Pub Date : 2026-01-01Epub Date: 2025-11-13DOI: 10.1016/j.vetmic.2025.110803
Haotian Yang , Han Gu , He Qiu , Bicheng Li , Jidong Xu , Tong Cao , Du Liuyang , Xiaoliang Li , Fang He
Porcine reproductive and respiratory syndrome virus (PRRSV) is an immune-suppressive pathogen that poses a significant challenge to the global swine industry. The mechanism by which PRRSV regulating host inflammation to evade innate immunity remains unclear. Here, Na+ /K+-ATPase beta1 subunit (ATP1B1), a pivotal antiviral protein, was shown to interact with PRRSV nsp6, a tiny viral protein encoded by ORF1a. ATP1B1 stabilized the protein level of TRAF6 by downregulating K48-linked ubiquitination of TRAF6, thus triggering NF-κB signaling and inflammatory response. Moreover, PRRSV nsp6 competetively interacted with ATP1B1 via the site of Leu 3 and impaired the formation of ATP1B1-TRAF6 complex, leading to TRAF6 proteasomal degradation and compromised inflammatory response. PRRSV with the corresponding mutation in nsp6 L3S was successfully rescued but presented defective virus growth in the late stage of infection, especially under the inflammation condition induced by either ATP1B1 overexpression or poly (I:C) stimulation. In addition, the halt in PRRSV replication was induced by treatment with autophagy inhibitor BafA1 during virus passage. L3S mutant virus impaired the recovery of virus growth even after the removal of BafA1, indicating the key role of nsp6 in sustaining virus vitality under innate immunity. Taken together, these results elucidate the functional mechanism by which PRRSV alleviates the inflammatory response to promote successful virus proliferation and growth recovery from the host innate immune response.
{"title":"Porcine reproductive and respiratory syndrome virus nsp6 hijacks ATP1B1 antagonizing TRAF6 mediated antiviral innate immunity","authors":"Haotian Yang , Han Gu , He Qiu , Bicheng Li , Jidong Xu , Tong Cao , Du Liuyang , Xiaoliang Li , Fang He","doi":"10.1016/j.vetmic.2025.110803","DOIUrl":"10.1016/j.vetmic.2025.110803","url":null,"abstract":"<div><div>Porcine reproductive and respiratory syndrome virus (PRRSV) is an immune-suppressive pathogen that poses a significant challenge to the global swine industry. The mechanism by which PRRSV regulating host inflammation to evade innate immunity remains unclear. Here, Na<sup>+</sup> /K<sup>+</sup>-ATPase beta1 subunit (ATP1B1), a pivotal antiviral protein, was shown to interact with PRRSV nsp6, a tiny viral protein encoded by ORF1a. ATP1B1 stabilized the protein level of TRAF6 by downregulating K48-linked ubiquitination of TRAF6, thus triggering NF-κB signaling and inflammatory response. Moreover, PRRSV nsp6 competetively interacted with ATP1B1 via the site of Leu 3 and impaired the formation of ATP1B1-TRAF6 complex, leading to TRAF6 proteasomal degradation and compromised inflammatory response. PRRSV with the corresponding mutation in nsp6 L3S was successfully rescued but presented defective virus growth in the late stage of infection, especially under the inflammation condition induced by either ATP1B1 overexpression or poly (I:C) stimulation. In addition, the halt in PRRSV replication was induced by treatment with autophagy inhibitor BafA1 during virus passage. L3S mutant virus impaired the recovery of virus growth even after the removal of BafA1, indicating the key role of nsp6 in sustaining virus vitality under innate immunity. Taken together, these results elucidate the functional mechanism by which PRRSV alleviates the inflammatory response to promote successful virus proliferation and growth recovery from the host innate immune response.</div></div>","PeriodicalId":23551,"journal":{"name":"Veterinary microbiology","volume":"312 ","pages":"Article 110803"},"PeriodicalIF":2.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145551194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"农林科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2025-10-20DOI: 10.1016/j.vetmic.2025.110769
Ashley Belinfante , Janel Kolar , Sarah M. Shore , Tracy L Nicholson
A high prevalence of acquired bleomycin resistance has been reported in both clinical and non-clinical settings. Streptococcus suis is a zoonotic swine pathogen capable of causing a spectrum of clinical disease outcomes in both pigs and humans and contributes to significant economic losses to the swine industry worldwide. A recent report evaluating the genomic diversity of S. suis isolates obtained from within the U.S. identified a ble gene predicted to encode a bleomycin resistance protein in all isolates evaluated. The goal of this study was to compare the amino acid sequence similarity among the predicted S. suis bleomycin resistance proteins and to functionally test the predicted ble gene allelic variants for the ability to confer bleomycin resistance. A high degree of similarity was observed among the predicted S. suis bleomycin resistance proteins. However, a weak similarity was observed in comparison to other well-characterized bleomycin resistance proteins. All tested S. suis strains exhibited phenotypic resistance to bleomycin. However, none of the S. suis ble genes tested encoded a functional bleomycin resistance protein capable of conferring resistance to bleomycin or bleomycin-like molecules.
