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A 72-year-old male diagnosed with cholangiocarcinoma was initiated on third-line therapy comprising Tislelizumab and Anlotinib. Within four days of treatment, he developed fulminant hepatic injury concurrent with acute kidney injury. Despite aggressive management with high-dose glucocorticoids, hepatoprotective agents, comprehensive supportive care, and subsequent anti-infective therapy, his clinical status declined rapidly. In view of the grave prognosis and the family's decision to decline intensive interventions such as plasma exchange, the patient ultimately succumbed to multiorgan failure. This case highlights a potential synergistic interaction between concomitant infection (e.g.,influenza virus) and immune checkpoint inhibitor(ICI) therapy, possibly mediated through enhanced antigenic stimulation and loss of immunoregulatory control, culminating in exaggerated immune activation. This mechanism may have profoundly amplified ICI-related toxicity, leading to fatal multiorgan irAEs. Regarding the issue of immune storms, it is challenging for clinical practice to provide favorable outcomes for patients, and we need to remain highly vigilant.

Influenza A virus (IAV) is a respiratory virus that causes epidemics and pandemics. Knowledge of IAV RNA secondary structure in vivo is crucial for a better understanding of virus biology. Moreover, it is a fundament for the development of new RNA-targeting antivirals. Chemical RNA mapping using selective 2’-hydroxyl acylation analyzed by primer extension (SHAPE) coupled with Mutational Profiling (MaP) allows for the thorough examination of secondary structures in low-abundance RNAs in their biological context. So far, the method has been used for analyzing the RNA secondary structures of several viruses including SARS-CoV-2 in virio and in cellulo. Here, we used SHAPE-MaP and dimethyl sulfate mutational profiling with sequencing (DMS-MaPseq) for genome-wide secondary structure analysis of viral RNA (vRNA) of the pandemic influenza A/California/04/2009 (H1N1) strain in both in virio and in cellulo environments. Experimental data allowed the prediction of the secondary structures of all eight vRNA segments in virio and, for the first time, the structures of vRNA5, 7, and 8 in cellulo. We conducted a comprehensive structural analysis of the proposed vRNA structures to reveal the motifs predicted with the highest accuracy. We also performed a base-pairs conservation analysis of the predicted vRNA structures and revealed many highly conserved vRNA motifs among the IAVs. The structural motifs presented herein are potential candidates for new IAV antiviral strategies.

Influenza A virus (IAV), like other viruses, depends on the host cellular machinery for replication and production of progeny. The relationship between a virus and a host is complex, shaped by many spatial and temporal interactions between viral and host proteome, ultimately dictating disease outcome. Therefore, it is imperative to identify host-virus interactions as crucial determinants of disease pathogenies. Heterogeneous ribonucleoprotein A1 (hnRNPA1) is an RNA binding protein involved in the life cycle of many DNA and RNA viruses; however, its role in IAV remains undiscovered. Here we report that human hnRNPA1 physically interacts with the nucleoprotein (NP) of IAV in mammalian cells at different time points of the viral replication cycle. Temporal distribution studies identify hnRNPA1 and NP co-localize in the same cellular milieu in both nucleus and mitochondria in NP-transfected and IAV-infected mammalian cells. Interestingly, hnRNPA1 influenced NP gene expression and affected viral replication. Most importantly, hnRNPA1 knockdown caused a significant increase in NP expression and enhanced viral replication (93.82%) in IAV infected A549 cells. Conversely, hnRNPA1 overexpression reduced NP expression at the mRNA and protein levels and impeded virus replication by (60.70%), suggesting antagonistic function. Taken together, results from this study demonstrate that cellular hnRNPA1 plays a protective role in the host hitherto unknown and may hold potential as an antiviral target to develop host-based therapeutics against IAV.

Background In recent years, accumulating evidences have revealed that influenza A virus (IAV) infections induce significant differential expression of host long noncoding RNAs (lncRNAs), some of which play important roles in the regulation of virus-host interactions and determining the virus pathogenesis. However, whether these lncRNAs bear post-translational modifications and how their differential expression is regulated remain largely unknown. In this study, the transcriptome-wide 5-methylcytosine (m 5 C) modification of lncRNAs in A549 cells infected with an H1N1 influenza A virus was analyzed and compared with uninfected cells by Methylated RNA immunoprecipitation sequencing (MeRIP-Seq). Results Our data identified 1317 upregulated m 5 C peaks and 1667 downregulated peaks in the H1N1 infected group. Gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that the differentially modified lncRNAs were associated with protein modification, organelle localization, nuclear export and other biological processes. Furthermore, conjoint analysis of the differentially modified (DM) and differentially expressed (DE) lncRNAs identified 143 ‘hyper-up’, 81 ‘hypo-up’, 6 ‘hypo-down’ and 4 ‘hyper-down’ lncRNAs. GO and KEGG analyses revealed that these DM and DE lncRNAs were predominantly associated with pathogen recognition and disease pathogenesis pathways, indicating that m 5 C modifications could play an important role in the regulation of host response to IAV replication by modulating the expression and/or stability of lncRNAs. Conclusion This study presented the first m 5 C modification profile of lncRNAs in A549 cells infected with IAV and demonstrated a significant alteration of m 5 C modifications on host lncRNAs upon IAV infection. These data could give a reference to future researches on the roles of m 5 C methylation in virus infection.

