mBio最新文献

{"title":"Minor prion substrains overcome transmission barriers.","authors":"Benjamin S Steadman, Jifeng Bian, Ronald A Shikiya, Jason C Bartz","doi":"10.1128/mbio.02721-24","DOIUrl":"10.1128/mbio.02721-24","url":null,"abstract":"<p><p>Mammalian prion diseases are infectious neurodegenerative diseases caused by the self-templating form of the prion protein PrP^Sc. Much evidence supports the hypothesis that prions exist as a mixture of a dominant strain and minor prion strains. While it is known that prions can infect new species, the relative contribution of the dominant prion strain and minor strains in crossing the species barrier is unknown. We previously identified minor prion strains from a biologically cloned drowsy (DY) strain of hamster-adapted transmissible mink encephalopathy (TME). Here we show that these minor prion strains have increased infection efficiency to rabbit kidney epithelial cells that express hamster PrP^C compared to the dominant strain DY TME. Using protein misfolding cyclic amplification (PMCA), we found that the dominant strain DY TME failed to convert mouse PrP^C to PrP^Sc, even after several serial passages. In contrast, the minor prion strains isolated from biologically cloned DY TME robustly converted mouse PrP^C to PrP^Sc in the first round of PMCA. This observation indicates that minor prion strains from the mutant spectra contribute to crossing the species barrier. Additionally, we found that the PMCA conversion efficiency for the minor prion strains tested was significantly different from each other and from the short-incubation period prion strain HY TME. This suggests that minor strain diversity may be greater than previously anticipated. These observations further expand our understanding of the mechanisms underlying the species barrier effect and has implications for assessing the zoonotic potential of prions.</p><p><strong>Importance: </strong>Prions from cattle with bovine spongiform encephalopathy have transmitted to humans, whereas scrapie from sheep and goats likely has not, suggesting that some prions can cross species barriers more easily than others. Prions are composed of a dominant strain and minor strains, and the contribution of each population to adapt to new replicative environments is unknown. Recently, minor prion strains were isolated from the biologically cloned prion strain DY TME, and these minor prion strains differed in properties from the dominant prion strain, DY TME. Here we found that these minor prion strains also differed in conversion efficiency and host range compared to the dominant strain DY TME. These novel findings provide evidence that minor prion strains contribute to interspecies transmission, underscoring the significance of minor strain components in important biological processes.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0272124"},"PeriodicalIF":5.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11559082/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142503527","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":"A global lipid map of severe fever with thrombocytopenia syndrome virus infection reveals glycerophospholipids as novel prognosis biomarkers.","authors":"Panpan Tian, Liwei Zhao, Guiting Zhang, Shixing Chen, Wanying Zhang, Mingrong Ou, Yidan Sun, Yuxin Chen","doi":"10.1128/mbio.02628-24","DOIUrl":"https://doi.org/10.1128/mbio.02628-24","url":null,"abstract":"<p><p>Severe fever with thrombocytopenia syndrome (SFTS) is a rapidly progressing infectious disease caused by a novel bunyavirus characterized by high fever, thrombocytopenia, and multiple organ damage. While lipids play an important role in viral infections, the specific alterations in lipid metabolism during SFTSV infection remain unclear. This study aimed to elucidate the global lipid metabolic profiles of SFTS patients with mild, severe, and fatal outcomes. A total of 60 SFTS patients, consisting of 30 mild, 15 severe and 15 fatal patients, and 30 healthy controls, were enrolled for the investigation of global lipidomics in serum using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Our findings revealed global alterations in the lipid signature induced by SFTSV infection and further confirmed that the glycerophospholipid metabolism pathway was profoundly affected during the progression of mild, severe, and fatal outcomes in SFTS patients. Importantly, LysoPC (20:0) and LysoPC (P-16:0) are strongly correlated with the clinical parameters of SFTSV infection. Furthermore, we demonstrated the substantial prognostic value of LysoPC (20:0) and LysoPC (P-16:0) by receiver operating characteristic (ROC) curve analysis, providing evidence for their remarkable value as prognostic biomarkers for predicting SFTS clinical outcomes. In particular, LysoPC (20:0) and LysoPC (P-16:0), along with APTT, yielded superior prognostic performance for fatal SFTS [area under the curve (AUC) = 98.4%], outperforming routine clinical parameters. Collectively, our findings revealed the lipidomic landscape after SFTSV infection, which offers new insights into the mechanisms of SFTS disease progression and suggests that targeting lipid metabolism may serve as a potential therapeutic strategy.