{"title":"The Streptococcus suis ble gene does not encode a functional bleomycin resistance protein","authors":"Ashley Belinfante , Janel Kolar , Sarah M. Shore , Tracy L Nicholson","doi":"10.1016/j.vetmic.2025.110769","DOIUrl":"10.1016/j.vetmic.2025.110769","url":null,"abstract":"<div><div>A high prevalence of acquired bleomycin resistance has been reported in both clinical and non-clinical settings. <em>Streptococcus suis</em> is a zoonotic swine pathogen capable of causing a spectrum of clinical disease outcomes in both pigs and humans and contributes to significant economic losses to the swine industry worldwide. A recent report evaluating the genomic diversity of <em>S. suis</em> isolates obtained from within the U.S. identified a <em>ble</em> gene predicted to encode a bleomycin resistance protein in all isolates evaluated. The goal of this study was to compare the amino acid sequence similarity among the predicted <em>S. suis</em> bleomycin resistance proteins and to functionally test the predicted <em>ble</em> gene allelic variants for the ability to confer bleomycin resistance. A high degree of similarity was observed among the predicted <em>S. suis</em> bleomycin resistance proteins. However, a weak similarity was observed in comparison to other well-characterized bleomycin resistance proteins. All tested <em>S. suis</em> strains exhibited phenotypic resistance to bleomycin. However, none of the <em>S. suis ble</em> genes tested encoded a functional bleomycin resistance protein capable of conferring resistance to bleomycin or bleomycin-like molecules.</div></div>","PeriodicalId":23551,"journal":{"name":"Veterinary microbiology","volume":"312 ","pages":"Article 110769"},"PeriodicalIF":2.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145519073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"农林科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2025-11-13DOI: 10.1016/j.vetmic.2025.110790
Guihong Yang , Shimao Tian , Jinyu Yang , Yubing Tang , Ke Tian , Song Wang , Yinli Bao
Neuromedin B (NMB) and its receptor NMBR constitute a neuropeptide system implicated in various physiological processes. While previously associated with innate immunity, their precise antiviral action against influenza A virus (IAV) infection have remained poorly defined. Here, we elucidate the function of the NMB/NMBR axis in the host defense against H9N2 influenza virus. We demonstrate that NMB treatment and NMBR overexpression potentiate IFN-β production and restrict viral replication in H9N2-infected A549 cells and mouse lungs. Conversely, NMBR knockdown compromises the antiviral response, diminishing IFN-β expression and enhancing viral propagation. We further show that NMB/NMBR signaling targets the viral non-structural protein 1 (NS1) by upregulating the E3 ubiquitin ligase TRIM25. Mechanistically, NMB/NMBR activation engages a positive feedback loop with the retinoic acid-inducible gene I (RIG-I) pathway, reinforcing RIG-I activation through enhanced K63-linked ubiquitination while transcriptionally repressing the deubiquitinase CYLD. Consequently, this augmented signaling potentiates the JAK-STAT1 pathway, leading to increased STAT1 phosphorylation and elevated expression of interferon-stimulated gene 15 (ISG15). Our findings establish that the NMB/NMBR axis confers protection against H9N2 IAV by amplifying RIG-I-mediated innate immunity and facilitating NS1 suppression, revealing a pivotal neuroimmune mechanism and suggesting a promising target for developing broad-spectrum, host-directed therapeutics against IAV.
