mBio最新文献

{"title":"Nisin-like biosynthetic gene clusters are widely distributed across microbiomes.","authors":"David Hourigan, Des Field, Ellen Murray, Ivan Sugrue, Paula M O'Connor, Colin Hill, R Paul Ross","doi":"10.1128/mbio.01545-25","DOIUrl":"10.1128/mbio.01545-25","url":null,"abstract":"<p><p>Bacteriocins are antimicrobial peptides/proteins that can have narrow or broad inhibitory spectra and remarkable potency against clinically relevant pathogens. One such bacteriocin that is extensively used in the food industry and with potential for biotherapeutic application is the post-translationally modified peptide, nisin. Recent studies have shown the impact of nisin on the gastrointestinal microbiome, but relatively little is known of how abundant nisin production is in nature, the breadth of existing variants, and their antimicrobial potency. Whether or not nisin production and immunity are widespread in gut microbiomes could be a deciding factor in determining the suitability of nisin as a prospective therapeutic for human and/or animal infections. Here, we used publicly available data sets to determine the presence of widespread and diverse nisin biosynthetic gene clusters (nBGCs) across the biosphere. We show that 30% of these nBGCs are predicted to be located on mobile genetic elements, with some found in pathogenic bacteria. Furthermore, we highlight evidence of horizontal gene transfer of nBGCs between genera, including <i>Streptococcus suis</i>, <i>Enterococcus hirae</i>, and <i>Staphylococcus aureus</i>. In all, we describe 107 novel nisin-like peptides. Five representatives were heterologously expressed and all exhibited antimicrobial activity. We further characterized nisin VP, a novel natural nisin variant produced by <i>Velocimicrobium porci</i> isolated from the porcine gut. The peptide has a completely novel hinge region \"AIQ\" not detected in other nisin variants to date. While nisin VP could be induced by nisin A, the latter could not be induced by nisin VP.IMPORTANCEOur research reveals the heretofore underappreciated presence of diverse and widespread nisin-like biosynthetic gene clusters in microbiomes across the globe. Notably, different clusters share similar biosynthetic machinery but differ in sequence, suggesting gene transfer and adaptation. We identify >100 new nisin-like variants, including several in species not previously known to produce nisin. This emphasizes the widespread dissemination of nisin-like gene clusters and the diversity of novel core peptides with biotherapeutic potential. These findings point to a role for nisin in microbial competition in microbiomes. We heterologously expressed nine nisin variants, five of which are completely novel peptides, using the nisin A biosynthetic machinery and confirmed that all exhibited antimicrobial activity.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0154525"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506125/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145030031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Aspergillus fumigatus</i> effector crpA orchestrates host prostaglandin signaling to promote fungal virulence.","authors":"Camila Figueiredo Pinzan, Camila Diehl, Patrícia Alves de Castro, Endrews Delbaje, Peter Rocha, Camila Langer Marciano, Nathalia Gonsales da Rosa-Garzon, Hamilton Cabral, Rosanne Sprute, Androniki Kolovou, Adriana Ferreira Lopes Vilela, Carlos Arterio Sorgi, Agathe Ecoutin, Mélanie Berbon, Antoine Loquet, Edismauro Garcia Freitas-Filho, Larissa Dias Cunha, Savini U Thrikawala, Emily E Rosowski, Thaila Fernanda Dos Reis, Gustavo H Goldman","doi":"10.1128/mbio.02481-25","DOIUrl":"10.1128/mbio.02481-25","url":null,"abstract":"<p><p>Conidia are the primary infection structures in <i>Aspergillus fumigatus</i>, the etiologic agent of aspergillosis. Here, we characterized CrpA (a <u>c</u>ysteine-<u>r</u>ich <u>p</u>rotein), a conidial surface-associated protein important for fungal evasion and host immunity modulation. Δ<i>crpA</i> conidia elicited decreased production of proinflammatory cytokines and increased production of anti-inflammatory cytokine IL-10 from murine macrophages and in the lungs of infected mice. Murine macrophages exposed to Δ<i>crpA</i> conidia produce significantly higher levels of prostaglandins PGE2 and PGD2, suggesting that deletion of CrpA modulates cytokine production through effects on eicosanoid signaling. While Δ<i>crpA</i> spores have lower virulence in larval zebrafish, this difference is abrogated in larvae that cannot produce prostaglandins. The CrpA protein can directly modulate PGE2 and cytokine production by macrophages, and solid-state NMR shows that Δ<i>crpA</i> swollen conidia present lower β-1,3-glucan and chitin than the wild-type strain, suggesting that the effects of the Δ<i>crpA</i> mutant on macrophages are due to the combinatorial effects of direct CrpA action and altered cell wall PAMP recognition. Δ<i>crpA</i> mutants are avirulent in an immunocompetent murine model of