</p><p><strong>Importance: </strong>This study systematically investigated the lipid landscape profile of SFTS-infected patients with different clinical outcomes. Our results revealed a global alteration in the lipid signature, particularly the glycerophospholipid metabolic pathway, induced by SFTSV infection. Notably, LysoPC (20:0) and LysoPC (P-16:0) presented remarkable prognostic value as novel biomarkers for SFTSV infection and may contribute to the prognosis of SFTS progression and appropriate interventions.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0262824"},"PeriodicalIF":5.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"When more sugar is better-a GPI side chain modification results in a less virulent phenotype during a protozoan infection.","authors":"Frank Seeber","doi":"10.1128/mbio.02740-24","DOIUrl":"https://doi.org/10.1128/mbio.02740-24","url":null,"abstract":"<p><p>The assembly and function of side chain modifications of glycosylphosphatidylinositol (GPI) units (anchors or free forms) are poorly defined. In a recent study, two enzymes, PIGJ and PIGE, of the protozoan parasite <i>Toxoplasma gondii</i> were identified and shown to be involved in the assembly of such GPI side chains (J. A. Alvarez, E. Gas-Pascual, S. Malhi, J. C. Sánchez-Arcila, et al., mBio 15:e00527-24, 2024, https://doi.org/10.1128/mbio.00527-24). PIGJ adds N-acetylgalactosamine to the GPI core structure, while PIGE subsequently adds a terminal glucose. Deletion of PIGJ resulted in the loss of the side chain and, strikingly, increased mortality in infected mice, in contrast to PIGE knockouts. Absence of the side chain led to increased binding of the scavenger receptor CD36 to mutant parasites. In galectin-3 knockout mice, the virulent phenotype of side-chain-deficient parasites was largely lost. While the exact mechanisms remain to be elucidated by more experiments, these findings provide the first evidence for the importance of GPI side chains in parasite-host interactions <i>in vivo</i>.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0274024"},"PeriodicalIF":5.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142622413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antiviral mechanisms of guanylate-binding protein 5: versatile inhibition of multiple viral glycoproteins.","authors":"Daniel Sauter, Frank Kirchhoff","doi":"10.1128/mbio.02374-24","DOIUrl":"10.1128/mbio.02374-24","url":null,"abstract":"<p><p>Guanylate-binding proteins (GBPs) are interferon-inducible cellular factors known to inhibit a wide variety of pathogens. Humans encode seven GBPs that have functionally diversified to provide broad protection against a variety of bacteria, protozoa, and viruses. Here, we discuss recent data on the mechanisms underlying the broad antiviral activity of GBP5 (H. Veler, C. M. Lun, A. A. Waheed, and E. O. Freed, mBio e02086-24, 2024, https://doi.org/10.1128/mbio.02086-24) and place them in the context of previous studies on the ability of this antiviral factor to impair the function of numerous viral envelope (Env) glycoproteins. We focus on the effects of GBP5 on the glycosylation, proteolytic processing, and anterograde transport of Env and discuss mechanistic interdependencies of these maturation steps. Understanding the induction and action of broadly acting immune factors, such as GBP5, may help develop effective immune-based strategies against numerous pathogens.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0237424"},"PeriodicalIF":5.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11559056/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142469436","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":"Integrative genomic, virulence, and transcriptomic analysis of emergent <i>Streptococcus dysgalactiae</i> subspecies <i>equisimilis</i> (SDSE) <i>emm</i> type <i>stG62647</i> isolates causing human infections.","authors":"Jesus M Eraso, Randall J Olsen, S Wesley Long, Ryan Gadd, Sarrah Boukthir, Ahmad Faili, Samer Kayal, James M Musser","doi":"10.1128/mbio.02578-24","DOIUrl":"10.1128/mbio.02578-24","url":null,"abstract":"<p><p><i>Streptococcus dysgalactiae</i> subspecies <i>equisimilis</i> (SDSE) is a Gram-positive bacterial pathogen that infects humans and is closely related to group A streptococcus (GAS). Compared with GAS, far less is known about SDSE pathobiology. Increased rates of invasive SDSE infections have recently been reported in many countries. One SDSE <i>emm</i> type (<i>stG62647</i>) is