{"title":"Neuromedin B and its receptor NMBR inhibit H9N2 infection","authors":"Guihong Yang , Shimao Tian , Jinyu Yang , Yubing Tang , Ke Tian , Song Wang , Yinli Bao","doi":"10.1016/j.vetmic.2025.110790","DOIUrl":"10.1016/j.vetmic.2025.110790","url":null,"abstract":"<div><div>Neuromedin B (NMB) and its receptor NMBR constitute a neuropeptide system implicated in various physiological processes. While previously associated with innate immunity, their precise antiviral action against influenza A virus (IAV) infection have remained poorly defined. Here, we elucidate the function of the NMB/NMBR axis in the host defense against H9N2 influenza virus. We demonstrate that NMB treatment and NMBR overexpression potentiate IFN-β production and restrict viral replication in H9N2-infected A549 cells and mouse lungs. Conversely, NMBR knockdown compromises the antiviral response, diminishing IFN-β expression and enhancing viral propagation. We further show that NMB/NMBR signaling targets the viral non-structural protein 1 (NS1) by upregulating the E3 ubiquitin ligase TRIM25. Mechanistically, NMB/NMBR activation engages a positive feedback loop with the retinoic acid-inducible gene I (RIG-I) pathway, reinforcing RIG-I activation through enhanced K63-linked ubiquitination while transcriptionally repressing the deubiquitinase CYLD. Consequently, this augmented signaling potentiates the JAK-STAT1 pathway, leading to increased STAT1 phosphorylation and elevated expression of interferon-stimulated gene 15 (ISG15). Our findings establish that the NMB/NMBR axis confers protection against H9N2 IAV by amplifying RIG-I-mediated innate immunity and facilitating NS1 suppression, revealing a pivotal neuroimmune mechanism and suggesting a promising target for developing broad-spectrum, host-directed therapeutics against IAV.</div></div>","PeriodicalId":23551,"journal":{"name":"Veterinary microbiology","volume":"312 ","pages":"Article 110790"},"PeriodicalIF":2.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145519074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"农林科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In this study, using 16S rRNA gene-based metagenomics, we aimed to determine the presence of infectious bacteria in the ticks collected from Punjab state in north India. Tick samples were collected from the domesticated animals from the Patiala, Ropar, and Mohali districts of Punjab, India from February 2022- April 2022. DNA was extracted, and the library was prepared by targeting the V3–V4 hypervariable region of the 16S rRNA gene. The sequencing was conducted in Illumina using the 300 bp paired-end chemistry. Eight tick samples were analyzed from the Patiala, Ropar and Mohali districts of Punjab, India, revealing a diverse range of bacterial species within the tick microbiome. Seven out of eight samples were found to harbour Coxiella-like bacteria (46–181,607 reads; closely related to C. burnetii based on 16S rRNA [V3–V4] sequence similarity), indicating their abundance in the tick population. Furthermore, the analysis uncovered the presence of other pathogenic bacterial genera, including Staphylococcus, Streptococcus, Corynebacterium, Enterococcus, Pseudomonas, Bordetella, and Micrococcus in the tick microbiome, highlighting the abundance and diversity of infectious organisms within ticks. 16S rRNA gene-based metagenomics enables valuable insights into infectious agents in disease-transmitting vectors. Coxiella-like bacteria were found to be predominant bacterial species in the tick microbiomes in this study. The public health significance of this finding in animals and humans needs to be explored in this region. However, as 16S rRNA sequencing offers limited resolution for distinguishing closely related taxa, further confirmation using additional loci or whole-genome sequencing is warranted.
