Infectious bronchitis virus (IBV), a member of the γ-coronavirus genus within the Coronaviridae family, is a major pathogenic threat to the global poultry industry. Most IBV infections induce severe renal pathological lesions in chickens, yet the renal metabolic perturbations triggered by IBV infection remain largely elusive. Herein, we applied a metabolomic approach to characterize the metabolic profiles of kidney tissues from IBV-infected specific-pathogen-free (SPF) chickens. IBV infection caused profound alterations in the renal metabolome, encompassing amino acids and their derivatives, energy metabolites, and lipid molecules. Most amino acids and their derivatives were significantly downregulated at 7 days post-infection (dpi), indicating that IBV usurps host amino acid pools to support its own replication in SPF chickens. In addition, the levels of L-glutamine, D-mannose 1-phosphate, and D-galacturonate were markedly elevated post-infection, implying their potential roles in mediating host energy utilization and facilitating viral replication during IBV infection. Subsequently, sphingosine-1-phosphate (S1P)—a key bioactive lipid molecule—was identified as a prominently upregulated metabolite in IBV-infected kidney tissues. Follow-up functional experiments revealed that IBV infection upregulates the S1P-S1PR1 signaling axis, and concomitantly activates the p38/JNK/MAPK pathway as well as the NLRP3/caspase-1 inflammasome. Notably, S1PR1 was found to modulate the p38/MAPK signaling pathway and NLRP3/caspase-1 inflammasome, thereby regulating the expression of the proinflammatory cytokines IL-1β and IL-18. Collectively, our study delineates the comprehensive renal metabolic landscape of chickens in response to IBV infection and identifies S1PR1 as a pivotal regulatory target of IBV-induced renal inflammation. These findings provide novel mechanistic insights for the development of preventive and therapeutic strategies targeting metabolic signaling pathways against IBV infection.

Newcastle disease virus (NDV), a highly contagious avian pathogen, causes devastating economic losses in poultry worldwide, yet the role of epitranscriptomic regulators in its pathogenesis remains poorly defined. Here we demonstrate that the m6A reader protein YTHDF2 functions as a potent antiviral effector against NDV. Through integrated functional genomics and multi-omics approaches, we establish that YTHDF2 deficiency significantly enhances NDV replication, while its overexpression suppresses viral propagation. Temporal transcriptomics and machine learning algorithms converged on HSPA2, ATF3, and IRF9 as high-confidence YTHDF2-regulated targets during infection, with HSPA2 emerging as the principal mechanistic mediator. Mechanistically, YTHDF2 directly binds m6A-modified sites within the HSPA2 coding sequence to augment its translational efficiency, as validated by RNA immunoprecipitation, isothermal titration calorimetry, and m6A-modified reporter assays. HSPA2 overexpression reduced NDV nucleoprotein levels by 68-74%, establishing its direct antiviral function. Crucially, this YTHDF2-HSPA2 axis operates independently of classical innate immune pathways, as transcriptomics revealed intact induction of antiviral genes in YTHDF2-knockout cells. Our findings unveil a previously unrecognized epitranscriptome-governed antiviral strategy wherein YTHDF2 amplifies host defense through selective translational enhancement of m6A-modified effector transcripts. This paradigm extends beyond canonical RNA decay functions of YTHDF2 and identifies the HSPA2 chaperone as a novel restriction factor against paramyxoviruses, offering new avenues for targeted antiviral interventions.

The frequent outbreaks of avian influenza have caused huge economic losses to the poultry industry. Its pathogen, avian influenza virus (AIV), can infect not only birds, but also some subtypes can infect humans and other animals crossing species barriers, which poses a continuous threat to global biosafety. Autophagy, as a highly conserved degradation process that maintains cellular homeostasis, plays a dual role (both antiviral and proviral) in viral infections. Research has shown that AIV can actively intervene in autophagic flux through viral proteins such as NS1, M2 and PB1-F2 to obtain the membrane structures required for self-replication and evade host immune monitoring, especially targeting mitophagy processes. In addition, virus-induced mitochondrial dysfunction not only leads to an outbreak of reactive oxygen species, but in severe cases, it can further cause mitochondrial oxidative membrane rupture and death, known as “Mitoxyperilysis”. This article systematically reviewed the signaling network of AIV-activated mitophagy, focusing on the interaction between viral proteins and core autophagy components, and deeply explored the oxidative stress, lipid peroxidation, and “Mitoxyperilysis” effects caused by mitophagy dysfunction, aiming to provide a theoretical basis for the development of new antiviral strategies targeting host mitochondrial homeostasis.

