Ma Xing Shi Gan Decoction reduces influenza A virus nucleoprotein levels in association with modulation of lactate-HMGB1 lactylation and autophagosome accumulation.

NRF2 controls a diverse network of antiviral effectors with p62 acting as a central restriction factor effective across virus families.

Ferritinophagy is crucial for maintaining iron homeostasis and regulating iron-dependent viral replication. This study demonstrates that ferritinophagy reprograms carnitine-dependent lipid metabolism by impairing Fe-S clusters biogenesis, thereby inhibiting iron-dependent viral replication. Specifically, NCOA4-mediated ferritinophagy disrupts Fe-S clusters assembly through the autophagic degradation of MMS19, leading to mitochondrial metabolic remodeling and suppression of carnitine biosynthesis. Carnitine deficiency subsequently destabilizes the proteins TMED10, HDLBP, and RAB40C via specific amino acid residues (Asp78, Leu336, and Glu154, respectively), and we reveal that carnitine directly stabilizes these lipid droplet-associated proteins, promoting lipid droplet formation. Collectively, these changes orchestrate an iron-lipid metabolic axis that inhibits the replication of diverse PRRSV strains as well as influenza A virus (IAV). Conversely, PRRSV counteracts this antiviral mechanism by promoting autophagic degradation of NCOA4 via K63-linked ubiquitination, a process in which the viral protein Nsp5 recruits the E3 ligase adaptor DDB1 to mediate ubiquitination. Our findings establish NCOA4 as a link between ferritinophagy and lipid metabolic reprogramming, revealing a novel antiviral pathway and providing foundational insights for developing innovative antiviral strategies.

Influenza A virus (IAV) is an important zoonotic pathogen responsible for substantial respiratory morbidity and mortality. Elucidating the mechanisms by which IAV evades host innate immunity is critical for developing novel antiviral strategies. Although the IAV non-structural protein 2 (NS2) is well-characterized for the export of viral ribonucleoproteins (vRNPs) from the host cell nucleus, the function of NS2 in evading host innate immunity, especially the NFKB/NF-κB (nuclear factor kappa B) signaling pathway, remains poorly understood. The present study uncovered that NS2 is a novel viral inhibitor of the NFKB pathway. Mechanistically, NS2 interacted with and mediated the degradation of the NFKB essential modulator (IKBKG/NEMO), thereby suppressing downstream signal transduction. The macroautophagy/autophagy receptor OPTN (optineurin) was exploited by NS2 to mediate the selective autophagic degradation. Furthermore, the K72 residue was critical for the NS2-mediated degradation of IKBKG/NEMO, as the K72R substitution in NS2 disrupted the IKBKG/NEMO-NS2 interaction and abrogated the autophagic degradation. In addition, NS2K72R mutant virus displayed less viral load and milder pathogenicity in mice. In conclusion, these findings highlighted the novel biological function of IAV NS2 in exploiting selective autophagy to evade host defenses, and offered a potential target for controlling IAV infections.

Airborne transmission of influenza A virus (IAV) poses significant challenges to public health. However, the mechanisms governing viral inactivation in aerosols remain poorly understood. IAVs exhibit morphological variability, ranging from 100 nm spherical virions to micrometer-long filaments, depending on strain and growth conditions. Although virion morphology was shown to influence transmissibility, the mechanisms of how morphology affects airborne transmission are yet to be delineated. Here, we investigated the impact of virion shape on IAV stability in bulk solutions and an aerosol system with a focus on particles in the submicrometer range to examine how physicochemical aerosol properties, such as elevated solute concentration and low pH, affect infectivity. We show that filamentous viruses exhibit enhanced stability in aerosol particles at 80% relative humidity (RH) and in bulk solution mimicking increased salinity at this RH. Similarly, filamentous viruses exhibited slower decay under acidic conditions, both in bulk solutions and in acidified aerosol particles. Using primary human airway cultures, we further found that filamentous IAVs possess an infectivity advantage under mucosal immune pressures, including neutralizing antibodies and mucus. These results reveal that filamentous shape provides IAV with enhanced stability under diverse environmental conditions in the aerosol phase and increased infectivity in the respiratory epithelium.