{"title":"Unveiling the Presence of Coxiella-like bacteria in Rhipicephalus microplus Ticks from Punjab, North India: A 16S rRNA metagenomic study","authors":"Vikas Sharma , Shriya Goel , Kamlesh Bisht , Taruna Kaura , Salony Verma , Abhishek Mewara , Gagandeep Singh Grover , Manisha Biswal","doi":"10.1016/j.vetmic.2025.110783","DOIUrl":"10.1016/j.vetmic.2025.110783","url":null,"abstract":"<div><div>In this study, using 16S rRNA gene-based metagenomics, we aimed to determine the presence of infectious bacteria in the ticks collected from Punjab state in north India. Tick samples were collected from the domesticated animals from the Patiala, Ropar, and Mohali districts of Punjab, India from February 2022- April 2022<strong>.</strong> DNA was extracted, and the library was prepared by targeting the V3–V4 hypervariable region of the 16S rRNA gene. The sequencing was conducted in Illumina using the 300 bp paired-end chemistry. Eight tick samples were analyzed from the Patiala, Ropar and Mohali districts of Punjab, India, revealing a diverse range of bacterial species within the tick microbiome. Seven out of eight samples were found to harbour <em>Coxiella</em>-like bacteria (46–181,607 reads; closely related to <em>C. burnetii</em> based on 16S rRNA [V3–V4] sequence similarity), indicating their abundance in the tick population. Furthermore, the analysis uncovered the presence of other pathogenic bacterial genera, including <em>Staphylococcus, Streptococcus</em>, <em>Corynebacterium</em>, <em>Enterococcus</em>, <em>Pseudomonas</em>, <em>Bordetella</em>, and <em>Micrococcus</em> in the tick microbiome, highlighting the abundance and diversity of infectious organisms within ticks. 16S rRNA gene-based metagenomics enables valuable insights into infectious agents in disease-transmitting vectors. <em>Coxiella</em>-like bacteria were found to be predominant bacterial species in the tick microbiomes in this study. The public health significance of this finding in animals and humans needs to be explored in this region. However, as 16S rRNA sequencing offers limited resolution for distinguishing closely related taxa, further confirmation using additional loci or whole-genome sequencing is warranted.</div></div>","PeriodicalId":23551,"journal":{"name":"Veterinary microbiology","volume":"312 ","pages":"Article 110783"},"PeriodicalIF":2.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145514301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"农林科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2025-12-05DOI: 10.1016/j.vetmic.2025.110826
Haolong Wang , Congzhu , Junhui Wang , Xuan Lin , YuYang Guo , Faisal Ayub Kiani , Xiaoshu Zhou , Yi Ding
During the periparturient period, reduced feed intake often causes negative energy balance in dairy cows, leading to fat mobilization, hepatic lipid accumulation, and fatty liver disease (FLD), ultimately compromising health and milk production. This study investigated the association between FLD and gut microbiota dysbiosis, with a particular focus on the role of Clostridium perfringens within the gut–liver axis.
Metagenomic sequencing of ileal contents revealed a marked decrease in microbial diversity in cows with FLD, along with increased abundances of potential pathogens such as C. perfringens, Enterobacter cloacae, and Vibrio alginolyticus. Functional annotation indicated elevated expression of virulence factors (e.g., Hsp60, flagella, mu-toxin), antibiotic resistance genes (e.g., otrA, lsaC), and pathways related to lipopolysaccharide (LPS) biosynthesis and mitogen-activated protein kinase (MAPK) signaling pathways, suggesting enhanced pro-inflammatory potential. qPCR analysis of ileal tissue demonstrated reduced expression of tight junction proteins (zona occludens 1 (ZO-1), Claudin-1, and Occludin) and increased levels of pro-inflammatory cytokines (Interleukin-1 beta (IL-1β), Interleukin-6 (IL-6), Tumour necrosis factor-alpha (TNF-α)), alongside a decrease in the anti-inflammatory cytokine interleukin-10 (IL-10), indicating compromised intestinal barrier function and local inflammation.
Given the significant enrichment of C. perfringens in the ileum of FLD cows, we hypothesized its involvement in disease pathogenesis. To test this, C. perfringens was isolated and orally administered to antibiotic-pretreated mice fed a high-fat diet. These mice developed exacerbated hepatic steatosis, metabolic disturbances, and heightened inflammatory responses. Moreover, Western blot analysis revealed reduced expression of intestinal tight junction proteins (ZO-1, Claudin-1, Occludin), indicating increased intestinal permeability. Quantitative PCR confirmed upregulation of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) and downregulation of IL-10 in both intestinal and hepatic tissues. These findings indicate that C. perfringens may promote FLD by impairing gut barrier integrity and enhancing inflammatory responses.
In conclusion, our findings suggest that C. perfringens may contribute to the development of FLD in dairy cows by impairing intestinal barrier integrity and promoting systemic inflammation.
