[Research progress on structures, activities, and biosynthesis of blazeispirol compounds from Agaricus blazei].

Agaricus blazei is a rare medicinal and edible fungus with a crispy taste and delicious flavor. Both fruiting body and mycelium are rich in polysaccharides, sterols, terpenoids, peptides, lipids, polyphenols, and other active ingredients, which have strong pharmacological activities such as anti-tumor, lipid-lowering, glucose-lowering, immunomodulation, optimization of intestinal flora, and anti-oxidation. Therefore, it is a kind of fungal resource with a great prospect of edible and medicinal development. Among the reported chemical components of A. blazei, blazeispirol is a series of sterol compounds unique to A. blazei, which has a spiral structure and is different from classical steroids. It is an important active ingredient found in the mycelium of A. blazei and has significant hepatoprotective activity. It can be used as a phylogenetic and chemotaxonomic marker of A. blazei strains and is considered an excellent lead compound for drug development. According to the skeleton structure characteristics, the 17 discovered blazeispirol compounds can be divided into two types: blazeispirane and problazeispirane. In order to further explore the resource of blazeispirol compounds of A. blazei, the discovery, isolation, structure, biological activity, and biosynthetic pathways of blazeispirol compounds of A. blazei were systematically reviewed. Besides, the metabolic regulation strategies related to the fermentation synthesis of blazeispirol A by A. blazei were discussed. This review could provide a reference for the efficient synthesis and development of blazeispirol compounds, the research and development of related drugs and functional foods, and the quality improvement of A. blazei and other medicinal and edible fungi resources and derivatives.

The Ca2+-dependent phosphatase calcineurin dephosphorylates TBK1 to suppress antiviral innate immunity.

Tumor necrosis factor receptor-associated factor family member-associated NF-κB activator-binding kinase 1 (TBK1) plays a key role in the induction of the type 1 interferon (IFN-I) response, which is an important component of innate antiviral defense. Viruses target calcium (Ca2+) signaling networks, which participate in the regulation of the viral life cycle, as well as mediate the host antiviral response. Although many studies have focused on the role of Ca2+ signaling in the regulation of IFN-I, the relationship between Ca2+ and TBK1 in different infection models requires further elucidation. Here, we examined the effects of the Newcastle disease virus (NDV)-induced increase in intracellular Ca2+ levels on the suppression of host antiviral responses. We demonstrated that intracellular Ca2+ increased significantly during NDV infection, leading to impaired IFN-I production and antiviral immunity through the activation of calcineurin (CaN). Depletion of Ca²+ was found to lead to a significant increase in virus-induced IFN-I production resulting in the inhibition of viral replication. Mechanistically, the accumulation of Ca2+ in response to viral infection increases the phosphatase activity of CaN, which in turn dephosphorylates and inactivates TBK1 in a Ca2+-dependent manner. Furthermore, the inhibition of CaN on viral replication was counteracted in TBK1 knockout cells. Together, our data demonstrate that NDV hijacks Ca2+ signaling networks to negatively regulate innate immunity via the CaN-TBK1 signaling axis. Thus, our findings not only identify the mechanism by which viruses exploit Ca2+ signaling to evade the host antiviral response but also, more importantly, highlight the potential role of Ca2+ homeostasis in the viral innate immune response.IMPORTANCEViral infections disrupt intracellular Ca2+ homeostasis, which affects the regulation of various host processes to create conditions that are conducive for their own proliferation, including the host immune response. The mechanism by which viruses trigger TBK1 activation and IFN-I induction through viral pathogen-associated molecular patterns has been well defined. However, the effects of virus-mediated Ca2+ imbalance on the IFN-I pathway requires further elucidation, especially with respect to TBK1 activation. Herein, we report that NDV infection causes an increase in intracellular free Ca2+ that leads to activation of the serine/threonine phosphatase CaN, which subsequently dephosphorylates TBK1 and negatively regulates IFN-I production. Furthermore, depletion of Ca2+ or inhibition of CaN activity exerts antiviral effects by promoting the production of IFN-I and inhibiting viral replication. Thus, our results reveal the potential role of Ca2+ in the innate immune response to viruses and provide a theoretical reference for the treatment of viral infectious diseases.

