Pub Date : 2024-08-28DOI: 10.1038/s41564-024-01788-6
Yunhui Zhang, Chuang Sun, Zihua Guo, Liyan Liu, Xiaotong Zhang, Kai Sun, Yanfen Zheng, Andrew J. Gates, Jonathan D. Todd, Xiao-Hua Zhang
Hydrogen sulfide (H2S), methanethiol (MeSH) and dimethylsulfide (DMS) are abundant sulfur gases with roles in biogeochemical cycling, chemotaxis and/or climate regulation. Catabolism of the marine osmolyte dimethylsulfoniopropionate (DMSP) is a major source of DMS and MeSH, but both also result from S-methylation of H2S via MddA, an H2S and MeSH S-methyltransferase whose gene is abundant in soil but scarce in marine environments. Here we identify the S-adenosine methionine (SAM)-dependent MeSH and H2S S-methyltransferase ‘MddH’, which is widespread in diverse marine bacteria and some freshwater and soil bacteria. mddH is predicted in up to ~5% and ~15% of seawater and coastal sediment bacteria, respectively, which is considerably higher than mddA. Furthermore, marine mddH transcript levels are similar to those for the most abundant DMSP lyase gene dddP. This study implies that the importance of H2S and MeSH S-methylation pathways in marine environments is significantly underestimated. The S-methyltransferase enzyme MddH produces DMS from hydrogen sulfide and methanethiol and its gene abundance rivals that of other known genes whose products generate DMS in marine environments.
{"title":"An S-methyltransferase that produces the climate-active gas dimethylsulfide is widespread across diverse marine bacteria","authors":"Yunhui Zhang, Chuang Sun, Zihua Guo, Liyan Liu, Xiaotong Zhang, Kai Sun, Yanfen Zheng, Andrew J. Gates, Jonathan D. Todd, Xiao-Hua Zhang","doi":"10.1038/s41564-024-01788-6","DOIUrl":"10.1038/s41564-024-01788-6","url":null,"abstract":"Hydrogen sulfide (H2S), methanethiol (MeSH) and dimethylsulfide (DMS) are abundant sulfur gases with roles in biogeochemical cycling, chemotaxis and/or climate regulation. Catabolism of the marine osmolyte dimethylsulfoniopropionate (DMSP) is a major source of DMS and MeSH, but both also result from S-methylation of H2S via MddA, an H2S and MeSH S-methyltransferase whose gene is abundant in soil but scarce in marine environments. Here we identify the S-adenosine methionine (SAM)-dependent MeSH and H2S S-methyltransferase ‘MddH’, which is widespread in diverse marine bacteria and some freshwater and soil bacteria. mddH is predicted in up to ~5% and ~15% of seawater and coastal sediment bacteria, respectively, which is considerably higher than mddA. Furthermore, marine mddH transcript levels are similar to those for the most abundant DMSP lyase gene dddP. This study implies that the importance of H2S and MeSH S-methylation pathways in marine environments is significantly underestimated. The S-methyltransferase enzyme MddH produces DMS from hydrogen sulfide and methanethiol and its gene abundance rivals that of other known genes whose products generate DMS in marine environments.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"9 10","pages":"2614-2625"},"PeriodicalIF":20.5,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41564-024-01788-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142085509","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}
Pub Date : 2024-08-28DOI: 10.1038/s41564-024-01789-5
Francisco J. Zapatero-Belinchón, Priti Kumar, Melanie Ott, Olivier Schwartz, Alex Sigal
On 8–11 April 2024, a Keystone meeting on human immunodeficiency virus and emerging and re-emerging viruses convened in Hannover, Germany, aiming to unite researchers studying viruses of global concern, and gain a deep understanding of unique and shared viral disease mechanisms to facilitate pandemic preparedness.