ETHNOPHARMACOLOGICAL RELEVANCE:Platycodon grandiflorus (PG) is a traditional herb widely used for respiratory infections. Newcastle disease virus (NDV) is a highly contagious and devastating pathogen that causes severe economic losses to the poultry industry. Platycodin D (PD), a bioactive component of PG, has not been investigated for its antiviral activity against NDV. AIM OF THE STUDY:We investigated the antiviral activity of PD against NDV and elucidated its underlying host-targeted mechanisms. MATERIALS AND METHODS:The anti-NDV activity of PD was evaluated in vitro and in vivo. Transcriptomic and network pharmacology were employed to map PD-targeted pathways. Mechanistic dissection was achieved by examining MAPK signaling cascade, NLRP3 inflammasome assembly, inflammatory cytokine profiling, apoptosis regulation, and type I interferon response. RESULTS:PD significantly inhibited NDV replication in vitro and in vivo, reducing viral loads and tissue injury in infected chickens. Transcriptomic profiling combined with network pharmacology analysis identified inflammation-, apoptosis-, and interferon-related pathways as major targets of PD, with MAPK signaling emerging as a central regulatory node. Mechanistic studies demonstrated that PD suppressed NDV-induced activation of the MAPK pathway and NLRP3 inflammasome assembly, leading to decreased production of pro-inflammatory cytokines (IL-1β, IL-6, IL-8, and IL-18). In parallel, PD attenuated virus-induced apoptosis through upregulation of the anti-apoptotic protein Bcl-2. Moreover, PD enhanced antiviral immunity by promoting IFN-α/β expression and STAT1 phosphorylation. CONCLUSION:PD restricts NDV infection by coordinately modulating host inflammatory, apoptotic, and innate antiviral signaling pathways, supporting its potential as a host-targeted antiviral candidate for the control of Newcastle disease.

Circular RNAs (circRNAs) are a class of endogenous non-coding RNAs widely expressed across diverse organisms. These molecules are involved in various biological processes, such as transcriptional and post-transcriptional regulation, protein scaffolding, and acting as miRNA sponges. Newcastle disease virus (NDV) replicates and proliferates in a variety of cells, inducing severe organelle stress damage, autophagy, and even cell death. Previous studies have reported that NDV hijacks and uses autophagy to promote its replication and proliferation. However, the involvement and regulatory mechanisms of circRNAs in this process remain largely unexplored. The present study aimed to identify novel circRNAs that modulate NDV replication through autophagy and elucidate their underlying mechanisms. Our findings revealed that circRNA0857 was significantly upregulated in NDV-infected cells. Functional assays showed that silencing circRNA0857 markedly inhibited NDV replication, while its overexpression enhanced viral replication. Mechanistic analyses demonstrated that circRNA0857 functions as a "miRNA sponge," specifically targeting and sequestering miR1709 and miR1746. These miRNAs were found to regulate the expression of ATG3 and ATG7, respectively, two key autophagy-related genes in the autophagy pathway. By sponging miR1709 and miR1746, circRNA0857 upregulates the expression of ATG3 and ATG7, thereby enhancing autophagy and promoting NDV infection. This study is the first to identify circRNA0857 as a critical regulator in NDV infection, elucidating its role in enhancing NDV-induced autophagy via the miR1709/ATG3 and miR1746/ATG7 signaling axes. These findings significantly advance our understanding of how circRNAs regulate viral infections and provide novel insights into the molecular mechanisms underlying NDV replication.IMPORTANCECircular RNAs (circRNAs), as endogenous non-coding RNAs, are widely involved in various biological processes, particularly in the regulatory modulation of miRNA functions. Newcastle disease virus (NDV) can replicate in a variety of cells and promote its proliferation by hijacking and utilizing autophagy. In this study, we screened for novel circular RNAs that regulate NDV replication through modulating host autophagy and identified circRNA0857 as a key regulator of NDV infection. It enhances autophagy and promotes viral replication by acting as a "miRNA sponge," simultaneously targeting the two signaling axes miR1709/ATG3 and miR1746/ATG7. This research fills a gap in understanding how circRNAs regulate NDV-induced autophagy and provides a new perspective for understanding the interactions between host non-coding RNAs and viruses. This finding deepens our understanding of the pathogenic mechanisms of NDV and offers potential molecular targets for the development of antiviral strategies based on circular RNAs or miRNAs.