known to cause severe diseases, including necrotizing soft-tissue infections, endocarditis, and osteoarticular infections. To increase our understanding of the molecular pathogenesis of <i>stG62647</i> SDSE isolates causing human infections, we sequenced to closure the genomes of 120 <i>stG62647</i> SDSE isolates. The genomes varied in size from 2.1 to 2.24 Mb pairs. The great majority of <i>stG62647</i> isolates had <i>IS1548</i> integrated into the <i>silB</i> gene, thereby inactivating it. Regions of difference, such as mobile genetic elements, were the largest source of genomic diversity. All 120 <i>stG62647</i> isolates were assayed for virulence using a well-established mouse model of necrotizing myositis. An unexpectedly wide range of virulence was identified (20% to 95%), as assessed by near-mortality data. To explore the molecular mechanisms underlying virulence differences, we analyzed RNAseq transcriptome profiles for 38 <i>stG62647</i> isolates (comprising the 19 least and most virulent) grown <i>in vitro</i>. Genetic polymorphisms were identified from whole-genome sequence data. Collectively, the results suggest that these SDSE isolates use multiple genetic pathways to alter virulence phenotype. The data also suggest that human genetics and underlying medical conditions contribute to disease severity. Our study integrates genomic, mouse virulence, and RNAseq data to advance our understanding of SDSE pathobiology and its molecular pathogenesis.</p><p><strong>Importance: </strong>This study integrated genomic sequencing, mouse virulence assays, and bacterial transcriptomic analysis to advance our understanding of the molecular mechanisms contributing to <i>Streptococcus dysgalactiae</i> subsp. <i>equisimilis emm</i> type <i>stG62647</i> pathogenesis. We tested a large cohort of genetically closely related <i>stG62647</i> isolates for virulence using an established mouse model of necrotizing myositis and discovered a broad spectrum of virulence phenotypes, with near-mortality rates ranging from 20% to 95%. This variation was unexpected, given their close genetic proximity. Transcriptome analysis of <i>stG62647</i> isolates responsible for the lowest and highest near-mortality rates suggested that these isolates used multiple molecular pathways to alter their virulence. In addition, some genes encoding transcriptional regulators and putative virulence factors likely contribute to SDSE <i>emm</i> type <i>stG62647</i> pathogenesis. These data underscore the complexity of pathogen-host interactions in an emerging SDSE clonal group.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0257824"},"PeriodicalIF":5.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11559094/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142469440","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":"A molecular comparison of [Fe-S] cluster-based homeostasis in <i>Escherichia coli</i> and <i>Pseudomonas aeruginosa</i>.","authors":"Alessandra Lo Sciuto, Francesca D'Angelo, Maria Concetta Spinnato, Pierre Simon Garcia, Shirley Genah, Cervoni Matteo, Emmanuel Séchet, Ehud Banin, Frédéric Barras, Francesco Imperi","doi":"10.1128/mbio.01206-24","DOIUrl":"10.1128/mbio.01206-24","url":null,"abstract":"<p><p>Iron-sulfur [Fe-S] clusters are essential protein cofactors allowing bacteria to perceive environmental redox modification and to adapt to iron limitation. <i>Escherichia coli</i>, which served as a bacterial model, contains two [Fe-S] cluster biogenesis systems, ISC and SUF, which ensure [Fe-S] cluster synthesis under balanced and stress conditions, respectively. However, our recent phylogenomic analyses revealed that most bacteria possess only one [Fe-S] cluster biogenesis system, most often SUF. The opportunist human pathogen <i>Pseudomonas aeruginosa</i> is atypical as it harbors only ISC. Here, we confirmed the essentiality of ISC in <i>P. aeruginosa</i> under both normal and stress conditions. Moreover, <i>P. aeruginosa</i> ISC restored viability, under balanced growth conditions, to an <i>E. coli</i> strain lacking both ISC and SUF. Reciprocally, the <i>E. coli</i> SUF system sustained growth and [Fe-S] cluster-dependent enzyme activities of ISC-deficient <i>P. aeruginosa</i>. Surprisingly, an ISC-deficient <i>P. aeruginosa</i> strain expressing <i>E. coli</i> SUF showed defects in resistance to H₂O₂ stress and paraquat, a superoxide generator. Similarly, the <i>P. aeruginosa</i> ISC system did not confer stress resistance to a SUF-deficient <i>E. coli</i> mutant. A survey of 120 Pseudomonadales genomes confirmed that all but five species have selected ISC over SUF. While highlighting the great versatility of bacterial [Fe-S] cluster biogenesis systems, this study emphasizes that their contribution to cellular homeostasis must be assessed in the context of each species and its own repertoire of stress adaptation functions. As a matter of fact, despite having only one ISC system, <i>P. aeruginosa</i> shows higher fitness in the face of ROS and iron limitation than <i>E. coli</i>.