Occludin and collagen IV degradation mediated by the T9SS effector SspA contributes to blood-brain barrier damage in ducks during Riemerella anatipestifer infection.

Riemerella anatipestifer infection is characterized by meningitis with neurological symptoms in ducklings and has adversely affected the poultry industry. R. anatipestifer strains can invade the duck brain to cause meningitis and neurological symptoms, but the underlying mechanism remains unknown. In this study, we showed that obvious clinical symptoms, an increase in blood‒brain barrier (BBB) permeability, and the accumulation of inflammatory cytokines occurred after intravenous infection with the Yb2 strain but not the mutant strain Yb2ΔsspA, indicating that Yb2 infection can lead to cerebrovascular dysfunction and that the type IX secretion system (T9SS) effector SspA plays a critical role in this pathological process. In addition, we showed that Yb2 infection led to rapid degradation of occludin (a tight junction protein) and collagen IV (a basement membrane protein), which contributed to endothelial barrier disruption. The interaction between SspA and occludin was confirmed by coimmunoprecipitation. Furthermore, we found that SspA was the main enzyme mediating occludin and collagen IV degradation. These data indicate that R. anatipestifer SspA mediates occludin and collagen IV degradation, which functions in BBB disruption in R. anatipestifer-infected ducks. These findings establish the molecular mechanisms by which R. anatipestifer targets duckling endothelial cell junctions and provide new perspectives for the treatment and prevention of R. anatipestifer infection.

Single-cell profiling of African swine fever virus disease in the pig spleen reveals viral and host dynamics.

African swine fever, one of the major viral diseases of swine, poses an imminent threat to the global pig industry. The high-efficient replication of the causative agent African swine fever virus (ASFV) in various organs in pigs greatly contributes to the disease. However, how ASFV manipulates the cell population to drive high-efficient replication of the virus in vivo remains unclear. Here, we found that the spleen reveals the most severe pathological manifestation with the highest viral loads among various organs in pigs during ASFV infection. By using single-cell-RNA-sequencing technology and multiple methods, we determined that macrophages and monocytes are the major cell types infected by ASFV in the spleen, showing high viral-load heterogeneity. A rare subpopulation of immature monocytes represents the major population infected at late infection stage. ASFV causes massive death of macrophages, but shifts its infection into these monocytes which significantly arise after the infection. The apoptosis, interferon response, and antigen-presentation capacity are inhibited in these monocytes which benefits prolonged infection of ASFV in vivo. Until now, the role of immature monocytes as an important target by ASFV has been overlooked due to that they do not express classical monocyte marker CD14. The present study indicates that the shift of viral infection from macrophages to the immature monocytes is critical for maintaining prolonged ASFV infection in vivo. This study sheds light on ASFV tropism, replication, and infection dynamics, and elicited immune response, which may instruct future research on antiviral strategies.

Oncolytic Newcastle disease virus induced degradation of YAP through E3 ubiquitin ligase PRKN to exacerbate ferroptosis in tumor cells.

Ferroptosis, a form of programmed cell death characterized by iron-dependent lipid peroxidation, has recently gained considerable attention in the field of cancer therapy. There is significant crosstalk between ferroptosis and several classical signaling pathways, such as the Hippo pathway, which suppresses abnormal growth and is frequently aberrant in tumor tissues. Yes-associated protein 1 (YAP), the core effector molecule of the Hippo pathway, is abnormally expressed and activated in a variety of malignant tumor tissues. We previously proved that the oncolytic Newcastle disease virus (NDV) activated ferroptosis to kill tumor cells. NDV has been used in tumor therapy; however, its oncolytic mechanism is not completely understood. In this study, we demonstrated that NDV exacerbated ferroptosis in tumor cells by inducing ubiquitin-mediated degradation of YAP at Lys90 through E3 ubiquitin ligase parkin (PRKN). Blocking YAP degradation suppressed NDV-induced ferroptosis by suppressing the expression of Zrt/Irt-like protein 14 (ZIP14), a metal ion transporter that regulates iron uptake. These findings demonstrate that NDV exacerbated ferroptosis in tumor cells by inducing YAP degradation. Our study provides new insights into the mechanism of NDV-induced ferroptosis and highlights the critical role that oncolytic viruses play in the treatment of drug-resistant cancers.IMPORTANCEThe oncolytic Newcastle disease virus (NDV) is being developed for use in cancer treatment; however, its oncolytic mechanism is still not completely understood. The Hippo pathway, which is a tumor suppressor pathway, is frequently dysregulated in tumor tissues due to aberrant yes-associated protein 1 (YAP) activation. In this study, we have demonstrated that NDV degrades YAP to induce ferroptosis and promote virus replication in tumor cells. Notably, NDV was found to induce ubiquitin-mediated degradation of YAP at Lys90 through E3 ubiquitin ligase parkin (PRKN). Our study reveals a new mechanism by which NDV induces ferroptosis and provides new insights into NDV as an oncolytic agent for cancer treatment.