The H9N2 subtype of avian influenza is highly contagious, and although it is classified as a low-pathogenic avian influenza virus, its tendency to recombine with other subtypes of avian influenza viruses has made it a potential problem for the poultry industry. Vaccines currently used to prevent this disease are all inactivated, making it difficult to stimulate long-lasting immunity, and have a very weak ability to trigger cellular immunity, thus failing to address the problem of virus shedding. Live-attenuated vaccines are capable of stimulating cellular immunity but carry the risk of recombination with wild-type strains. In this study, we successfully rescued a replication-deficient H9N2 strain (H9-SD18GD12HA) using reverse genetic techniques, which was obtained by replacing the neuraminidase (NA) gene with the open reading frame of the hemagglutinin (HA) gene with the PR8 strain as the backbone. Dynamic growth results showed that H9-SD18GD12HA can proliferate only under NA-containing conditions and therefore cannot grow in normal animals or cells. After immunization of chickens with H9-SD18GD12HA using eye and nose drops, both humoral and cellular immunity were stimulated, and some degree of reduction in virus shedding was observed. These results indicate that H9-SD18GD12HA has good immunogenicity, does not proliferate in vivo, and has the potential to be developed into a novel live-attenuated vaccine for the H9N2 subtype of avian influenza.

Newcastle disease, caused by the Newcastle disease virus (NDV) and characterised by rapid onset and high mortality rates, is a highly contagious disease in the poultry industry. Interferons (IFN) play a key role in host defence against NDV, however, the non-structural protein V of NDV can antagonise IFN to facilitate NDV immune escape. DNA methyltransferase (DNMT)3A, an important regulator of IFN signalling molecules, may participate in the process by which the V protein inhibits IFN. Here, we found that NDV and V protein can inhibit DNMT3A expression, and DNMT3A participates in V protein inhibition of IFN expression. Further analysis revealed that the V protein interacts with DNMT3A and promotes its degradation via the K48-ubiquitin pathway. DNMT3A enhances the transcription and expression of IFN-β without altering the methylation status of the IFN-β gene. Instead, DNMT3A reduces the methylation of the CpG island in the IRF7 promoter region and increases the overall CpG island methylation within the IRF7 gene body, thereby increasing IRF7 expression and modulating IFN-β expression. Our study shows that NDV V protein can bind to and degrade DNMT3A, thereby affecting the methylation level of IRF7 and inhibiting IRF7 expression, ultimately leading to decreased IFN-β expression.

The majority of Newcastle disease virus (NDV) strains circulating in China, which exhibit a tendency toward increased virulence, are from genotype Ⅻ infections obtained from waterfowl. Based on our previous findings, the genotype Ⅻ strain E115 was non-pathogenic in geese but induced notable clinical symptoms in chickens without mortality. However, in recent years, we isolated the genotype Ⅻ strain E117 from dead geese and confirmed its lethality in geese through animal regression tests. Genotype-matched vaccination has been proposed as a potential solution. In this study, two NDV vaccination strains, mE115 and mE117, were rescued and evaluated for their resistance to wild-type virus attacks. In vivo analysis revealed that compared with that of the commercial vaccine group, the mE117, and mE115 immune groups exhibited higher antibody levels. The results of the immune protection test showed that the mE117 and mE115 vaccines prevented geese from dying when exposed to the E117 challenge. In contrast, the commercial vaccine group exhibited a survival rate of 62.5%. Furthermore, viral shedding drastically decreased to 0% in the mE117 and mE115 immunised groups, whereas virus shedding was observed in the visceral organs, oropharynx, or cloaca in the commercial vaccine group. Compared with that of the commercial vaccine, the two vaccine candidates developed in this study provided complete protection for geese against genotype Ⅻ challenges. These findings provide a foundation for the development of more effective vaccines to control Newcastle disease.