</p><p><strong>Importance: </strong>ISC and SUF molecular systems build and transfer Fe-S cluster to cellular apo protein clients. The model <i>Escherichia coli</i> has both ISC and SUF and study of the interplay between the two systems established that the ISC system is the house-keeping one and SUF the stress-responding one. Unexpectedly, our recent phylogenomic analysis revealed that in contrast to <i>E. coli</i> (and related enterobacteria such as Salmonella), most bacteria have only one system, and, in most cases, it is SUF. <i>Pseudomonas aeruginosa</i> fits the general rule of having only one system but stands against the rule by having ISC. This study aims at engineering <i>P. aeruginosa</i> harboring <i>E. coli</i> systems and vice versa. Comparison of the recombinants allowed to assess the functional versatility of each system while appreciating their contribution to cellular homeostasis in different species context.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0120624"},"PeriodicalIF":5.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11559095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365782","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":"Biochemical analysis of packing and assembling heptad repeat motifs in the coronavirus spike protein trimer.","authors":"Jun Kobayashi, Kazuhiko Kanou, Hiyori Okura, Tahmina Mst Akter, Shuetsu Fukushi, Shutoku Matsuyama","doi":"10.1128/mbio.01203-24","DOIUrl":"10.1128/mbio.01203-24","url":null,"abstract":"<p><p>During a coronavirus infection, the spike protein undergoes sequential structural transitions triggered by its receptor and the host protease at the interface between the virus and cell membranes, thereby mediating membrane fusion. After receptor binding, the heptad repeat motif (HR1/HR2) within the viral spike protein bridges the viral and cellular membranes; however, the intermediate conformation adopted by the spike protein when drawing the viral and cellular membranes into close proximity remains unclear due to its transient and unstable nature. Here, we experimentally induced conformational changes in the spike protein of a murine coronavirus by incubating the virus with its receptor, followed by exposure to trypsin. We then treated the virus/receptor complex with proteinase K to probe the tightly packed core structure of the spike protein. The conformations of the spike protein were predicted from the sizes of the protease digestion products detected by western blot analysis. Upon receptor binding, two bands (each showing different reactivity with a fusion-inhibiting HR2-peptide) were detected; we propose that these bands correspond to the packed and unpacked HR1/HR2 motifs. After trypsin-mediated triggering, measurement of temperature and time dependency revealed that packing of the remaining unpacked HR1/HR2 motifs and assembly of three HR1 motifs in a trimer occur almost simultaneously. Thus, the trimeric spike protein adopts an asymmetric-unassembled conformation after receptor binding, followed by direct assembly into the post-fusion form triggered by the host protease. This biochemical study provides mechanistic insight into the previously unknown intermediate structure of the viral fusion protein.IMPORTANCEDuring infection by an enveloped virus, receptor binding triggers fusion between the cellular membrane and the virus envelope, enabling delivery of the viral genome to the cytoplasm. The viral spike protein mediates membrane fusion; however the molecular mechanism underlying this process is unclear. This is because using structural biology methods to track the transient conformational changes induced in the unstable spike trimer is challenging. Here, we harnessed the ability of protease enzymes to recognize subtle differences on protein surfaces, allowing us to detect structural differences in the spike protein before and after conformational changes. Differences in the size of the degradation products were analyzed by western blot analysis. The proposed model explaining the conformational changes presented herein is a plausible candidate that provides valuable insight into unanswered questions in the field of virology.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0120324"},"PeriodicalIF":5.