Newcastle disease virus infection remodels plasma phospholipid metabolism in chickens.

Newcastle disease is a global problem that causes huge economic losses and threatens the health and welfare of poultry. Despite the knowledge gained on the metabolic impact of NDV on cells, the extent to which infection modifies the plasma metabolic network in chickens remains unknown. Herein, we performed targeted metabolomic and lipidomic to create a plasma metabolic network map during NDV infection. Meanwhile, we used single-cell RNA sequencing to explore the heterogeneity of lung tissue cells in response to NDV infection in vivo. The results showed that NDV remodeled the plasma phospholipid metabolism network. NDV preferentially targets infected blood endothelial cells, antigen-presenting cells, fibroblasts, and neutrophils in lung tissue. Importantly, NDV may directly regulate ribosome protein transcription to facilitate efficient viral protein translation. In conclusion, NDV infection remodels the plasma phospholipid metabolism network in chickens. This work provides valuable insights to further understand the pathogenesis of NDV.

The HN protein of Newcastle disease virus induces cell apoptosis through the induction of lysosomal membrane permeabilization.

Lysosomes are acidic organelles that mediate the degradation and recycling of cellular waste materials. Damage to lysosomes can cause lysosomal membrane permeabilization (LMP) and trigger different types of cell death, including apoptosis. Newcastle disease virus (NDV) can naturally infect most birds. Additionally, it serves as a promising oncolytic virus known for its effective infection of tumor cells and induction of intensive apoptotic responses. However, the involvement of lysosomes in NDV-induced apoptosis remains poorly understood. Here, we demonstrate that NDV infection profoundly triggers LMP, leading to the translocation of cathepsin B and D and subsequent mitochondria-dependent apoptosis in various tumor and avian cells. Notably, the released cathepsin B and D exacerbate NDV-induced LMP by inducing the generation of reactive oxygen species. Additionally, we uncover that the viral Hemagglutinin neuraminidase (HN) protein induces the deglycosylation and degradation of lysosome-associated membrane protein 1 (LAMP1) and LAMP2 dependent on its sialidase activity, which finally contributes to NDV-induced LMP and cellular apoptosis. Overall, our findings elucidate the role of LMP in NDV-induced cell apoptosis and provide novel insights into the function of HN during NDV-induced LMP, which provide innovative approaches for the development of NDV-based oncolytic agents.

The diverse roles of peroxisomes in the interplay between viruses and mammalian cells.

Peroxisomes are ubiquitous organelles found in eukaryotic cells that play a critical role in the oxidative metabolism of lipids and detoxification of reactive oxygen species (ROS). Recently, the role of peroxisomes in viral infections has been extensively studied. Although several studies have reported that peroxisomes exert antiviral activity, evidence indicates that viruses have also evolved diverse strategies to evade peroxisomal antiviral signals. In this review, we summarize the multiple roles of peroxisomes in the interplay between viruses and mammalian cells. Focus is given on the peroxisomal regulation of innate immune response, lipid metabolism, ROS production, and viral regulation of peroxisomal biosynthesis and degradation. Understanding the interactions between peroxisomes and viruses provides novel insights for the development of new antiviral strategies.

Newcastle disease virus activates the PI3K/AKT signaling pathway by targeting PHLPP2 degradation to delay cell apoptosis and promote viral replication.

