based on next-generation platforms, including messenger RNA (mRNA)-based technologies, and paved the way for the future of mRNA-based therapeutics to provide protection against a wide range of infectious diseases. Multiple vaccines have been developed at an unprecedented pace to protect against COVID-19 worldwide. However, important knowledge gaps remain to be addressed, especially in terms of how vaccines induce immunogenicity and efficacy in those who are elderly. Here, we discuss the various vaccine platforms that have been utilized to combat COVID-19 and emphasize how these platforms can be a powerful tool to react quickly to future pandemics.

SARS-CoV-2-mediated evasion strategies for antiviral interferon pathways.

With global expansion of the COVID-19 pandemic and the emergence of new variants, extensive efforts have been made to develop highly effective antiviral drugs and vaccines against SARS-CoV-2. The interactions of coronaviruses with host antiviral interferon pathways ultimately determine successful viral replication and SARS-CoV-2-induced pathogenesis. Innate immune receptors play an essential role in host defense against SARS-CoV-2 via the induction of IFN production and signaling. Here, we summarize the recent advances in innate immune sensing mechanisms of SARS-CoV-2 and various strategies by which SARS-CoV-2 antagonizes antiviral innate immune signaling pathways, with a particular focus on mechanisms utilized by multiple SARS-CoV-2 proteins to evade interferon induction and signaling in host cell. Understanding the underlying immune evasion mechanisms of SARS-CoV-2 is essential for the improvement of vaccines and therapeutic strategies.

miR-10a, miR-30c, and miR-451a Encapsulated in Small Extracellular Vesicles Are Prosenescence Factors in Human Dermal Fibroblasts.

Although small extracellular vesicles (sEV) have been reported to play an important role in cellular senescence and aging, little is known about the potential role and function of microRNAs (miRNAs) contained within the sEV. To determine the senescence-associated factors secreted from sEV of human dermal fibroblasts (HDFs), we isolated and characterized sEV from nonsenescent versus that from senescent HDFs. Small RNA-sequencing analysis identified many enriched miRNAs in sEV of senescent HDF, as shown by the upregulation of miR-10a, miR-30c, and miR-451a and downregulation of miR-128, miR-184, miR-200c, and miR-125a. Overexpression of miR-10a, miR-30c, and miR-451a induced an aging phenotype in HDFs, whereas inhibition of these miRNAs reduced senescent-like phenotypes in senescent HDFs. Moreover, treatment with sEV or sEV-containing conditioned medium promoted cellular senescence in HDFs, whereas sEV depletion abrogated prosenescence effects of the senescent HDF secretome. Interestingly, prosenescence sEV miRNAs were found to have an essential role in regulating ROS production and mitophagy activation. Taken together, our results revealed miR-10a, miR-30c, and miR-451a as prosenescence factors that are differentially expressed in sEV of senescent HDFs, showing the essential role of sEV miRNAs in the biological processes of aging.

Investigation of d-Amino Acid-Based Surfactants and Nanocomposites with Gold and Silica Nanoparticles as against Multidrug-Resistant Bacteria Agents.

d-amino acid-based surfactants (d-AASs) were synthesized and their antimicrobial activity was evaluated. N-α-lauroyl-d-arginine ethyl ester hydrochloride (d-LAE), d-proline dodecyl ester (d-PD), and d-alanine dodecyl ester (d-AD) were found to have antibacterial activity against both Gram-positive and -negative bacteria, but less efficacy against Gram-negative bacteria. For these reasons, combining antimicrobial agents with nanoparticles is a promising technique for improving their antibacterial properties to eliminate drug-resistant pathogens. d-LAE coated on gold (AuNP) and silica (SiNP) nanoparticles has more efficient antibacterial activity than that of d-LAE alone. However, unlike d-LAE, d-PD has enhanced antibacterial activity upon being coated on AuNP. The antibacterial d-AASs and their nanocomposites with nanoparticles were synthesized in an environmentally friendly manner and are expected to be valuable new antimicrobial agents against multidrug-resistant (MDR) pathogens.

Anti-Viral Activities of Umbilical Cord Mesenchymal Stem Cell-Derived Small Extracellular Vesicles Against Human Respiratory Viruses.

The endemic and pandemic caused by respiratory virus infection are a major cause of mortality and morbidity globally. Thus, broadly effective antiviral drugs are needed to treat respiratory viral diseases. Small extracellular vesicles derived from human umbilical cord mesenchymal stem cells (U-exo) have recently gained attention as a cell-free therapeutic strategy due to their potential for safety and efficacy. Anti-viral activities of U-exo to countermeasure respiratory virus-associated diseases are currently unknown. Here, we tested the antiviral activities of U-exo following influenza A/B virus (IFV) and human seasonal coronavirus (HCoV) infections in vitro. Cells were subject to IFV or HCoV infection followed by U-exo treatment. U-exo treatment significantly reduced IFV or HCoV replication and combined treatment with recombinant human interferon-alpha protein (IFN-α) exerted synergistically enhanced antiviral effects against IFV or HCoV. Interestingly, microRNA (miR)-125b, which is one of the most abundantly expressed small RNAs in U-exo, was found to suppress IFV replication possibly via the induction of IFN-stimulated genes (ISGs). Furthermore, U-exo markedly enhanced RNA virus-triggered IFN signaling and ISGs production. Similarly, human nasal epithelial cells cultured at the air-liquid interface (ALI) studies broadly effective anti-viral and anti-inflammatory activities of U-exo against IFV and HCoV, suggesting the potential role of U-exo as a promising intervention for respiratory virus-associated diseases.