Respiratory viruses, such as influenza A virus (IAV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remain major global health threats, and the emergence of drug-resistant variants underscores the urgent need for host-targeted antiviral strategies. Prohibitins (PHBs), mitochondrial scaffold proteins involved in diverse cellular processes, are host factors exploited by multiple viruses. Here, we investigated the antiviral potential of two PHB-binding triazine melanogenin derivatives, Mel56 and Mel6, against IAV and SARS-CoV-2. Mel56, but not Mel6, exhibited potent anti-IAV activity. In particular, Mel56 increased cell survival, suppressed viral nucleoprotein expression, and reduced viral gene transcription in IAV-infected Madin-Darby canine kidney (MDCK) cells and A549 human lung carcinoma cells. PHB2 knockdown enhanced the inhibitory effect of Mel56, supporting the involvement of PHBs in its antiviral mechanism. Transcriptomic profiling revealed that Mel56 downregulates virus-induced immune response genes while upregulating antioxidant response-related genes, including nuclear factor erythroid 2-related factor 2 (NRF2) target genes. NRF2 activation by Mel56 was confirmed using a reporter assay. Consistent with these findings, Mel56 impaired mitochondrial ATP synthesis and electron transport in isolated rat liver mitochondria and attenuated mitochondrial membrane potential and promoted mitochondrial reactive oxygen species production in live MDCK cells. Importantly, Mel56 exhibited potent anti-SARS-CoV-2 activity in human induced pluripotent stem cell-derived lung organoids. Mel56 did not upregulate NRF2 target genes in SARS-CoV-2-infected organoids. These findings identify Mel56 as a PHB-binding compound with broad-spectrum antiviral activity and support the development of PHB-targeting ligands as a novel host-directed therapeutic strategy against respiratory viral infections.IMPORTANCEThis study identifies Mel56 as a novel host-directed antiviral compound that targets prohibitins and suppresses both influenza A virus and severe acute respiratory syndrome coronavirus 2. Mel56 exhibits broad-spectrum antiviral activity in conventional cell culture models as well as in physiologically relevant human lung organoids. Mechanistically, Mel56 upregulates antioxidant response-related genes, activates nuclear factor erythroid 2-related factor 2, impairs mitochondrial function, and enhances mitochondrial reactive oxygen species production. Notably, its effects differ depending on the cellular context, underscoring the complexity of host signaling pathways during viral infection. These findings highlight prohibitins as promising therapeutic targets and provide proof of concept for the development of host-directed strategies to combat respiratory viruses and mitigate the emergence of drug resistance.

Multiplex serological profiling reveals diverse avian and mammalian influenza A virus exposure in swine.

Amplified-free and rapid nucleic acid detection of respiratory viruses based on streptavidin-functionalized quantum dot microspheres and magnetic beads.

Elucidating the material basis and mechanism of Shegan Mahuang decoction in inhibiting influenza virus pneumonia based on UHPLC-HRMS, network pharmacology and experimental verification.

Combination of andrographolide and baicalin inhibited influenza A virus infection through suppressing RORγt-IL-17A pathway.

Mechanistic analysis of an IRF7-dependent pathway in virus-induced fibrosis in chronic lung allograft dysfunction.

Influenza A, an acute or subacute respiratory infectious disease caused by the influenza A virus (IAV), affects humans and animals, and poses a serious threat to public health. Currently, IAV prevention and treatment rely primarily on antiviral drugs and nebulization therapy. Although these methods offer rapid efficacy, prolonged or excessive use often induces drug resistance and sequelae, and has high costs. Throughout China’s history, traditional Chinese medicine (TCM) has repeatedly resisted major epidemics, and substantially contributed to the survival and cultural continuity of the Chinese nation. Modern medical research has demonstrated that certain traditional Chinese medicinal formulas or their primary active constituents exhibit significant antiviral activity and immunomodulatory effects. Consequently, exploring the antiviral mechanisms of TCM or their active components, alongside their synergistic application with influenza vaccines and existing antiviral drugs, could enable novel approaches and research directions to achieve influenza prevention and control. This article reviews the current status of IAV transmission, as well as progress in modern medical research in influenza A prevention and treatment with TCMs or their active constituents.

The role of glucose restriction in host antiviral defense remains elusive. Here, we investigate the impact of pre-existing hypoglycemia on host susceptibility to influenza infections. We find that mouse models with intermittent hypoglycemia exhibit heightened vulnerability to influenza A virus (IAV) infections at low to moderate exposure levels. This vulnerability is attributed to reduced expression of TRIM5 in the lung subsequent to hypoglycemic stress. Hypoglycemic stress activates AMPK protein to down-regulate ERK1/2 signaling and inhibit the transactivation activity of AP-1, thereby suppressing Trim5 transcription. Diminished expression of TRIM5 renders the animals more susceptible to influenza infections as it compromises pulmonary antiviral immunity by attenuating type I interferon (IFN-I) production and signaling. These findings provide mechanistic insights into how pre-existing hypoglycemia detrimentally impacts host antiviral defense, and establish TRIM5 as a molecular link connecting metabolic stress to innate antiviral immunity.

Increased detection rate of macrolide-resistant Mycoplasma pneumoniae during the Mycoplasma pneumoniae epidemic in children: A multi-campus hospital retrospective study in Guangzhou, 2023-2024.