Red blood cells (RBCs) are the most abundant cell type in the blood and play a critical role as the primary carriers of oxygen to tissues and organs through blood circulation. The hemagglutinin-neuraminidase (HN) protein on the surface of the Newcastle disease virus (NDV) contains receptors that bind to the surface of RBCs, endowing NDV with agglutination properties that hold significant clinical diagnostic value. This raises an important question: could NDV bind to RBCs and use their carrier properties to facilitate transport to various tissues and organs? This study conducted both in vivo and in vitro experiments to confirm the adhesion and transport capabilities of chicken RBCs for the Newcastle disease virus. In addition, we found that NDV infection induces apoptosis in RBCs. These findings systematically explored the infection process of NDV in chicken RBCs and its subsequent effects, providing direct evidence of the potential role of chicken RBCs as a transport vehicle for the virus. This research offers a novel perspective on the mechanisms of NDV transmission.

The infectious bronchitis virus (IBV) belongs to the γ-coronavirus family and posing a serious threat to poultry health. Here, a single IBV strain, designated as IBV-250607GXCX, was isolated and identified from a poultry farm. S1 gene typing classified 250607GXCX as belonging to the genotype GVII-1 of IBV. Nucleotide sequence similarity and phylogenetic analyses revealed that 250607GXCX shares high sequence similarity and a close evolutionary relationship with I0636/16, suggesting that 250607GXCX may be the result of the long-term evolution of the parental strain I0636/16 in the Guangxi region. Recombination analysis showed that the S gene of 20250607GXCX did not undergo significant recombination during evolution, whereas the 1b, 3a, M, and N genes underwent recombination events with locally circulating strains. This study confirmed that 250607GXCX can efficiently infect Vero and DF-1 cells, exhibiting cell infection capacity and cell tropism similar to those of the Beaudette strain, and that this infectivity does not require passage through chicken embryos. Pathogenicity studies revealed that 250607GXCX is not lethal, that it primarily affects the respiratory tract of chickens, and that viral replication and shedding efficiency significantly decrease at 14 days post-infection. Receptor binding analysis showed that 250607GXCX and Beaudette have weak binding capacities for alpha-2,3-sialyltransferase, suggesting that there may be other accessory adhesion factors or secondary receptors assisting IBV cell invasion besides alpha-2,3-sialyltransferase. Overall, our study identified an IBV strain with good infectivity in cell lines and reduced pathogenicity, making 250607GXCX a promising tool for studying IBV invasion mechanisms and as a reverse genetic vaccine vector.

Lipid nanoparticles-mRNA play important roles in SARS-CoV-2 infection control. Avian coronavirus infectious bronchitis virus (IBV) comprises eight genotypes with a lack of cross-protection, causing severe economic losses to the poultry industry. Using immunoinformatics methods, five consensus sequence antigens against prevalent IBV strains were designed. Four monovalent lipid nanoparticles-mRNA (GI-19, GI-13, GI-7, GVI-1) and one quadrivalent lipid nanoparticles-mRNA were constructed to develop a broad-spectrum IBV vaccine. The safety and biodistribution of the lipid nanoparticles-mRNA were evaluated in SPF chickens and confirmed that it induced a strong and durable immune response. The lipid nanoparticles-mRNA efficacy in SPF chickens was verified in infection assays with four genotypes of IBV strains, the results showed that immunization with a 10 µg dose provided complete protection for the chickens, while immunization with a 5 µg dose reduced disease severity, organ damage, and mortality, and inhibited viral replication and shedding. Our results indicate that these Lipid nanoparticles-mRNA are immunogenic and protective in preclinical animal models. These data can provide a basis for IBV prevention and control and the development of mRNA vaccines against other prevalent viruses.