Deoxyshikonin (DS) is a derivative of shikonin, the main compound present in Lithospermi radi, the root of Lithospermum erythrorhizon Siebold and Zucc. In this study, we investigated the antiviral effects of DS using Influenza A/PR8/34, which expresses green fluorescent protein (GFP) as well as wild-type PR8/34 H1N1 Influenza A virus (IAV). Fluorescence microscopy and flow cytometry results showed that DS from 1.25 to 5 µM significantly and dose-dependently inhibited PR8-GFP IAV infection. A plaque assay confirmed the inhibitory effect of DS against H1N1 IAV infection. Consistently, immunofluorescence results showed that DS suppresses IAV protein expression. Time-of-drug-addition and hemagglutination inhibition assays revealed that DS exhibits anti-influenza virus efficacy by blocking the viral attachment and penetration into the cells and has a direct virus-eradication effect in the early stages of infection. However, DS did not repress neuraminidase activity. Our findings suggest that DS could be used not only to protect against the early stages of IAV infection, but also to treat influenza virus infections in combination with NA inhibitors.

Background Influenza A viruses (IAV) result in severe public health problems with worldwide each year. Overresponse of immune system to IAV infection leads to complications, and ultimately causing morbidity and mortality. Objective Curcumin has been reported to have anti‐inflammatory ability. However, its molecular mechanism in immune responses remains unclear. Methods We detected the pro‐inflammatory cytokine secretion and nuclear factor kappa‐light‐chain‐enhancer of activated B cell (NF‐κB)‐related protein expression in human macrophages or mice infected by IAV with or without curcumin treatment. Results We found that the IAV infection caused a dramatic enhancement of pro‐inflammatory cytokine productions of human macrophages and mice immune cells. However, curcumin treatment after IAV infection downregulated these cytokines production in a dose‐dependent manner. Moreover, the NF‐κB has been activated in human macrophages after IAV infection, while administration of curcumin inhibited NF‐κB signaling pathway via promoting the expression of nuclear factor of kappa light polypeptide gene enhancer in B‐cells inhibitor, alpha (IκBα), and inhibiting the translocation of p65 from cytoplasm to nucleus. Conclusions In summary, IAV infection could result in the inflammatory responses of immune cells, especially macrophages. Curcumin has the therapeutic potentials to relieve these inflammatory responses through inhibiting the NF‐κB signaling pathway.

Emerging and re-emerging respiratory viruses represent a continuing threat to human health. The pandemic severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and influenza A viruses (IAVs) are co-circulating, presenting serious threats to public health. Therefore, screening for safe and broad-spectrum antiviral candidates to control such viral infections is prioritized. Herein, this study reports the in vitro antiviral activity of some essential volatile oils (EOs) and volatile oil components including Peppermint oil, Eucalyptus oil, Clove oil, Thymol, Camphor and Limonin against two different IAVs, namely influenza A/H1N1 and A/H5N1 viruses, and SARS-CoV-2 virus. All tested samples were safe in MDCK and Vero E6 cell lines with CC 50 values that exceed 1 mg/ml, allowing the screening of their antiviral activities using a wide range of concentrations. The results show the potency of Thymol and Limonin against influenza A/H1N1 virus with IC 50 values of 0.022 and 4.25 µg/ml, respectively. The anti-influenza activities of Thymol and Limonin were further validated by testing them against the avian influenza A/H5N1 virus, resulting in anti-influenza activities with IC 50 values of 18.5 and 15.6 ng/ml, respectively. The broad-spectrum potential of the highly potent antiviral candidates, Thymol and Limonin, were further tested against the pandemic SARS-CoV-2 and, both exerted anti-coronavirus activities with IC 50 values of 0.591 and 4.04 µg/ml, respectively. Further investigations against influenza A/H1N1 virus revealed that Thymol and Limonin could inhibit IAV by hindering viral replication. The Biochemical analyses of the interaction of Limonin and Thymol with FDA-approved anti-influenza drug targets, neuraminidase and viral polymerases, revealed that both compounds can partially inhibit IAV polymerase activity, but have no effect on neuraminidase activity. Likely, molecular docking studies indicated that Thymol and Limonin obstruct active binding sites of IAV polymerases. These findings presented on the antiviral activity of Limonin and Thymol might be used to support the development of supplemental therapy against currently emerging and reemerging respiratory viral infections.