{"title":"Clostridium perfringens can promote the formation of fatty liver in cows","authors":"Haolong Wang , Congzhu , Junhui Wang , Xuan Lin , YuYang Guo , Faisal Ayub Kiani , Xiaoshu Zhou , Yi Ding","doi":"10.1016/j.vetmic.2025.110826","DOIUrl":"10.1016/j.vetmic.2025.110826","url":null,"abstract":"<div><div>During the periparturient period, reduced feed intake often causes negative energy balance in dairy cows, leading to fat mobilization, hepatic lipid accumulation, and fatty liver disease (FLD), ultimately compromising health and milk production. This study investigated the association between FLD and gut microbiota dysbiosis, with a particular focus on the role of <em>Clostridium perfringens</em> within the gut–liver axis.</div><div>Metagenomic sequencing of ileal contents revealed a marked decrease in microbial diversity in cows with FLD, along with increased abundances of potential pathogens such as <em>C. perfringens</em>, <em>Enterobacter cloacae</em>, and <em>Vibrio alginolyticus</em>. Functional annotation indicated elevated expression of virulence factors (e.g., Hsp60, flagella, mu-toxin), antibiotic resistance genes (e.g., <em>otrA</em>, <em>lsaC</em>), and pathways related to lipopolysaccharide (LPS) biosynthesis and mitogen-activated protein kinase (MAPK) signaling pathways, suggesting enhanced pro-inflammatory potential. qPCR analysis of ileal tissue demonstrated reduced expression of tight junction proteins (zona occludens 1 (ZO-1), Claudin-1, and Occludin) and increased levels of pro-inflammatory cytokines (Interleukin-1 beta (IL-1β), Interleukin-6 (IL-6), Tumour necrosis factor-alpha (TNF-α)), alongside a decrease in the anti-inflammatory cytokine interleukin-10 (IL-10), indicating compromised intestinal barrier function and local inflammation.</div><div>Given the significant enrichment of <em>C. perfringens</em> in the ileum of FLD cows, we hypothesized its involvement in disease pathogenesis. To test this, <em>C. perfringens</em> was isolated and orally administered to antibiotic-pretreated mice fed a high-fat diet. These mice developed exacerbated hepatic steatosis, metabolic disturbances, and heightened inflammatory responses. Moreover, Western blot analysis revealed reduced expression of intestinal tight junction proteins (ZO-1, Claudin-1, Occludin), indicating increased intestinal permeability. Quantitative PCR confirmed upregulation of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) and downregulation of IL-10 in both intestinal and hepatic tissues. These findings indicate that <em>C. perfringens</em> may promote FLD by impairing gut barrier integrity and enhancing inflammatory responses.</div><div>In conclusion, our findings suggest that <em>C. perfringens</em> may contribute to the development of FLD in dairy cows by impairing intestinal barrier integrity and promoting systemic inflammation.</div></div>","PeriodicalId":23551,"journal":{"name":"Veterinary microbiology","volume":"312 ","pages":"Article 110826"},"PeriodicalIF":2.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145715993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"农林科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Atypical porcine pestivirus (APPV) is an emerging pathogen that poses a significant threat to the global swine industry. The nonstructural protein 5 A (NS5A) of Flavivirus is a known immunomodulator; however, its precise role in APPV pathogenesis, particularly its interaction with host interferon (IFN) responses, remains poorly understood. This study elucidates a novel molecular mechanism by which APPV NS5A manipulates host IFN production. We demonstrate that APPV NS5A exerts a dual effect on the phosphorylation of interferon regulatory factor 3 (IRF3): it inhibits the phosphorylation of IRF3 at Ser396 by disrupting the formation of the TBK1-IKKε-IRF3 complex, while simultaneously promoting the interaction between PKR and IRF3 by inducing PKR activation, ultimately resulting in the phosphorylation of IRF3 at Ser386. This phosphorylation switch consequently inhibits the production of IFN. Our research provides critical insights into the immune evasion strategies and pathogenic mechanisms of APPV, identifying the NS5A-PKR-IRF3 axis as a potential therapeutic target for developing novel antiviral interventions.