Newcastle disease, a highly contagious avian illness caused by the Newcastle disease virus (NDV), inflicts substantial economic losses upon the global poultry industry. While NDV is known to enter host cells via multiple pathways, critical aspects of its infection and pathogenic mechanisms, particularly the role of host lipids, remain incompletely understood. Here, we demonstrate that NDV infection strategically manipulates host phosphatidylserine (PS) metabolism to enhance its replication cycle. We found that the NDV hemagglutinin-neuraminidase (HN) protein triggers an elevation in intracellular Ca2+ levels, which in turn activates the host phospholipid scramblase TMEM16F. This activation leads to the externalization of PS to the outer leaflet of the plasma membrane. Consequently, NDV virions budding from these PS-rich membrane domains acquire a PS-enriched envelope. Mass spectrometry analysis confirmed high PS abundance on the viral surface. These PS-decorated progeny virions then engage host cell PS receptors, specifically the receptor tyrosine kinase TYRO3 and T-cell immunoglobulin and mucin domain-containing receptor 4 (TIM-4), to facilitate enhanced viral adsorption and entry. This process, known as “apoptotic mimicry,” represents a novel, parallel entry pathway for NDV. These findings provide new mechanistic insights into NDV-host interactions and identify the PS scrambling and recognition axis as a potential therapeutic target for developing novel anti-NDV strategies.

Leaf shape is a key trait for plant architecture relating to photosyn-thesis and transpiration in plants(Lawson et al.,2020).Erect leaves with proper leaf length and width,particularly the upper three leaves in cereal crops,could significantly improve light absorption efficiency in canopy and ultimately increase crop yield(Jiao et al.,2010).Rice leaves initiate at the peripheral zone of shoot apical meristem,then develop along the proximal-distal,adaxial-abaxial,and medial-lateral axes to form a flat symmetric architecture(Du et al.,2018).

ABSTRACT The phosphatidyl-inositol 3-kinase/serine-threonine kinase (PI3K/ AKT) signaling pathway constitutes a classical phosphorylation cascade that integrates tyrosine, lipid, and serine acid-threonine phosphorylation, affecting cell function. The pathway is vulnerable to viral infection. Newcastle disease virus (NDV) poses a significant threat to the global poultry industry; however, its mechanism of early viral cell invasion and pathogenesis remain unclear. Previous in vivo and in vitro studies have shown that NDV infection activates PI3K/AKT signaling; however, it remains unclear whether NDV establishes infection through endocytosis regulated by this pathway. This study aimed to examine whether different genotypes of NDV strains could activate the PI3K/AKT signaling pathway within 2 h of in vitro infection. This activation, which relies on PI3K phosphorylation, remains unaffected by the phosphorylation-phosphatase and tensin homolog/phosphatase and tensin homolog (p-PTEN/PTEN) signaling pathway. Moreover, inhibition of PI3K activity impedes NDV replication. Additionally, interfering with the PI3K regulatory subunit p85 has no significant effect on NDV replication. Conversely, the tyrosine kinase activity upstream of PI3K can influence AKT activation and viral replication, particularly through vascular endothelial growth factor receptor 2 (VEGFR2). Additionally, NDV F protein primarily mediates PI3K and AKT phosphorylation to activate the PI3K/AKT signaling pathway. NDV F and VEGFR2 proteins, along with the PI3K p85α subunit, interact and co-localize at the cell membrane. NDV-induced PI3K/AKT signaling pathway activation impacts clathrin-mediated endocytosis, with VEGFR2 playing a pivotal role. In conclusion, this study shows that NDV infection is established early through F protein binding to VEGFR2, activating the PI3K/AKT signaling pathway and inducing clathrin-mediated endocytosis, supporting infection prevention and control measures. IMPORTANCE Newcastle disease virus (NDV) is a threat to the global poultry industry; however, the mechanisms of NDV infection remain unclear. NDV affects the phosphatidyl-inositol 3-kinase/serine-threonine kinase (PI3K/ AKT) signaling pathway, requiring endocytosis for successful infection. Based on previous studies, we identified a close correlation between NDV infection and replication and the PI3K/AKT signaling pathway activity. This study examined the molecular mechanisms through which NDV activates the PI3K/AKT signaling pathway to regulate endocytosis and facilitate infection. This study showed that early-stage in vitro NDV infection activated the PI3K/AKT signaling pathway, enhancing clathrin-mediated endocytosis, crucial for infection onset. Notably, this process involves the interaction between NDV F protein and the vascular endothelial growth factor receptor 2 tyrosine kinase, leading to the subsequent binding and phosphorylation of the PI3K p85α regulatory subunit. This activation primes PI3K, initiating a cascade that promotes clathrin-mediated endocytosis. Our findings elucidate how NDV capitalizes on the PI3K/AKT signaling pathway to establish infection through endocytosis.