Newcastle disease (ND) is a highly pathogenic, contagious, and fatal infectious disease in poultry caused by the Newcastle disease virus (NDV). The PI3K/AKT signaling pathway is a phosphorylation cascade that participates in regulating several cellular functions. Viruses reportedly regulate the course of infection through the PI3K/AKT axis. Here, we aimed to analyze the pathogenesis of NDV infection mediated by the PI3K/AKT signaling pathway activation. We found that NDV infection can phosphorylate AKT to activate the PI3K/AKT axis both in vitro and in vivo. Flow cytometry and Caspase-3 activity assay showed that NDV infection could inhibit cell apoptosis. The activation or inhibition of the PI3K/AKT signaling pathway activity significantly inhibited or promoted NDV-mediated apoptosis. Furthermore, inhibition of cell apoptosis significantly promoted NDV replication. Overall, our results showed that NDV infection activates the PI3K/AKT signaling pathway and inhibits cell apoptosis, thus promoting viral replication. In this context, the reduced expression of PHLPP2 protein mediated by NDV infection could be inhibited by MG132. PHLPP2 expression reversely and positively regulated NDV replication and cell apoptosis, respectively. These results indicated that NDV infection-mediated activation of the PI3K/AKT signaling pathway and the inhibition of apoptosis depend on the ubiquitin-proteasome degradation of the PHLPP2 protein. Co-IP and indirect immunofluorescence results showed that NDV V protein could interact with PHLPP2 protein, indicating that NDV targeted PHLPP2 protein degradation through V protein to activate the PI3K/AKT signaling pathway. This study deepens our understanding of the molecular mechanisms of NDV infection, providing a theoretical basis for ND prevention and control.

ESCRT machinery and virus infection.

The endosomal sorting complex required for transport (ESCRT) machinery plays a significant role in the spread of human viruses. However, our understanding of how the host ESCRT machinery responds to viral infection remains limited. Emerging evidence suggests that the ESCRT machinery can be hijacked by viruses of different families to enhance their replication. Throughout their life cycle, these viruses can interfere with or exploit ESCRT-mediated physiological processes to increase their chances of infecting the host. In contrast, to counteract virus infection, the interferon-stimulated gene 15 (ISG15) or the E3 ISG15-protein ligase (HERC5) system within the infected cells is activated to degrade the ESCRT proteins. Many retroviral and RNA viral proteins have evolved "late (L) domain" motifs, which enable them to recruit host ESCRT subunit proteins to facilitate virus transport, replication, budding, mature, and even endocytosis, Therefore, the L domain motifs and ESCRT subunit proteins could serve as promising drug targets for antiviral therapy. This review investigated the composition and essential functions of the ESCRT, shedding light on the impact of ESCRT subunits and viral L domain motifs on the replication of viruses. Furthermore, the antiviral effects facilitated by the ESCRT machinery have been investigated, aiming to provide valuable insights to guide the development and utilization of antiviral drugs.

Identification of key genes associated with poor prognosis and neoplasm staging in gastric cancer.

BACKGROUND: Gastric cancer (GC) is highly biologically and genetically heterogeneous disease with poor prognosis. Increasing evidence indicates that biomarkers can serve as prediction and clinical intervention. Therefore, it is vital to identify core molecules and pathways participating in the development of GC. METHODS: In this study, GSE54129, GSE56807, GSE63089, and GSE118916 were used for identified overlapped 75 DEGs. GO and Kyoto Encyclopedia of Genes and Genomes pathway analysis showed DEGs mainly enriched in biological process about collagen-containing extracellular matrix and collagen metabolic. Next, protein-protein interaction network was built and the hub gene was excavated. Clinicopathological features and prognostic value were also evaluated. RESULTS: Hub genes were shown as below, FN1, COL1A2, COL1A1, COL3A1, COL4A1, COL6A3, COL5A2, SPARC, PDGFRB, COL12A1. Those genes were upregulation in GC and related to the poor prognosis (except COL5A2, P = .73). What is more, high expression indicated worse T stage and tumor, node, metastasis stage in GC patients. Later, the results of 25 GC tumor specimens and 34 normal tissues showed that FN1, COL3A1, COL4A1, SPARC, COL5A2, and COL12A1 were significantly upregulated in cancer samples. CONCLUSION: Our study systematically explored the core genes and crucial pathways in GC, providing insights into clinical management and individual treatment.