Influenza A viruses (IAV) have been a major public health threat worldwide, and options for antiviral therapy become increasingly limited with the emergence of drug-resisting virus strains. New and effective anti-IAV drugs, especially for highly pathogenic influenza, with different modes of action, are urgently needed. The influenza virus glycoprotein hemagglutinin (HA) plays critical roles in the early stage of virus infection, including receptor binding and membrane fusion, making it a potential target for the development of anti-influenza drugs. In this study, we show that OA-10, a newly synthesized triterpene out of 11 oleanane-type derivatives, exhibited significant antiviral activity against four different subtypes of IAV (H1N1, H5N1, H9N2 and H3N2) replications in A549 cell cultures with EC50 ranging from 6.7 to 19.6 μM and a negligible cytotoxicity (CC50 > 640 μM). It inhibited acid-induced hemolysis in a dose-dependent manner, with an IC50 of 26 µM, and had a weak inhibition on the adsorption of H5 HA to chicken erythrocytes at higher concentrations (≥40 µM). Surface plasmon resonance (SPR) analysis showed that OA-10 interacted with HA in a dose-dependent manner with the equilibrium dissociation constants (KD) of the interaction of 2.98 × 10−12 M. Computer-aided molecular docking analysis suggested that OA-10 might bind to the cavity in HA stem region which is known to undergo significant rearrangement during membrane fusion. Our results demonstrate that OA-10 inhibits H5N1 IAV replication mainly by blocking the conformational changes of HA2 subunit required for virus fusion with endosomal membrane. These findings suggest that OA-10 could serve as a lead for further development of novel virus entry inhibitors to prevent and treat IAV infections.

In this comprehensive large-scale study, conducted from 2015 to 2019, 7,209 wild boars across South Korea were sampled to assess their exposure to influenza A viruses (IAVs). Of these, 250 (3.5%) were found to be IAV-positive by ELISA, and 150 (2.1%) by the hemagglutination inhibition test. Detected subtypes included 23 cases of pandemic 2009 H1N1, six of human seasonal H3N2, three of classical swine H1N1, 13 of triple-reassortant swine H1N2, seven of triple-reassortant swine H3N2, and seven of swine-origin H3N2 variant. Notably, none of the serum samples tested positive for avian IAV subtypes H3N8, H5N3, H7N7, and H9N2 or canine IAV subtype H3N2. This serologic analysis confirmed the exposure of Korean wild boars to various subtypes of swine and human influenza viruses, with some serum samples cross-reacting between swine and human strains, indicating potential infections with multiple IAVs. The results highlight the potential of wild boar as a novel mixing vessel, facilitating the adaptation of IAVs and their spillover to other hosts, including humans. In light of these findings, we recommend regular and frequent surveillance of circulating influenza viruses in the wild boar population as a proactive measure to prevent potential human influenza pandemics and wild boar influenza epizootics.

Influenza A virus (IAV) is a member of the single-stranded RNA (ssRNA) family of viruses. The most recent global pandemic caused by the SARS-CoV-2 virus has shown the major threat that RNA viruses can pose to humanity. In comparison, influenza has an even higher pandemic potential as a result of its high rate of mutations within its relatively short (<13 kbp) genome, as well as its capability to undergo genetic reassortment. In light of this threat, and the fact that RNA structure is connected to a broad range of known biological functions, deeper investigation of viral RNA (vRNA) structures is of high interest. Here, for the first time, we propose a secondary structure for segment 8 vRNA (vRNA8) of A/California/04/2009 (H1N1) formed in the presence of cellular and viral components. This structure shows similarities with prior in vitro experiments. Additionally, we determined the location of several well-defined, conserved structural motifs of vRNA8 within IAV strains with possible functionality. These RNA motifs appear to fold independently of regional nucleoprotein (NP)-binding affinity, but a low or uneven distribution of NP in each motif region is noted. This research also highlights several accessible sites for oligonucleotide tools and small molecules in vRNA8 in a cellular environment that might be a target for influenza A virus inhibition on the RNA level.