Hydropericardium hepatitis syndrome (HHS) is primarily caused by fowl adenovirus serotype 4 (FAdV-4), causing high mortality in chickens. Although vaccination strategies against FAdV-4 have been adopted, HHS still occurs sporadically. Furthermore, no effective drugs are available for controlling FAdV-4 infection. However, type I and III interferon (IFN) are crucial therapeutic agents against viral infection. The following experiments were conducted to investigate the inhibitory effect of chicken IFN against FadV-4. We expressed recombinant chicken type I IFN-α (ChIFN-α) and type III IFN-λ (ChIFN-λ) in Escherichia coli and systemically investigated their antiviral activity against FAdV-4 infection in Leghorn male hepatocellular (LMH) cells. ChIFN-α and ChIFN-λ dose dependently inhibited FAdV-4 replication in LMH cells. Compared with ChIFN-λ, ChIFN-α more significantly inhibited viral genome transcription but less significantly suppressed FAdV-4 release. ChIFN-α- and ChIFN-λ-induced IFN-stimulated gene (ISG) expression, such as PKR, ZAP, IRF7, MX1, Viperin, IFIT5, OASL, and IFI6, in LMH cells; however, ChIFN-α induced a stronger expression level than ChIFN-λ. Thus, our data revealed that ChIFN-α and ChIFN-λ might trigger different ISG expression levels, inhibiting FAdV-4 replication via different steps of the FAdV-4 lifecycle, which furthers the potential applications of IFN antiviral drugs in chickens.

Infectious bronchitis virus (IBV) is distributed worldwide and causes significant losses in the poultry industry. In recent decades, lineages GI-19 and GI-7 have become the most prevalent IBV strains in China. However, the molecular evolution and phylodynamics of the lineage GI-7 IBV strains remain largely unknown. In this study, we identified 19 IBV strains from clinical samples from January 2021 to June 2022 in China, including 12 strains of GI-19, 3 strains of GI-7, and 1 strain each of GI-1, GI-9, GI-13, and GI-28. These results indicated that lineages GI-19 and GI-7 IBVs are still the most prevalent IBVs in China. Here, we investigated the evolution and transmission dynamics of lineage GI-7 IBVs. Our results revealed that the Taiwan province might be the origin of lineage GI-7 IBVs and that South China plays an important role in the spread of IBV. Furthermore, we found low codon usage bias of the S1 gene in lineage GI-7 IBVs. This allowed IBV to replicate in the host during evolution as a result of reduced competition, mainly driven by natural selection and mutational pressure, where the role of natural selection is more prominent. Collectively, our results reveal the genetic diversity and evolutionary dynamics of lineage GI-7 IBVs, which could assist in the prevention and control of viral infection.

Avian infectious bronchitis is a serious and highly contagious disease that is caused by the infectious bronchitis virus (IBV). From January 2021 to June 2022, 1008 chicken tissue samples were collected from various regions of southern China, and 15 strains of the IBV were isolated. Phylogenetic analysis revealed that the strains mainly comprised the QX type, belonging to the same genotype as the currently prevalent LX4 type, and identified four recombination events in the S1 gene, among which lineages GI-13 and GI-19 were most frequently involved in recombination. Further study of seven selected isolates revealed that they caused respiratory symptoms, including coughing, sneezing, nasal discharge, and tracheal sounds, accompanied by depression. Inoculation of chicken embryos with the seven isolates resulted in symptoms such as curling, weakness, and bleeding. Immunization of specific pathogen-free (SPF) chickens with inactivated isolates produced high antibody levels that neutralized the corresponding strains; however, antibodies produced by vaccine strains were not effective in neutralizing the isolates. No unambiguous association was found between IBV genotypes and serotypes. In summary, a new trend in IBV prevalence has emerged in southern China, and currently available vaccines do not provide protection against the prevalent IBV strains in this region, facilitating the continued spread of IBV.

