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Highly pathogenic avian influenza (HPAI) subtype H5N1 clade 2.3.4.4b virus has spread globally, causing unprecedented large-scale avian influenza outbreaks since 2020. In 2021, we isolated 17 highly pathogenic avian influenza H5N1 viruses from wild birds in China. To determine virus origin, we genetically analyzed 1,529 clade 2.3.4.4b H5N1 viruses reported globally since October 2020 and found that they formed 35 genotypes. The 17 viruses belonged to genotypes G07, which originated from eastern Asia, and G10, which originated from Russia. The viruses were moderately pathogenic in mice but were highly lethal in ducks. The viruses were in the same antigenic cluster as the current vaccine strain (H5-Re14) used in China. In chickens, the H5/H7 trivalent vaccine provided complete protection against clade 2.3.4.4b H5N1 virus challenge. Our data indicate that vaccination is an effective strategy for preventing and controlling the globally prevalent clade 2.3.4.4b H5N1 virus.

In January 2020, the subclade 2.3.4.4h of highly pathogenic avian influenza (H5N6) virus infected migratory whooper swans and mute swans in Xinjiang, western China. The virus is lethal to chickens and ducks but has low pathogenicity in mice. Antigenically, this subclade is similar to the H5N1 vaccine seed virus Re-11.

The H5N8 avian influenza viruses have been widely circulating in wild birds and are responsible for the loss of over 33 million domestic poultry in Europe, Russia, Middle East, and Asia since January 2020. To monitor the invasion and spread of the H5N8 virus in China, we performed active surveillance by analyzing 317 wild bird samples and swab samples collected from 41,172 poultry all over the country. We isolated 22 H5N8 viruses from wild birds and 14 H5N8 viruses from waterfowls. Genetic analysis indicated that the 36 viruses formed two different genotypes: one genotype viruses were widely detected from different wild birds and domestic waterfowls; the other genotype was isolated from a whopper swan. We further revealed the origin and spatiotemporal spread of these two distinct H5N8 virus genotypes in 2020 and 2021. Animal studies indicated that the H5N8 isolates are highly pathogenic to chickens, mildly pathogenic in ducks, but have distinct pathotypes in mice. Moreover, we found that vaccinated poultry in China could be completely protected against H5N8 virus challenge. Given that the H5N8 viruses are likely to continue to spread in wild birds, vaccination of poultry is highly recommended in high-risk countries to prevent H5N8 avian influenza.

Lethal infection of wild birds with different subtypes of H5 viruses continuously occur. To investigate the genetic evolution and pathogenicity of H5 viruses in wild birds, we performed a detailed genetic and biologic analysis of 27 viruses, including H5N1, H5N2, H5N6, and H5N8 subtypes, that were responsible for avian influenza outbreaks in wild birds in China over the past decade. We found that these 27 viruses, bearing different clades/subclades of HA, were complicated reassortants and formed 12 different genotypes. Ten of the viruses tested were highly pathogenic in chickens, but showed distinct pathotypes in ducks and mice. Five of these 10 viruses, which were all from clade2.3.4.4, could bind human-type receptors. Our findings reveal the diversity of the genetic and biologic properties of H5 viruses circulating in wild birds and highlight the need to carefully monitor and evaluate the risks these viruses pose to animal and public health.

During the active surveillance, we isolated nine H4N6 subtype influenza A viruses from wild birds in China. To reveal the epidemiology and biology characteristics of H4 subtype influenza A virus from wild birds, we investigated H4 subtype viruses available in the public source, and found that the H4 viruses have been detected in at least 37 countries to date, and more than 73.6% of the viruses were from wild Anseriformes. Bayesian phylogeographic analysis showed that Mongolia worked as the important transmission centre for Eurasian lineage H4 viruses spreading. Phylogenetic analysis of HA genes indicated that global H4 influenza A viruses were divided into Eurasian and North American lineage, our nine H4N6 isolates fell into the Eurasian lineage. Recombination analysis suggested that nine H4N6 isolates underwent complex gene recombination with various subtypes of influenza A viruses and formed two genotypes. Notably, nine H4N6 isolates acquired mammalian virulence-increasing residues. Two representative H4N6 viruses possessed dual receptor binding specificity, they could efficiently replicate in MDCK and 293 T cells in vitro infection, also could cross the species barrier to infect mice directly without prior adaption in vivo experiments. These findings emphasize the public health issues represented by H4 viruses, and highlight the need to strengthen the active surveillance of H4 viruses from wild birds.