非典型猪瘟病毒（APPV）是一种新兴病原体，对全球养猪业构成重大威胁。黄病毒非结构蛋白5 A （NS5A）是一种已知的免疫调节剂；然而，其在APPV发病机制中的确切作用，特别是其与宿主干扰素（IFN）反应的相互作用，仍然知之甚少。本研究阐明了APPV NS5A调控宿主IFN产生的一种新的分子机制。我们发现APPV NS5A对干扰素调节因子3 （IRF3）的磷酸化具有双重作用：通过破坏TBK1-IKKε-IRF3复合物的形成，抑制IRF3在Ser396位点的磷酸化；同时通过诱导PKR活化，促进PKR与IRF3的相互作用，最终导致IRF3在Ser386位点的磷酸化。这种磷酸化开关因此抑制IFN的产生。我们的研究为APPV的免疫逃避策略和致病机制提供了重要的见解，确定了NS5A-PKR-IRF3轴作为开发新型抗病毒干预措施的潜在治疗靶点。
{"title":"APPV NS5A employs PKR activation to redirect IRF3 phosphorylation from Ser396 to Ser386, ultimately resulting in the inhibition of IFN production","authors":"Yingjie Xiang , Yongchen Ji , Jingwen Zhao , Huiguang Wu","doi":"10.1016/j.vetmic.2025.110830","DOIUrl":"10.1016/j.vetmic.2025.110830","url":null,"abstract":"<div><div>Atypical porcine pestivirus (APPV) is an emerging pathogen that poses a significant threat to the global swine industry. The nonstructural protein 5 A (NS5A) of Flavivirus is a known immunomodulator; however, its precise role in APPV pathogenesis, particularly its interaction with host interferon (IFN) responses, remains poorly understood. This study elucidates a novel molecular mechanism by which APPV NS5A manipulates host IFN production. We demonstrate that APPV NS5A exerts a dual effect on the phosphorylation of interferon regulatory factor 3 (IRF3): it inhibits the phosphorylation of IRF3 at Ser396 by disrupting the formation of the TBK1-IKKε-IRF3 complex, while simultaneously promoting the interaction between PKR and IRF3 by inducing PKR activation, ultimately resulting in the phosphorylation of IRF3 at Ser386. This phosphorylation switch consequently inhibits the production of IFN. Our research provides critical insights into the immune evasion strategies and pathogenic mechanisms of APPV, identifying the NS5A-PKR-IRF3 axis as a potential therapeutic target for developing novel antiviral interventions.</div></div>","PeriodicalId":23551,"journal":{"name":"Veterinary microbiology","volume":"312 ","pages":"Article 110830"},"PeriodicalIF":2.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145736165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"农林科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2025-11-16DOI: 10.1016/j.vetmic.2025.110807
Jiannan Li , Xueting Li , Xiao Li , Wenjie Xu , Liming Yuan , Hongzhao Shi , Zuo Lei , Na Li , Yulei Wei , Jinlian Hua
Bovine viral diarrhea virus (BVDV) is a major viral pathogen that affects ruminants, resulting in significant economic losses due to issues such as immunosuppression, reproductive disorders, and growth retardation. Bulls infected with this virus may become infertile within a few months and can transmit the virus to susceptible cattle during mating. However, the mechanism of BVDV impairing the reproductive function of male livestock is not clear, as there is no suitable cell model. This study used spermatogonial stem cells(SSCs) from cattle and goats as research materials to explore the mechanism by which BVDV affects the reproductive function of male livestock. The results of this study indicate that both cytopathic (cp) and noncytopathic (ncp) BVDV can replicate in SSCs and that SSCs are capable of producing infectious BVDV. Giemsa staining showed significant changes in the morphology of SSCs after BVDV infection. Western blot and mRNA analysis showed that proliferation-related genes (PCNA, CCND1, CDK2) and SSC functional genes (Lin28A, OCT4, SOX2) were down regulated after infection. In addition, BVDV infection can induce ferroptosis in SSCs. Furthermore, CRISPR-Cas9 mediated editing of CD46 in goat SSCs resulted in a decrease in BVDV infection rate and alleviated the negative impact of the virus on cell survival and proliferation. This study provides new insights into the mechanism of reduced reproductive function in male livestock infected with BVDV, and lays the foundation for developing targeted disease resistant breeding strategies.