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11559096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142503521","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":"Type I interferon signaling in dendritic cells limits direct antigen presentation and CD8⁺ T cell responses against an arthritogenic alphavirus.","authors":"Christopher B Bullock, Leran Wang, Brian C Ware, Ngan Wagoner, Ray A Ohara, Tian-Tian Liu, Pritesh Desai, Bjoern Peters, Kenneth M Murphy, Scott A Handley, Thomas E Morrison, Michael S Diamond","doi":"10.1128/mbio.02930-24","DOIUrl":"https://doi.org/10.1128/mbio.02930-24","url":null,"abstract":"<p><p>Ross River virus (RRV) and other alphaviruses cause chronic musculoskeletal syndromes that are associated with viral persistence, which suggests deficits in immune clearance mechanisms, including CD8⁺ T-cell responses. Here, we used a recombinant RRV-gp33 that expresses the immunodominant CD8⁺ T-cell epitope of lymphocytic choriomeningitis virus (LCMV) to directly compare responses with a virus, LCMV, that strongly induces antiviral CD8⁺ T cells. After footpad injection, we detected fewer gp33-specific CD8⁺ T cells in the draining lymph node (DLN) after RRV-gp33 than LCMV infection, despite similar viral RNA levels in the foot. However, less RRV RNA was detected in the DLN compared to LCMV, with RRV localizing principally to the subcapsular region and LCMV to the paracortical T-cell zones. Single-cell RNA-sequencing analysis of adoptively transferred gp33-specific transgenic CD8⁺ T cells showed rapid differentiation into effector cells after LCMV but not RRV infection. This defect in RRV-specific CD8⁺ T effector cell maturation was corrected by local blockade of type I interferon (IFN) signaling, which also resulted in increased RRV infection in the DLN. Studies in <i>Wdfy4</i>^-/-, CD11c-Cre <i>B2m</i>^fl/fl, or Xcr1-Cre <i>Ifnar1</i>^fl/fl mice that respectively lack cross-presenting capacity, MHC-I antigen presentation by dendritic cells (DCs), or type I IFN signaling in the DC1 subset show that RRV-specific CD8⁺ T-cell responses can be improved by enhanced direct antigen presentation by DCs. Overall, our experiments suggest that antiviral type I IFN signaling in DCs limits direct alphavirus infection and antigen presentation, which likely delays CD8⁺ T-cell responses.IMPORTANCEChronic arthritis and musculoskeletal disease are common outcomes of infections caused by arthritogenic alphaviruses, including Ross River virus (RRV), due to incomplete virus clearance. Unlike other viral infections that are efficiently cleared by cytotoxic CD8⁺ T cells, RRV infection is surprisingly unaffected by CD8⁺ T cells as mice lacking or having these cells show similar viral persistence in joint and lymphoid tissues. To elucidate the basis for this deficient response, we measured the RRV-specific CD8⁺ T-cell population size and activation state relative to another virus known to elicit a strong T-cell response. Our findings reveal that RRV induces fewer CD8⁺ T cells due to limited infection of immune cells in the draining lymph node. By increasing RRV susceptibility in antigen-presenting cells, we elicited a robust CD8⁺ T-cell response. These results highlight antigen availability and virus tropism as possible targets for intervention against RRV immune evasion and persistence.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0293024"},"PeriodicalIF":5.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142622369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Chlamydia</i>-driven ISG15 expression dampens the immune response of epithelial cells independently of ISGylation.","authors":"Yongzheng Wu, Chang Liu, Chongfa Tang, Béatrice Niragire, Yaël Levy-Zauberman, Cindy Adapen, Thomas Vernay, Juliette Hugueny, Véronique Baud, Agathe Subtil","doi":"10.1128/mbio.02401-24","DOIUrl":"10.1128/mbio.02401-24","url":null,"abstract":"<p><p>Excessive inflammation upon <i>Chlamydia trachomatis</i> infection can cause severe damages in the female genital tract. This obligate intracellular bacterium develops mainly in epithelial cells, whose innate response contributes to the overall inflammatory response to infection. The ubiquitin-like protein interferon-stimulated gene 15 (ISG15) stimulates interferon γ (IFNγ) production and is required for bacterial clearance in several infectious contexts. Here, we describe and investigate the consequences of the increase in ISG15 expression by epithelial cells infected with <i>C. trachomatis</i>. Infection of HeLa cells and primary ecto-cervical epithelial cells resulted in a transcriptional upregulation of <i>ISG15</i> expression. This did not involve the canonical type I interferon (IFN-I) signaling pathway and depended instead on the activation of the STING/TBK1/IRF3 pathway. The absence or reduction of ISG15 synthesis led to increased production of several cytokines and chemokines, including interleukin (IL) 6 and IL8. This implicates that ISG15 normally dampens the immune response induced by <i>C. trachomatis</i> infection in epithelial cells. ISG15 exerted its control from an intracellular location, but without involving ISGylation. Finally, higher levels of inflammation and delayed bacterial clearance were observed in the genital tracts of ISG15-KO mice