aspergillosis, and high CrpA-specific IgG responses were found in antisera from individual patients with invasive pulmonary aspergillosis, suggesting a role for CrpA in <i>A. fumigatus</i> pathogenesis.IMPORTANCEConidia serve as the primary infectious units of <i>Aspergillus fumigatus</i>, the causative agent of aspergillosis. This study identifies CrpA, a cysteine-rich protein found on the conidial surface, as a crucial regulator of immune modulation and fungal virulence. Loss of CrpA (Δ<i>crpA</i>) alters host immune responses, resulting in reduced production of proinflammatory cytokines and increased IL-10 levels in both murine macrophages and infected lungs. ΔcrpA conidia also stimulate elevated levels of prostaglandins PGE2 and PGD2. This immunomodulatory effect is dependent on eicosanoid signaling as the virulence of Δ<i>crpA</i> is restored in prostaglandin-deficient zebrafish larvae. CrpA directly modulates macrophage production of PGE2 and cytokines. Solid-state NMR analysis shows that Δ<i>crpA</i> conidia expose lower levels of β-1,3-glucan and chitin, suggesting that CrpA influences both cell wall composition and host pattern recognition receptor engagement. Δ<i>crpA</i> strains are avirulent in immunocompetent mice, and patients with invasive pulmonary aspergillosis exhibit elevated CrpA-specific IgG. These results highlight CrpA as a key virulence factor in <i>A. fumigatus</i> and a promising target for antifungal therapy.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0248125"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506137/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145040506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effective treatment of advanced Oropouche virus, Rift Valley fever virus, and Dabie bandavirus infections with 4'-fluorouridine.","authors":"Jonna B Westover, Kie Hoon Jung, Inioska Rojas, Kevin W Bailey, Julio Landinez-Aponte, Gregory R Blumeling, Shuli Mao, Alexander A Kolykhalov, Michael G Natchus, George R Painter, Brian B Gowen","doi":"10.1128/mbio.01467-25","DOIUrl":"10.1128/mbio.01467-25","url":null,"abstract":"<p><p>Oropouche virus (OROV), Rift Valley fever virus (RVFV), and Dabie bandavirus (DBV) are significant re-emerging and emerging human pathogens with major public health implications. Notably, the ongoing OROV disease epidemic spanning South America, Central America, and the Caribbean now exceeds 11,000 cases, including several fatalities and reports of neurological disease and congenital abnormalities associated with infection. Rift Valley fever outbreaks continue to plague sub-Saharan Africa, and DBV, the etiologic agent of severe fever with thrombocytopenia syndrome (SFTS), is expanding its reach throughout several Asian countries. No vaccines or approved therapies are available to prevent or treat these viral infections. Here, we report on the antiviral activity and protective efficacy of the ribonucleoside analog, 4'-fluorouridine (4'-FlU), against OROV, RVFV, and DBV in cell culture and murine models of infection and disease. In cell culture, the potency of 4'-FlU was in the low nanomolar (OROV) to low micromolar (RVFV and DBV) range. In vivo, prophylactic oral dosing of the compound was fully protective against all three viruses in their respective mouse infection models. Importantly, post-exposure and therapeutic interventions of advanced infections in mice also responded remarkably well to treatments. Our findings extend the broad-spectrum antiviral capacity of 4'-FlU and support the compound's further development for treating severe bunyaviral infections.</p><p><strong>Importance: </strong>Re-emerging and emerging viral diseases, for which no approved vaccines or therapeutics exist, pose a significant public health threat in affected areas of the world. Antiviral drugs that are broadly active against multiple pathogenic viruses are much needed. Our findings demonstrating robust protection conferred by treatment with 4'-fluorouridine (4'-FlU) in viral infection models for Oropouche fever, Rift Valley fever, and severe fever with thrombocytopenia syndrome support the continuing development of this promising broad-spectrum antiviral drug candidate for the treatment of these notable viral diseases.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0146725"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505912/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145040527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of the assembly of <i>Plasmodium</i> Hsp70-1 and Hsp40 complex blocks DNA replication by destabilizing ribonucleotide reductase subunit-2.","authors":"Iman Alkhatib, Deepanshu Garg, Wahida Tabassum, Km Tanishka, Mrinal Kanti Bhattacharyya, Sunanda Bhattacharyya","doi":"10.1128/mbio.02129-25","DOIUrl":"10.1128/mbio.02129-25","url":null,"abstract":"<p><p><i>Plasmodium falciparum</i> undergoes endoreduplication, in which its nuclear, mitochondrial, and apicoplast genomes are replicated multiple times without cytokinesis,; enabling replication