Cellular vimentin regulates the infectivity of Newcastle disease virus through targeting of the HN protein.

The haemagglutinin-neuraminidase (HN) protein plays a crucial role in the infectivity and virulence of Newcastle disease virus (NDV). In a previous study, the mutant HN protein was identified as a crucial virulence factor for the velogenic variant NDV strain JS/7/05/Ch, which evolved from the prototypic vaccine strain Mukteswar. Furthermore, macrophages are the main susceptible target cells of NDV. However, the possible involvement of cellular molecules in viral infectivity remains unclear. Herein, we elucidate the crucial role of vimentin, an intermediate filament protein, in regulating NDV infectivity through targeting of the HN protein. Using LC‒MS/MS mass spectrometry and coimmunoprecipitation assays, we identified vimentin as a host protein that differentially interacted with prototypic and mutant HN proteins. Further analysis revealed that the variant NDV strain induced more significant rearrangement of vimentin fibres compared to the prototypic NDV strain and showed an interdependence between vimentin rearrangement and virus replication. Notably, these mutual influences were pronounced in HD11 chicken macrophages. Moreover, vimentin was required for multiple infection processes of the variant NDV strain in HD11 cells, including viral internalization, fusion, and release, while it was not necessary for those of the prototypic NDV strain. Collectively, these findings underscore the pivotal role of vimentin in NDV infection through targeting of the HN protein, providing novel targets for antiviral treatment strategies for NDV.

The Ubiquitin-Proteasome System Facilitates Membrane Fusion and Uncoating during Coronavirus Entry.

Although the involvement of the ubiquitin-proteasome system (UPS) in several coronavirus-productive infections has been reported, whether the UPS is required for infectious bronchitis virus (IBV) and porcine epidemic diarrhea virus (PEDV) infections is unclear. In this study, the role of UPS in the IBV and PEDV life cycles was investigated. When the UPS was suppressed by pharmacological inhibition at the early infection stage, IBV and PEDV infectivity were severely impaired. Further study showed that inhibition of UPS did not change the internalization of virus particles; however, by using R18 and DiOC-labeled virus particles, we found that inhibition of UPS prevented the IBV and PEDV membrane fusion with late endosomes or lysosomes. In addition, proteasome inhibitors blocked the degradation of the incoming viral protein N, suggesting the uncoating process and genomic RNA release were suppressed. Subsequently, the initial translation of genomic RNA was blocked. Thus, UPS may target the virus-cellular membrane fusion to facilitate the release of incoming viruses from late endosomes or lysosomes, subsequently blocking the following virus uncoating, initial translation, and replication events. Similar to the observation of proteasome inhibitors, ubiquitin-activating enzyme E1 inhibitor PYR-41 also impaired the entry of IBV, enhanced the accumulation of ubiquitinated proteins, and depleted mono-ubiquitin. In all, this study reveals an important role of UPS in coronavirus entry by preventing membrane fusion and identifies UPS as a potential target for developing antiviral therapies for coronavirus.

Brucella abortus Rough-Type Mutant Induces Ferroptosis and More Oxidative Stress in Infected Macrophages.

Brucella is an intracellular parasitic bacterium that uses multiple strategies to evade the host's defense mechanisms. However, how Brucella manipulates the host-induced oxidative stress and relevant biological processes are still poorly understood. In this study, a comparative transcriptome assay of macrophages infected with Brucella abortus S2308 and its rough mutant RB14 was performed to investigate the differentially expressed genes which might be associated with the pathogenic mechanism of Brucella. Our results showed that numerous host pro-oxidative and antioxidative stress genes were differentially expressed in macrophages infected with B. abortus S2308 and mutant RB14 at 4, 8, 24, and 48 h post-infection. Interestingly, we found that several ferroptosis-associated genes were differentially expressed during B. abortus RB14 infection. Moreover, we found that the rough mutant RB14-induced macrophage death was associated with reduced levels of host glutathione and glutathione peroxidase 4, together with increased free iron, lipid peroxidation, and ROS, all of which are important hallmarks of ferroptosis. The ferroptosis occurring during infection with RB14 was reduced by treatment with the inhibitor ferrostatin-1. However, B. abortus S2308 infection did not induce these hallmarks of ferroptosis. Taken together, our results demonstrate that ferroptosis is involved in rough B. abortus infection. Investigating how Brucella manipulates oxidative stress and ferroptosis in its host will be helpful to clarify the pathogenicity of B. abortus.