Dear Editor, Recently, an article in your journal reported the first human case of the novel H3N8 avian influenza virus (AIV) in Henan Province, China1Cheng D. Dong Y. Wen S. Shi C. A child with acute respiratory distress syndrome caused by avian influenza H3N8 virus.J Infect. 2022; 85: 174-211https://doi.org/10.1016/j.jinf.2022.05.007Abstract Full Text Full Text PDF Scopus (16) Google Scholar; the same year, another case of H3N8 subtype infection was reported in Hunan Province, China.2Yang R. Sun H. Gao F. Luo K. Huang Z. Tong Q. et al.Human infection of avian influenza A H3N8 virus and the viral origins: a descriptive study.Lancet Microbe. 2022; 3: e824-e834https://doi.org/10.1016/S2666-5247(22)00192-6Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar One of the two patients had acute respiratory distress syndrome, and the other had a mild condition. Moreover, the World Health Organization (WHO) reported a fatal human infection with H3N8 AIV on April 11, 2023, the first known human death caused by H3N8. The patient was a 56-year-old woman from Guangdong Province, China, who was hospitalized with severe pneumonia on March 3 and died on March 16, 2023. As the WHO reported, nucleic acid tests of environmental samples collected from the house and live poultry markets visited by the deceased patients were positive for H3N8 AIV. Initial epidemiological investigations have indicated that exposure to live poultry markets is a likely cause of H3N8 infection. However, the exact source of the infection and how the virus relates to other H3N8 AIVs circulating among animals remains unclear. No new cases were detected among close contacts or co-exposed individuals associated with the three known cases, suggesting a low H3N8 transmission risk and limited human-to-human infectivity at this stage. H3N8 AIV is prevalent among animals worldwide and is one of the most common subtypes infecting birds.3Zhang X. Li Y. Jin S. Zhang Y. Sun L. Hu X. et al.PB1 S524G mutation of wild bird-origin H3N8 influenza A virus enhances virulence and fitness for transmission in mammals.Emerg Microbes Infect. 2021; 10: 1038-1051https://doi.org/10.1080/22221751.2021.1912644Crossref PubMed Scopus (13) Google Scholar The cross-species transmission of H3N8 AIV has been reported in various mammalian species, including dogs and horses.4He W. Li G. Wang R. Shi W. Li K. Wang S. et al.Host-range shift of H3N8 canine influenza virus: a phylodynamic analysis of its origin and adaptation from equine to canine host.Vet Res. 2019; 50: 87https://doi.org/10.1186/s13567-019-0707-2Crossref PubMed Scopus (8) Google Scholar Our previous study confirmed that H3N8 could induce adaptive mammalian mutations.5Liang J. Li Q. Cai L. Yuan Q. Chen L. Lin Q. et al.Adaptation of two wild bird-origin H3N8 avian influenza viruses to mammalian hosts.Viruses. 2022; 14https://doi.org/10.3390/v14051097Crossref Scopus (5) Google Scholar AIV transmission from birds to humans is usually sporadic and occurs in specific contexts, mostly from contact with infected poultry or contaminated environments. However, owing to the widespread prevalence of this virus, more sporadic cases are expected in the future. AIVs mainly circulate among birds and need to be mutated for human infection to cause an epidemic among humans. Currently, it is difficult for most AIVs to infect humans and adapt for effective replication. However, influenza A viruses (IAVs) circulating in humans are mostly related to AIVs, and the possibility that AIVs may mutate and adapt to infect humans cannot be ruled out.6Zhou J. Chen Y. Shao Z. Ding S. Qi W. Zhang J. et al.Continuing evolution and transmission of avian influenza A(H3N8) viruses is a potential threat to public health.J Infect. 