as a promising target for arresting parasite growth and pathogenicity. Previously, it was reported that the inhibition of expression of small subunit of ribonucleotide reductase (PfR2) leads to the inhibition of DNA synthesis and growth of the parasites. Here, we report the molecular determinant that is necessary for aiding early folding intermediates of PfR2. We find that PfR2 interacts with the cytosolic Type-I Hsp40-cochaperone PfYdj1 (Pf3D7_1437900), which subsequently interacts with PfHsp70-1 through its Histidine-Proline-Aspartate (HPD) motif. Such association of PfR2 is specific toward PfYdj1 and not with other cytosolic Type II Hsp40-cochaperone PfSis1 (PF3D7_0213100). We show that perturbation of association between PfYdj1 and PfHsp70-1 by small molecule 116-9e results in the disruption of PfR2 homeostasis within the parasite. As a result, there is a significant reduction in dNTP production leading to a replication arrest. We demonstrate that the combination of 116-9e and benzo-hydroxamate, a catalytic inhibitor of PfR2, works in a synergistic fashion. Together, our work suggests that targeting PfYdj1-PfHsp70-1 complex assembly in the context of ribonucleotide reductase function can be used as an attractive strategy to curb malaria.IMPORTANCERibonucleotide reductase is an important enzyme which catalyzes the reduction of ribonucleotides to deoxyribonucleotides, and inhibition of the synthesis of its catalytic subunit (PfR2) leads to significant growth inhibition in malaria parasites. Our study deciphers the molecular determinants that are essential for the maturation of PfR2. We show that <i>Plasmodium</i> Hsp40 cochaperone, PfYdj1 (Pf3D7_1437900), is the molecular cochaperone that facilitates the binding of PfR2 with PfHsp70-1, which is crucial for PfR2 folding and stability. We show that perturbation of the assembly between PfYdj1-PfHsp70-1 by a small molecule 116-9e destabilizes PfR2 and subsequently inhibits dNTP formation, resulting in replication arrest in the parasite. We demonstrate that 116-9e and the catalytic inhibitor of PfR2, benzo hydroxamate, potentiate each other's action. Also, the combination of both the inhibitors displays profound synergism in 3D7 parasites. We propose that the combination of 116-9e and benzo hydroxamate can be employed as an attractive anti-malaria strategy.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0212925"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505967/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145040595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Step-by-step: the CD8 T cell journey in leishmaniasis.","authors":"Erin A Fowler, Fernanda O Novais","doi":"10.1128/mbio.03537-23","DOIUrl":"10.1128/mbio.03537-23","url":null,"abstract":"<p><p>Leishmaniasis is a group of vector-borne diseases caused by protozoan parasites of the genus <i>Leishmania</i> that affect millions of people across nearly 100 countries. Clinical presentations range from self-resolving cutaneous ulcers to life-threatening visceral disease, depending on the infecting species and host immune response. While CD4 T cells have long been recognized as central to parasite control, CD8 T cells also play an important role in disease. In this mini-review, we explore the many steps involved in CD8 T cell responses in leishmaniasis, with a focus on antigen recognition, recruitment, effector function, memory development, and dysfunction. Drawing on both murine models and human studies, we highlight the duality of CD8 T cells, which can contribute to protection but also drive immune-mediated tissue damage. Recent advances in transcriptomics, <i>in vivo</i> modeling, and immunophenotyping have begun to clarify the conditions under which CD8 T cells support vs hinder host defense. Despite this progress, critical questions remain, and continued investigation into the heterogeneity and regulation of CD8 T cells in leishmaniasis promises not only to deepen our understanding of host-pathogen interactions but also to guide the development of targeted immunotherapies and vaccines.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0353723"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506010/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145065080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Erratum for Tang et al., \"Gut microbe-derived betulinic acid alleviates sepsis-induced acute liver injury by inhibiting macrophage NLRP3 inflammasome in mice\".","authors":"Xuheng Tang, Tairan Zeng, Wenyan Deng, Wanning Zhao, Yanan Liu, Qiaobing Huang, Yiyu Deng, Weidang Xie, Wei Huang","doi":"10.1128/mbio.02792-25","DOIUrl":"10.1128/mbio.02792-25","url":null,"abstract":"","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0279225"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506052/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The MarR family transcription factor SlyA senses iron and respiratory status in enteric bacteria.","authors":"W Ryan Will, Ferric C