Coronaviruses and influenza A viruses (IAV) can cause severe respiratory disease and have pandemic potential. Both viruses depend on priming of their glycoproteins by host cell proteases for the acquisition of infectivity, and the responsible enzymes represent potential targets for intervention. Initial studies suggested that these viruses may exploit redundant proteolytic systems. However, research conducted over the last two decades has pointed to a key role for a single enzyme in coronavirus and IAV priming, the transmembrane protease serine 2 (TMPRSS2). Interest in TMPRSS2 as a host dependency factor and therapeutic target intensified during the COVID-19 pandemic, prompting extensive investigation into its biology, substrate specificity, and pharmacological inhibition. Here, we review recent efforts to define the role of TMPRSS2 in coronavirus infection and to target this protease for antiviral intervention.

Chimeric virus-like particles of nodavirus displaying human and avian influenza A M2e induce conserved anamnestic protective immunity against human and avian influenza A viruses.

Studies evaluating viral pathogenicity in small mammalian models often quantify disease severity using the magnitudes of temperature rise and weight loss post-challenge. However, no rigorous assessment on the transformation of serially collected data into features suitable for predictive models has been conducted. Using data aggregated from ferrets inoculated with a diverse panel of influenza A viruses (IAV) spanning a broad range of clinical outcomes, we assessed statistical correlations and predictive performance of temperature and weight loss, summarized by conventional and novel approaches. Conventional summary metrics (peak values or area under the curve) were weak and inconsistent correlates of overall disease severity and viral titers. Novel dynamic weight metrics capturing onset, duration, slope, and volatility over 14 days showed lower coefficients of variation than conventional summary approaches. However, inclusion of novel metrics did not meaningfully improve the predictive performance of machine learning models for disease severity outcomes in IAV-inoculated ferrets. Mixed-effects models indicated that weight loss post-IAV infection is driven by time and viral burden, with temperature contributing little additional information. Collectively, these findings support that derived metrics are at least comparable, if not enhanced, to conventional summaries for data science analyses of serially generated clinical data from in vivo pathogen studies. However, because pathogen disease severity in mammals is multifactorial, models that rely solely on weight and temperature metrics without additional quantitative measures of clinical perturbation within-host are unlikely to achieve strong predictive performance.

Pregnant women infected with influenza A virus (IAV) are at increased risk of severe disease, leading to maternal and fetal complications. Toll-like receptor 7 (TLR7) recognizes single-stranded RNA viruses, including IAV, yet its role in maternal immune responses and pregnancy outcomes during IAV infection is poorly understood. Here, we demonstrate that TLR7-knockout (TLR7-/-) pregnant mice showed reduced disease severity, despite similar pulmonary viral titers to wild-type (WT) mice. TLR7-/- dams exhibited distinct pulmonary responses, including reduced lymphocyte infiltration, enhanced neutrophil response, and a shift from type I to type II interferon activity. TLR7 signaling was found to be essential for the development of IAV-induced vascular dysfunction during pregnancy. Offspring from TLR7-/- mice showed improved body weight and reduced placental and fetal brain inflammation compared to WT counterparts. We provide evidence that TLR7 is a critical mediator of adverse pregnancy outcomes during IAV infection and a potential therapeutic target to reduce maternal and fetal morbidity.

Virtual screening targeting the conserved domain of the IAV M2 protein reveals the potential broad-spectrum anti-IAV activity of ajmaline.

Our previous studies have shown that major vault protein (MVP) is a virus-induced host factor that participates in the innate immune response. However, little is known about the role of MVP in Influenza A virus (IAV)- induced ferroptosis. In this study, the expression of MVP was found to positively correlate with that of interferon regulatory factor 1 (IRF1) and ferroptosis suppressor protein 1 (FSP1), but not with glutathione peroxidase 4 (GPX4), in peripheral blood mononuclear cells from patients with IAV. In vitro and in vivo evidence indicate that MVP is a potent factor in ferroptosis resistance during IAV infection. Upon investigating the mechanisms underlying this event, MVP was found to sequester IRF1 from tumor necrosis factor receptor-associated factor 6 (TRAF6), thereby suppressing its polyubiquitination and nuclear localization. Therefore, the transcription inhibition of IRF1 on the FSP1 promoter was removed, thereby enhancing FSP1 expression. A second wave of MVP regulation for IAV-induced ferroptosis also occurs. In the presence of the MVP, transcriptionally induced FSP1 is released from IRF1, leading to its ubiquitination and myristoylation, which enable its recruitment to the plasma membrane, where it functions as an oxidoreductase. These findings define a ferroptosis suppression pathway during IAV infection.