Subclade 2.3.4.4b H5Nx highly pathogenic avian influenza (HPAI) viruses, emerged in 2013 with multiple subtypes of H5N8, H5N1, and H5N6, had unprecedently caused a global epizootic by H5N1 since 2021, which had devasted multiple species of wild birds, poultry, and wild mammals (terrestrial and marine) with a high mortality, causing severe ecological damage. The infected wild mammals may become new “mixers” for influenza viruses, posing the potential transmission to human. Frequent outbreaks of subclade 2.3.4.4b H5Nx viruses among wild birds and poultry had exposed major gaps in our knowledge on their evolution, spatiotemporal diffusion, and species‐crossing transmission. Here, we integrated the phylogenetic and epidemiological data of subclade 2.3.4.4b H5Nx viruses in public database and used Bayesian phylodynamic analysis to reveal the pattern of the global large‐scale transmission. Phylogenic analysis demonstrated that the HA gene of these viruses diverged into two dominant clusters around 2015 and 2016. The Bayesian phylodynamic analysis illustrated that the viruses presented spatiotemporally complex transmission network with geographical and host relative expansion and recombination with different subtypes of NA segment. Spatially, the Russian Federation (Siberia) was identified as the primary hub for virus transmission, which was further facilitated by the establishment of strong epidemiological linkages between West Europe and broader regions, such as North America. As for hosts, wild Anseriformes were the primary species for the virus spillover, contributing to the spatial expansion and rapid diffusion globally of subclade 2.3.4.4b viruses. We investigated the phylogeny of subclade 2.3.4.4b H5Nx viruses and the spatiotemporal pattern of transmission with initial location and the primary host, which could provide comprehensive insights for subclade 2.3.4.4b H5Nx viruses. Due to the wild birds involved the widespread of subclade 2.3.4.4b H5Nx viruses, the epizootics in poultry are inevitable, so we highly recommend to apply the policy of culling plus with vaccination to protect the poultry industry and potentially protect the public health.

During the routine surveillance, we isolated nine H4N6 subtype avian influenza viruses (AIVs) in Jiangsu Province, China, in March 2023. Phylogenetic analysis revealed that nine H4N6 viruses belonged to the Eurasian lineage and underwent complex genetic recombination among Asian countries during their evolution. It is particularly noteworthy that the PB2 and PB1 genes of our representative virus were descended from clade 2.3.4.4b H5 high-pathogenic AIVs in Japan. Mutations of D3V and D622G in PB1, N66S in PB1-F2, N30D, I43M, and T215A in M1, and P42S and I106M in NS1 were observed in nine isolates, which may increase the pathogenicity of the viruses in mice. The receptor binding analysis showed that the tested H4N6 virus could bind to both avian-type and human-type receptors. Vitro infection kinetics revealed that the representative virus could efficiently replicate in mammalian cells, including MDCK and 293T cells. Pathogenicity tests in mice indicated that the representative virus could replicate in nasal turbinates and lungs without prior adaptation. Our data reveal the potential public health issues represented by H4N6 viruses from wild birds and highlight the need to strengthen routine surveillance of wild birds.

The global prevalence of gestational diabetes mellitus (GDM) is increasing, posing significant health risks to both mothers and infants. Visceral adipose tissue-derived serine protease inhibitor (Vaspin) has been identified as a potential insulin sensitizer that may mitigate insulin resistance (IR). However, the related mechanism by which Vaspin improves IR in patients with GDM remains unclear. This study aims to investigate whether Vaspin ameliorates IR in GDM via modulation of the ROS/eNOS/NO signaling pathway. Clinical samples from 58 pregnant women were collected and categorized into GDM and control (G) groups. Binary logistic regression analysis revealed significant associations between Vaspin, IR, and GDM. A GDM rat model was established using 50 female Sprague-Dawley (SD) rats, divided into GDM and G groups. Fasting blood glucose (FBG), fasting insulin (FINS), and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) levels were measured using ELISA and steady-state model evaluation. Vaspin intervention significantly reduced FBG, FINS, and HOMA-IR levels in the GDM group, while L-NAME, an endothelial nitric oxide synthase (eNOS) inhibitor, blocked these effects. INS-1 cells were used to establish a high-glucose model, and laser confocal microscopy, ELISA, and Griess reagent were employed to detect reactive oxygen species (ROS), eNOS, and nitric oxide (NO) levels. Exogenous Vaspin administration improved ROS, eNOS, and NO levels, but these effects were inhibited by L-NAME. Collectively, these results propose a model in which the protective effect of Vaspin against insulin resistance in GDM may be mediated, at least in part, through the ROS/eNOS/NO pathway.