[Virus hijacking ESCRT system to promote self-replication: a review].

Endosomal sorting complex required for transport (ESCRT) system drives various cellular processes, including endosome sorting, organelle biogenesis, vesicle transport, maintenance of plasma membrane integrity, membrane fission during cytokinesis, nuclear membrane reformation after mitosis, closure of autophagic vacuoles, and enveloped virus budding. Increasing evidence suggests that the ESCRT system can be hijacked by different family viruses for their proliferation. At different stages of the virus life cycle, viruses can interfere with or exploit ESCRT-mediated physiological processes in various ways to maximize their chance of infecting the host. In addition, many retroviral and RNA viral proteins possess "late domain" motifs, which can recruit host ESCRT subunit proteins to assist in virus endocytosis, transport, replicate, budding and efflux. Therefore, the "late domain" motifs of viruses and ESCRT subunit proteins could serve as promising drug targets in antiviral therapy. This review focuses on the composition and functions of the ESCRT system, the effects of ESCRT subunits and virus "late domain" motifs on viral replication, and the antiviral effects mediated by the ESCRT system, aiming to provide a reference for the development and utilization of antiviral drugs.

Circular RNAs are associated with the resistance to Newcastle disease virus infection in duck cells.

Introduction: Newcastle disease virus (NDV) is prevalent worldwide with an extensive host range. Among birds infected with velogenic NDV strains, chickens experience high pathogenicity and mortality, whereas ducks mostly experience mild symptoms or are asymptomatic. Ducks have a unique, innate immune system hypothesized to induce antiviral responses. Circular RNAs (circRNAs) are among the most abundant and conserved eukaryotic transcripts. These participate in innate immunity and host antiviral response progression. Methods: In this study, circRNA expression profile differences post-NDV infection in duck embryo fibroblast (DEF) cells were analyzed using circRNA transcriptome sequencing. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to reveal significant enrichment of differentially expressed (DE) circRNAs. The circRNA-miRNA-mRNA interaction networks were used to predict the related functions of circRNAs. Moreover, circ-FBXW7 was selected to determine its effect on NDV infection in DEFs. Results: NDV infection altered circRNA expression profiles in DEF cells, and 57 significantly differentially expressed circRNAs were identified post-NDV infection. DEF responded to NDV by forming circRNAs to regulate apoptosis-, cell growth-, and protein degradation-related pathways via GO and KEGG enrichment analyses. circRNA-miRNA-mRNA interaction networks demonstrated that DEF cells combat NDV infection by regulating cellular pathways or apoptosis through circRNA-targeted mRNAs and miRNAs. circ-FBXW7 overexpression and knockdown inhibited and promoted viral replication, respectively. DEF cells mainly regulated cell cycle alterations or altered cellular sensing to combat NDV infection. Conclusion: These results demonstrate that DEF cells exert antiviral responses by forming circRNAs, providing novel insights into waterfowl antiviral responses.

Erythronate utilization activates VdtR regulating its metabolism to promote Brucella proliferation, inducing abortion in mice.