{"title":"CRISPR/Cas9-generated CD46-knockout spermatogonial stem cells reveal mechanisms of BVDV-induced reproductive dysfunction in male livestock","authors":"Jiannan Li , Xueting Li , Xiao Li , Wenjie Xu , Liming Yuan , Hongzhao Shi , Zuo Lei , Na Li , Yulei Wei , Jinlian Hua","doi":"10.1016/j.vetmic.2025.110807","DOIUrl":"10.1016/j.vetmic.2025.110807","url":null,"abstract":"<div><div>Bovine viral diarrhea virus (BVDV) is a major viral pathogen that affects ruminants, resulting in significant economic losses due to issues such as immunosuppression, reproductive disorders, and growth retardation. Bulls infected with this virus may become infertile within a few months and can transmit the virus to susceptible cattle during mating. However, the mechanism of BVDV impairing the reproductive function of male livestock is not clear, as there is no suitable cell model. This study used spermatogonial stem cells(SSCs) from cattle and goats as research materials to explore the mechanism by which BVDV affects the reproductive function of male livestock. The results of this study indicate that both cytopathic (cp) and noncytopathic (ncp) BVDV can replicate in SSCs and that SSCs are capable of producing infectious BVDV. Giemsa staining showed significant changes in the morphology of SSCs after BVDV infection. Western blot and mRNA analysis showed that proliferation-related genes (<em>PCNA</em>, <em>CCND1</em>, <em>CDK2</em>) and SSC functional genes (<em>Lin28A</em>, <em>OCT4</em>, <em>SOX2</em>) were down regulated after infection. In addition, BVDV infection can induce ferroptosis in SSCs. Furthermore, CRISPR-Cas9 mediated editing of CD46 in goat SSCs resulted in a decrease in BVDV infection rate and alleviated the negative impact of the virus on cell survival and proliferation. This study provides new insights into the mechanism of reduced reproductive function in male livestock infected with BVDV, and lays the foundation for developing targeted disease resistant breeding strategies.</div></div>","PeriodicalId":23551,"journal":{"name":"Veterinary microbiology","volume":"312 ","pages":"Article 110807"},"PeriodicalIF":2.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145570253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"农林科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2025-10-30DOI: 10.1016/j.vetmic.2025.110775
Huafen Zheng , Yufan Chen , Ruyi Gao , Wenhao Yang , Xiaolong Lu , Yu Chen , Min Gu , Jiao Hu , Xiaowen Liu , Shunlin Hu , Kaituo Liu , Xiaoquan Wang , Xiufan Liu
The H7N9 subtype avian influenza virus (AIV) is currently the subtype with the highest number of human infection cases, with a mortality rate of nearly 40 %,40 %, posing a serious threat to public health. We have previously reported that two avian H7N9 isolates (A/chicken/Eastern China/JTC4/2013 and A/chicken/Eastern China/JTC11/2013) exhibit distinct pathogenicity in mice, in which the polymerase proteins cooperatively increased pathogenicity in mice. Still, the enhancement did not reach the level of JTC11. To further investigate the genetic basis of the virulence difference, we constructed a series of mutant viruses using reverse genetics. We found that the combination of NA-N322S or NA-G389D mutations with PB2-E627K was not sufficient to increase the pathogenicity of H7N9 in mice, although it was able to enhance the neuraminidase activity of the virus. However, the NA-N322S and NA-G389D mutations combined with PB2-E627K significantly enhanced H7N9 pathogenicity. In addition, these combined mutations enhanced neuraminidase enzyme activity, thereby enhancing viral replication, inflammatory cytokine expression, and lung damage, ultimately increasing pathogenicity in mice. In conclusion, this study reveals that the virulence in H7N9 is a polygenic trait and identifies new virulence-associated residues (NAN322S+G389D combined with PB2-E627K). These findings not only enhance our comprehension of the molecular mechanisms underlying AIVs pathogenicity in mammals, but also provide early warning information for preventing cross-species transmission of the H7N9 virus and for potential future pandemics.