Fang","doi":"10.1128/mbio.01396-25","DOIUrl":"10.1128/mbio.01396-25","url":null,"abstract":"<p><p>SlyA and its homologs are conserved transcription factors in enteric bacteria, including <i>Salmonella enterica</i>, in which it upregulates horizontally acquired virulence genes. SlyA is a member of the MarR family of transcription factors, which possess a small molecule binding pocket. Ligand binding causes the protein to undergo a conformational change that abrogates DNA binding. Although the original discovery of MarR was based on its ability to recognize xenobiotic compounds and promote their efflux, the conservation of MarR family members throughout Bacteria and Archaea suggests a more general function. Because SlyA is known to bind xenobiotic aromatic carboxylates, we performed a targeted analysis of aromatic metabolic genes in <i>Salmonella</i> Typhimurium to identify potential endogenous ligands. We found that SlyA is promiscuously inhibited by multiple aromatic carboxylates including 2,3-dihydroxybenzoate, a precursor of iron-scavenging catecholate siderophores, and 4-hydroxybenzoate, a precursor of quinone-based electron-carriers, which allows it to sense changes in iron availability, respiration, and growth on succinate. We suggest that SlyA and other MarR proteins sense metabolic status via the flux of aromatic carboxylates in biosynthetic pathways. This allows SlyA to function as a counter-silencer of horizontally acquired genes that is exquisitely responsive to the metabolic state of the cell.IMPORTANCEMarR proteins comprise an ancient group of transcription factors that emerged before the divergence of Archaea and Bacteria. First identified as regulators of antibiotic efflux, they have also been suggested to sense and regulate concentrations of endogenous intracellular metabolites, but such metabolites have not previously been identified. Here we show that SlyA, a conserved and essential MarR family virulence gene regulator in enteric pathogens, binds to and is inhibited by aromatic metabolites required for many essential cellular processes. Our findings show how SlyA integrates metabolic status into bacterial transcriptional networks that control both molecular efflux and virulence.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0139625"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506092/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disruptions in outer membrane-peptidoglycan interactions enhance bile salt resistance in O-antigen-producing <i>E. coli</i>.","authors":"Jilong Qin, Yaoqin Hong, Waldemar Vollmer, Renato Morona, Makrina Totsika","doi":"10.1128/mbio.02184-25","DOIUrl":"10.1128/mbio.02184-25","url":null,"abstract":"<p><p>Bile salts (BS) are antimicrobials that disrupt bacterial cell membranes and induce oxidative stress. The gut bacterium <i>Escherichia coli</i> is naturally resistant to BS, including the model strain K12 MG1655 that produces a lipopolysaccharide (LPS) without O-antigen (OAg) on the cell surface. Paradoxically, we have previously shown that restoring a wild-type like LPS with attached OAg (MG1655-S) sensitizes <i>E. coli</i> K12 to exogenous BS. In this study, we investigate this phenomenon. We show that mutations causing truncation of the LPS core oligosaccharide render MG1655-S strains even more susceptible to BS compared to MG1655. These mutants phenocopy a K-12 MG1655-S Δ<i>waaL</i> mutant, which is defective in OAg ligase, primarily due to periplasmic accumulation of the unligated lipid-linked UndPP-OAg. Through the characterization of BS-resistant suppressor mutants of MG1655-S Δ<i>waaL</i>, we identify key genetic disruptions involved in resistance. Notably, we observed the highest BS resistance in strains with a weaker connection between the outer membrane (OM) and peptidoglycan (PG), including strains lacking the major OM-anchored, PG-binding proteins OmpA or Lpp. Expressing versions of OmpA and Lpp that lack PG-binding capacity also enhanced the BS resistance. Our data suggest that BS-induced stress in OAg-producing <i>E. coli</i> is due to the spatial constraints between OM and PG and that mutations disrupting OM-PG interactions alleviate this stress, thereby enhancing BS resistance. These findings provide new insights into a major challenge <i>E. coli</i> faces in the gut environment, where it needs to produce OAg for stable colonization and immune evasion while resisting the antimicrobial activity of BS.IMPORTANCEEnteric bacteria residing in the human gut must withstand host-derived antimicrobial bile salts, but resistance mechanisms are not fully elucidated. In this study, we investigate bile salt resistance mechanisms in O-antigen (OAg)-producing <i>Escherichia coli</i> K-12. We show that the accumulation of carrier lipid-linked OAg in the periplasm of strains with truncated lipopolysaccharide (LPS) core oligosaccharide or defects in OAg ligase can sensitize <i>E. coli</i> more to bile salt, unless the physical links between outer membrane and peptidoglycan are disrupted, highlighting that bile salt-induced stress is attributed to spatial constraints between the outer membrane and peptidoglycan layer. Our work uncovers a previously unappreciated envelope stress response mechanism in <i>E. coli</i>, where reducing outer membrane-peptidoglycan connectivity mitigates bile salt-induced damage arising from OAg production. These findings reshape our understanding of how physical architecture and biosynthetic intermediates intersect to influence bacterial survival in hostile environments.