Brucella is a facultative intracellular pathogen that preferentially colonizes reproductive organs and utilizes erythritol as a preferred carbon source for its survival and proliferation. In this study, we identified a virulence-related DeoR-family transcriptional regulator (VdtR) and an erythronate metabolic pathway responsible for four-carbon acid sugar metabolism of D-erythronate and L-threonate in Brucella. We found that VdtR plays an important role in Brucella intracellular survival and trafficking to the endoplasmic reticulum in RAW 264.7 macrophages and in virulence in a mouse model. More importantly, we found that VdtR negatively regulates the erythronate metabolic pathway to promote extracellular proliferation of Brucella, depending on utilization of D-erythronate, an oxidative product of erythritol in the host. In a pregnant mouse model, the erythronate metabolic pathway was shown to cooperate with erythritol metabolism and play a crucial role in Brucella proliferation in the placenta, inducing placentitis and finally resulting in abortion or stillbirth. Our results demonstrate that, in addition to erythritol, erythronate is a preferred carbon source for Brucella utilization to promote its extracellular proliferation. This discovery updates the information on the preferential colonization of reproductive organs by Brucella and provides a novel insight into the Brucella-associated induction of abortion in pregnant animals. IMPORTANCE Brucella is an intracellular parasitic bacterium causing zoonosis, which is distributed worldwide and mainly characterized by reproductive disorders. Erythritol is found in allantoic fluid, chorion, and placenta of aborted animals, preferentially utilized by Brucella to cause infertility and abortion. However, the erythritol metabolism-defected mutant was unable to function as a vaccine strain due to its residual virulence. Here, we found that erythronate, an oxidative product of erythritol in the host, was also preferentially utilized by Brucella relying on the function of a deoxyribonucleoside regulator-family transcriptional regulator VdtR. Erythronate utilization activates VdtR regulation of the erythronate metabolic pathway to promote Brucella extracellular proliferation, inducing placentitis/abortion in mice. Double mutations on Brucella erythritol and D-erythronate metabolisms significantly reduced bacterial virulence. This study revealed a novel mechanism of Brucella infection-induced abortion, thus providing a new clue for the study of safer Brucella attenuated vaccines.

Newcastle disease virus nucleocapsid protein mediates the degradation of 14-3-3ε to antagonize the interferon response and promote viral replication.

Newcastle disease virus (NDV) is responsible for outbreaks that pose a threat to the global poultry industry. NDV triggers an interferon (IFN) response in the host upon infection. However, it also employs mechanisms that counteract this response. One important component in IFN-related signaling pathways is 14-3-3ε, which is known to interact with retinoic acid-inducible gene I (RIG-I) and mitochondrial antiviral signaling protein (MAVS). The relationship between 14 and 3-3ε and NDV infection has not been previously explored; therefore, this study aimed to investigate this relationship in vivo and in vitro using overexpressed and knockdown 14-3-3ε experiments, along with co-immunoprecipitation analysis. We found that NDV infection led to the degradation of 14-3-3ε. Furthermore, 14-3-3ε inhibited the replication of NDV, suggesting that NDV may enhance its own replication by promoting the degradation of 14-3-3ε during infection. The study revealed that 14-3-3ε is degraded by lysosomes and the viral protein nucleocapsid protein (NP) of NDV induces this degradation. It was also observed that 14-3-3ε is involved in activating the IFN pathway during NDV infection and mediates the binding of MDA5 to MAVS. Our study reveals that NDV NP mediates the entry of 14-3-3ε into lysosomes and facilitates its degradation. These findings contribute to the existing knowledge on the molecular mechanisms employed by NDV to counteract the IFN response and enhance its own replication.

NDV-induced autophagy enhances inflammation through NLRP3/Caspase-1 inflammasomes and the p38/MAPK pathway.

Newcastle disease (ND), caused by the Newcastle disease virus (NDV), is a highly virulent infectious disease of poultry. Virulent NDV can cause severe autophagy and inflammation in host cells. While studies have shown a mutual regulatory relationship between autophagy and inflammation, this relationship in NDV infection remains unclear. This study confirmed that NDV infection could trigger autophagy in DF-1 cells to promote cytopathic and viral replication. NDV-induced autophagy was positively correlated with the mRNA levels of inflammatory cytokines such as IL-1ß, IL-8, IL-18, CCL-5, and TNF-α, suggesting that NDV-induced autophagy promotes the expression of inflammatory cytokines. Further investigation demonstrated that NLRP3 protein expression, Caspase-1 activity, and p38 phosphorylation level positively correlated with autophagy, suggesting that NDV-induced autophagy could promote the expression of inflammatory cytokines through NLRP3/Caspase-1 inflammasomes and p38/MAPK pathway. In addition, NDV infection also triggered mitochondrial damage and mitophagy in DF-1 cells, but did not result in a large leakage of reactive oxygen species (ROS) and mitochondrial DNA (mtDNA), indicating that mitochondrial damage and mitophagy do not contribute to the inflammation response during NDV infection.

Antigenic Characterization of Infectious Bronchitis Virus in the South China during 2021-2022.

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.