2023; 86: 154-225https://doi.org/10.1016/j.jinf.2022.11.010Abstract Full Text Full Text PDF Scopus (1) Google Scholar Currently, the main subtypes of influenza A circulating in China are H1N1 and H3N2, both of which originate in birds and have caused pandemics infecting millions of people.7Tang J.W. Ngai K.L. Lam W.Y. Chan P.K. Seasonality of influenza A(H3N2) virus: a Hong Kong perspective (1997-2006).PLoS One. 2008; 3e2768https://doi.org/10.1371/journal.pone.0002768Crossref Scopus (28) Google Scholar, 8Taubenberger J.K. Morens D.M. 1918 Influenza: the mother of all pandemics.Emerg Infect Dis. 2006; 12: 15-22https://doi.org/10.3201/eid1201.050979Crossref PubMed Google Scholar Since the beginning of the coronavirus disease (COVID-19) pandemic, the number of influenza cases in China has fallen to its lowest level in decades. However, the prevention and control measures executed by China over the past 3 years have prevented the spread of COVID-19 as well as influenza, which has reduced the anti-influenza immunity of the entire population, providing favorable conditions for an epidemic. When the epidemic prevention and control measures implemented by China were changed on December 13, 2022, the number of weekly confirmed cases increased and subsequently decreased rapidly within a few weeks after people gained specific immunity to COVID-19 (Fig. 1); this can be attributed to the cancellation of large-scale nucleic acid testing. There is no cross-immunity protection against COVID-19 and influenza, and people who have recently been infected with COVID-19 do not exhibit a protective effect against influenza. With the alternation of winter and spring, the influenza epidemic in China peaked in March, and H3N2 and H1N1 IAVs were the main subtypes, with a small number of influenza B cases (Victoria) (Fig. 1). Following the height of COVID-19, citizen behavioral patterns have changed significantly, with more frequent contact resulting in greater susceptibility to influenza. Compared with the epidemic prevention and control period of the previous two years, the percentage of influenza-like illness cases reported by sentinel hospitals in China has increased significantly between December 2022 and March 2023 (Fig. 2).Fig. 2Percentages of influenza-like illness cases in total outpatient cases in southern and northern China between 2020 and 2023 (updated on April 30th, 2023). Data for influenza-like illness cases (%) are from the Chinese National Influenza Center (https://ivdc.chinacdc.cn/cnic).View Large Image Figure ViewerDownload Hi-res image Download (PPT) Currently, it is rare for a human to contract AIV to from another human who contracted it from a bird. But the warning is that once cross-species transmission occurs, human infections can lead to adaptive mutations in viruses that may allow them to spread more easily within species. The industrialization and mixed farming of different animal species, combined with live poultry markets, create an ideal environment for the recombination and interspecific transmission of influenza viruses. Continued human infection with the novel H3N8 virus may drive the virus to acquire a preference for binding to human receptors, a prerequisite for a potential H3N8 virus pandemic.2Yang R. Sun H. Gao F. Luo K. Huang Z. Tong Q. et al.Human infection of avian influenza A H3N8 virus and the viral origins: a descriptive study.Lancet Microbe. 2022; 3: e824-e834https://doi.org/10.1016/S2666-5247(22)00192-6Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar Although the virus transmission risk is low at this stage and no human-to-human transmission has been detected, we should not take it lightly and still adopt effective prevention and surveillance strategies. On May 5, 2023, the WHO officially declared that COVID-19 no longer constituted a “public health emergency of international concern.” However, in the post-COVID-19 era, the continued cocirculation of SARS-CoV-2 and influenza viruses is expected to present challenges to healthcare systems globally. We must anticipate and consider a holistic approach to combat this dual threat, which could pose a serious challenge owing to the concurrent burden of both diseases. Strengthening pathogen surveillance for emerging infectious diseases has become an important global public health topic. Local epidemics caused by viral mutations can be expected to occur frequently. In the future, the prevalence of other emerging infectious diseases will pose a public health challenge in China. None. This research was funded by the Science and Technology Program of Guangdong Province (No. 2021B1212030015), the Guangdong Provincial Special Fund for Modern Agriculture Industry Technology Innovation Teams (No. 2023KJ119), and the Forestry Technology Innovation Project of Guangdong Province (No. 2023KJCX028).