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0218425"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505904/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"What is the relationship between viral prospecting in animals and medical countermeasure development?","authors":"Aishani V Aatresh, Marc Lipsitch","doi":"10.1128/mbio.02033-25","DOIUrl":"10.1128/mbio.02033-25","url":null,"abstract":"<p><p>In recent decades, surveillance in non-human animals has aimed to detect novel viruses before they \"spill over\" to humans. However, the extent to which these viral prospecting efforts have enhanced outbreak preparedness remains poorly characterized, especially in terms of whether they are necessary, sufficient, or feasible to spur vaccine development. We find that several viruses which pose known threats to people lack approved vaccines, and known viruses discovered in human patients before 2000 have caused most major 21st-century outbreaks. With <i>Filoviridae</i> as a case study, we show there is little evidence that viral prospecting has accelerated vaccine or drug development or that systematically discovering novel zoonotic viruses in animal hosts before they cause human outbreaks has been feasible. These results suggest that surveillance for novel viral zoonoses does not accelerate vaccine development and underscore questions about its importance for outbreak preparedness. We consider limitations to these conclusions and alternative approaches to preparedness and response.IMPORTANCESampling in animal populations to detect novel viruses before they infect humans has been a major activity justified by several considerations, notably by the idea that finding such viruses will stimulate the development of medical countermeasures such as vaccines. This article examines the evidence that such research leads to earlier vaccine development and finds the evidence lacking. This is important because, in an era of scarce resources and biosafety considerations for researchers, efforts should be directed to those activities most likely to yield the desired outcomes.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0203325"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506108/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lumpy skin disease virus LSDV001 protein positively regulates inflammatory response by promoting assembly of the TAK1-TAB2/3 complex.","authors":"Yu-Lin Yang, Huai-Jie Jia, Meng-Yao Sun, Ai-Min Guo, Tian Xia, Hong-Bing Shu, Li-Bo Cao","doi":"10.1128/mbio.01677-25","DOIUrl":"10.1128/mbio.01677-25","url":null,"abstract":"<p><p>Lumpy skin disease (LSD) is an emerging transboundary viral disease of livestock caused by the lumpy skin disease virus (LSDV), which has caused substantial economic losses and negatively impacted veterinary public health. The underlying pathogenic mechanisms remain poorly understood, limiting the effective prevention and control of LSD. Here, we identify LSDV-encoded protein LSDV001 as a positive regulator of IL-1β- and TNFα-triggered signaling. LSDV001 interacts with TAK1 and TAB2/3 and promotes assembly of the TAK1-TAB2/3 complex. This leads to IKK-dependent activation of the transcription factor NF-κB and induction of downstream inflammatory cytokines. LSDV001-deficient virus (LSDVΔ001) has attenuated the ability to activate NF-κB and induce the expression of inflammatory cytokines. Infection with LSDVΔ001 leads to smaller skin nodules and reduced inflammation compared to wild-type LSDV. Our findings suggest that LSDV001 acts as a key virulence factor of LSDV by promoting excessive inflammatory response upon infection.</p><p><strong>Importance: </strong>Lumpy skin disease is a current global concern caused by the lumpy skin disease virus (LSDV), for which there is a lack of safe and efficient vaccines. In this study, we report that LSDV001 protein potentiates IL-1β- and TNFα-triggered IKK-dependent activation of NF-κB and transcription of inflammatory cytokines. Mechanistically, LSDV001 enhances inflammatory response by interacting with TAK1 and TAB2/3 to promote TAK1-TAB2/3 complex formation. We further demonstrate that LSDV001 deficiency attenuates LSDV-triggered inflammatory response and pathogenesis. Our findings identify a new virulence factor and reveal a novel pathogenic mechanism of LSDV by which LSDV001 enhances inflammatory response.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0167725"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505959/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}