{"title":"NA-N322S and G389D mutations synergize with PB2-627K to enhance H7N9 pathogenicity in mammals","authors":"Huafen Zheng , Yufan Chen , Ruyi Gao , Wenhao Yang , Xiaolong Lu , Yu Chen , Min Gu , Jiao Hu , Xiaowen Liu , Shunlin Hu , Kaituo Liu , Xiaoquan Wang , Xiufan Liu","doi":"10.1016/j.vetmic.2025.110775","DOIUrl":"10.1016/j.vetmic.2025.110775","url":null,"abstract":"<div><div>The H7N9 subtype avian influenza virus (AIV) is currently the subtype with the highest number of human infection cases, with a mortality rate of nearly 40 %,40 %, posing a serious threat to public health. We have previously reported that two avian H7N9 isolates (A/chicken/Eastern China/JTC4/2013 and A/chicken/Eastern China/JTC11/2013) exhibit distinct pathogenicity in mice, in which the polymerase proteins cooperatively increased pathogenicity in mice. Still, the enhancement did not reach the level of JTC11. To further investigate the genetic basis of the virulence difference, we constructed a series of mutant viruses using reverse genetics. We found that the combination of NA-N322S or NA-G389D mutations with PB2-E627K was not sufficient to increase the pathogenicity of H7N9 in mice, although it was able to enhance the neuraminidase activity of the virus. However, the NA-N322S and NA-G389D mutations combined with PB2-E627K significantly enhanced H7N9 pathogenicity. In addition, these combined mutations enhanced neuraminidase enzyme activity, thereby enhancing viral replication, inflammatory cytokine expression, and lung damage, ultimately increasing pathogenicity in mice. In conclusion, this study reveals that the virulence in H7N9 is a polygenic trait and identifies new virulence-associated residues (NA<sup>N322S+G389D</sup> combined with PB2-E627K). These findings not only enhance our comprehension of the molecular mechanisms underlying AIVs pathogenicity in mammals, but also provide early warning information for preventing cross-species transmission of the H7N9 virus and for potential future pandemics.</div></div>","PeriodicalId":23551,"journal":{"name":"Veterinary microbiology","volume":"312 ","pages":"Article 110775"},"PeriodicalIF":2.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145519075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"农林科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2025-11-29DOI: 10.1016/j.vetmic.2025.110822
Bingke Li , Bolun Zhou , Chenchen Sun , Shurou Li , Ye Bai , Ruibo Zhao , Yiwan Song , Yintao He , Lin Yi , Hongxing Ding , Shuangqi Fan , Jinding Chen , Keke Wu
Cellular pathogens exploit host machinery by forcibly relocalizing and repurposing nuclear proteins. Here, we reveal that Classic Swine Fever Virus (CSFV) hijacks DEAD-box helicase 21 (DDX21)，dynamically translocating it from nucleus to cytoplasm and converts it into a non-enzymatic scaffold that recruits ribosomal protein S18 (RPS18) onto viral double-stranded RNA (dsRNA). This virus-induced DDX21-RPS18 axis creates a self-amplifying loop: DDX21 upregulates RPS18 via its helicase domain, while RPS18 suppresses DDX21 levels. Crucially, RPS18 dose-dependently enhances viral NS4A protein synthesis, with DDX21’s pro-viral activity being strictly RPS18-dependent. By orchestrating RPS18-dsRNA binding independent of its helicase activity, cytoplasmic DDX21 spatially co-opts ribosomal components to selectively drive viral protein translation. Our findings reveal a mechanism in which CSFV-triggered relocalization of DDX21 enables viral hijacking of host translation, illustrating how spatial control of RNA-binding proteins can be exploited to redirect cellular functions for pathogen replication.
{"title":"DDX21 nuclear-cytoplasmic shuttling recruits RPS18 to viral dsRNA to promote CSFV replication","authors":"Bingke Li , Bolun Zhou , Chenchen Sun , Shurou Li , Ye Bai , Ruibo Zhao , Yiwan Song , Yintao He , Lin Yi , Hongxing Ding , Shuangqi Fan , Jinding Chen , Keke Wu","doi":"10.1016/j.vetmic.2025.110822","DOIUrl":"10.1016/j.vetmic.2025.110822","url":null,"abstract":"<div><div>Cellular pathogens exploit host machinery by forcibly relocalizing and repurposing nuclear proteins. Here, we reveal that Classic Swine Fever Virus (CSFV) hijacks DEAD-box helicase 21 (DDX21)，dynamically translocating it from nucleus to cytoplasm and converts it into a non-enzymatic scaffold that recruits ribosomal protein S18 (RPS18) onto viral double-stranded RNA (dsRNA). This virus-induced DDX21-RPS18 axis creates a self-amplifying loop: DDX21 upregulates RPS18 via its helicase domain, while RPS18 suppresses DDX21 levels. Crucially, RPS18 dose-dependently enhances viral NS4A protein synthesis, with DDX21’s pro-viral activity being strictly RPS18-dependent. By orchestrating RPS18-dsRNA binding independent of its helicase activity, cytoplasmic DDX21 spatially co-opts ribosomal components to selectively drive viral protein translation. Our findings reveal a mechanism in which CSFV-triggered relocalization of DDX21 enables viral hijacking of host translation, illustrating how spatial control of RNA-binding proteins can be exploited to redirect cellular functions for pathogen replication.</div></div>","PeriodicalId":23551,"journal":{"name":"Veterinary microbiology","volume":"312 ","pages":"Article 110822"},"PeriodicalIF":2.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145669820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"农林科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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