infected by <i>C. trachomatis</i> compared with wild-type animals; however, IFNγ production was unchanged. Altogether, our data show that ISG15 expression acts as a brake on the immune response to <i>C. trachomatis</i> infection in epithelial cells and limits bacterial burden and inflammation in mice.IMPORTANCEInfection of epithelial cells by <i>Chlamydia trachomatis</i> elicits an innate immune response by these cells. The signaling pathways involved, and their outcomes, are still very poorly understood. In this paper, we described how <i>Chlamydia</i> infection triggered the expression of ISG15, a small molecule normally associated to type I interferon (IFN-I) signaling and control of INF-γ production. ISG15 synthesis by epithelial cells attenuated their immune response to <i>Chlamydia</i> infection. In mice, we observed that ISG15 displayed a marginal role in modulating the production of IFN-γ, a key component of the host immune response to infection, but facilitated bacterial clearance. Overall, our study strengthens the importance of ISG15 not only in the resolution of viral but also of bacterial infection and document its role of \"immune brake\" in the context of <i>Chlamydia</i> infection.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0240124"},"PeriodicalIF":5.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11559041/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142349634","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":"Translation initiation or elongation inhibition triggers contrasting effects on <i>Caenorhabditis elegans</i> survival during pathogen infection.","authors":"Annesha Ghosh, Jogender Singh","doi":"10.1128/mbio.02485-24","DOIUrl":"10.1128/mbio.02485-24","url":null,"abstract":"<p><p>Diverse microbial pathogens are known to attenuate host protein synthesis. Consequently, the host mounts a defense response against protein translation inhibition, leading to increased transcript levels of immune genes. The seemingly paradoxical upregulation of immune gene transcripts in response to blocked protein synthesis suggests that the defense mechanism against translation inhibition may not universally benefit host survival. However, a comprehensive assessment of host survival on pathogens upon blockage of different stages of protein synthesis is currently lacking. Here, we investigate the impact of knockdown of various translation initiation and elongation factors on the survival of <i>Caenorhabditis elegans</i> exposed to <i>Pseudomonas aeruginosa</i>. Intriguingly, we observe opposing effects on <i>C. elegans</i> survival depending on whether translation initiation or elongation is inhibited. While translation initiation inhibition enhances survival, elongation inhibition decreases it. Transcriptomic studies reveal that translation initiation inhibition activates a bZIP transcription factor ZIP-2-dependent innate immune response that protects <i>C. elegans</i> from <i>P. aeruginosa</i> infection. In contrast, inhibiting translation elongation triggers both ZIP-2-dependent and ZIP-2-independent immune responses that, while effective in clearing the infection, are detrimental to the host. Thus, our findings reveal the opposing roles of translation initiation and elongation inhibition in <i>C. elegans</i> survival during <i>P. aeruginosa</i> infection, highlighting distinct transcriptional reprogramming that may underlie these differences.</p><p><strong>Importance: </strong>Several microbial pathogens target host protein synthesis machinery, potentially limiting the innate immune responses of the host. In response, hosts trigger a defensive response, elevating immune gene transcripts. This counterintuitive response can have either beneficial or harmful effects on host survival. In this study, we conduct a comprehensive analysis of the impact of knocking down various translation initiation and elongation factors on the survival of <i>Caenorhabditis elegans</i> exposed to <i>Pseudomonas aeruginosa</i>. Intriguingly, inhibiting initiation and elongation factors has contrasting effects on <i>C. elegans</i> survival. Inhibiting translation initiation activates immune responses that protect the host from bacterial infection, while inhibiting translation elongation induces aberrant immune responses that, although clear the infection, are detrimental to the host. Our study reveals divergent roles of translation initiation and elongation inhibition in <i>C. elegans</i> survival during <i>P. aeruginosa</i> infection and identifies differential transcriptional reprogramming that could underlie these differences.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0248524"},"PeriodicalIF":5.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11559039/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142349646","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}