{"title":"Understanding emerging and re-emerging viruses to facilitate pandemic preparedness","authors":"Francisco J. Zapatero-Belinchón, Priti Kumar, Melanie Ott, Olivier Schwartz, Alex Sigal","doi":"10.1038/s41564-024-01789-5","DOIUrl":"10.1038/s41564-024-01789-5","url":null,"abstract":"On 8–11 April 2024, a Keystone meeting on human immunodeficiency virus and emerging and re-emerging viruses convened in Hannover, Germany, aiming to unite researchers studying viruses of global concern, and gain a deep understanding of unique and shared viral disease mechanisms to facilitate pandemic preparedness.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"9 9","pages":"2208-2211"},"PeriodicalIF":20.5,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142085510","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}
Pub Date : 2024-08-27DOI: 10.1038/s41564-024-01782-y
Camila Figueiredo Pinzan, Clara Valero, Patrícia Alves de Castro, Jefferson Luiz da Silva, Kayleigh Earle, Hong Liu, Maria Augusta Crivelente Horta, Olaf Kniemeyer, Thomas Krüger, Annica Pschibul, Derya Nur Cömert, Thorsten Heinekamp, Axel A. Brakhage, Jacob L. Steenwyk, Matthew E. Mead, Nico Hermsdorf, Scott G. Filler, Nathalia Gonsales da Rosa-Garzon, Endrews Delbaje, Michael J. Bromley, Hamilton Cabral, Camila Diehl, Claudia B. Angeli, Giuseppe Palmisano, Ashraf S. Ibrahim, David C. Rinker, Thomas J. C. Sauters, Karin Steffen, Adiyantara Gumilang, Antonis Rokas, Sara Gago, Thaila F. dos Reis, Gustavo H. Goldman
Aspergillus fumigatus causes aspergillosis and relies on asexual spores (conidia) for initiating host infection. There is scarce information about A. fumigatus proteins involved in fungal evasion and host immunity modulation. Here we analysed the conidial surface proteome of A. fumigatus, two closely related non-pathogenic species, Aspergillus fischeri and Aspergillus oerlinghausenensis, as well as pathogenic Aspergillus lentulus, to identify such proteins. After identifying 62 proteins exclusively detected on the A. fumigatus conidial surface, we assessed null mutants for 42 genes encoding these proteins. Deletion of 33 of these genes altered susceptibility to macrophage, epithelial cells and cytokine production. Notably, a gene that encodes a putative glycosylasparaginase, modulating levels of the host proinflammatory cytokine IL-1β, is important for infection in an immunocompetent murine model of fungal disease. These results suggest that A. fumigatus conidial surface proteins are important for evasion and modulation of the immune response at the onset of fungal infection. Analysis of the conidial surface proteome of the fungal pathogen Aspergillus fumigatus and three closely related species reveals factors important for evasion and modulation of host immunity
{"title":"Aspergillus fumigatus conidial surface-associated proteome reveals factors for fungal evasion and host immunity modulation","authors":"Camila Figueiredo Pinzan, Clara Valero, Patrícia Alves de Castro, Jefferson Luiz da Silva, Kayleigh Earle, Hong Liu, Maria Augusta Crivelente Horta, Olaf Kniemeyer, Thomas Krüger, Annica Pschibul, Derya Nur Cömert, Thorsten Heinekamp, Axel A. Brakhage, Jacob L. Steenwyk, Matthew E. Mead, Nico Hermsdorf, Scott G. Filler, Nathalia Gonsales da Rosa-Garzon, Endrews Delbaje, Michael J. Bromley, Hamilton Cabral, Camila Diehl, Claudia B. Angeli, Giuseppe Palmisano, Ashraf S. Ibrahim, David C. Rinker, Thomas J. C. Sauters, Karin Steffen, Adiyantara Gumilang, Antonis Rokas, Sara Gago, Thaila F. dos Reis, Gustavo H. Goldman","doi":"10.1038/s41564-024-01782-y","DOIUrl":"10.1038/s41564-024-01782-y","url":null,"abstract":"Aspergillus fumigatus causes aspergillosis and relies on asexual spores (conidia) for initiating host infection. There is scarce information about A. fumigatus proteins involved in fungal evasion and host immunity modulation. Here we analysed the conidial surface proteome of A. fumigatus, two closely related non-pathogenic species, Aspergillus fischeri and Aspergillus oerlinghausenensis, as well as pathogenic Aspergillus lentulus, to identify such proteins. After identifying 62 proteins exclusively detected on the A. fumigatus conidial surface, we assessed null mutants for 42 genes encoding these proteins. Deletion of 33 of these genes altered susceptibility to macrophage, epithelial cells and cytokine production. Notably, a gene that encodes a putative glycosylasparaginase, modulating levels of the host proinflammatory cytokine IL-1β, is important for infection in an immunocompetent murine model of fungal disease. These results suggest that A. fumigatus conidial surface proteins are important for evasion and modulation of the immune response at the onset of fungal infection. Analysis of the conidial surface proteome of the fungal pathogen Aspergillus fumigatus and three closely related species reveals factors important for evasion and modulation of host immunity","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"9 10","pages":"2710-2726"},"PeriodicalIF":20.5,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142081007","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}
Pub Date : 2024-08-26DOI: 10.1038/s41564-024-01780-0
Lei-Jie Jia, Katherine González, Thomas Orasch, Franziska Schmidt, Axel A. Brakhage
An important host defence mechanism against pathogens is intracellular killing, which is achieved through phagocytosis, a cellular process for engulfing and neutralizing extracellular particles. Phagocytosis results in the formation of matured phagolysosomes, which are specialized compartments that provide a hostile environment and are considered the end point of the degradative pathway. However, all fungal pathogens studied to date have developed strategies to manipulate phagosomal function directly and also indirectly by redirecting phagosomes from the degradative pathway to a non-degradative pathway with the expulsion and even transfer of pathogens between cells. Here, using the major human fungal pathogens Aspergillus fumigatus, Candida albicans, Cryptococcus neoformans and Histoplasma capsulatum as examples, we discuss the processes involved in host phagosome–fungal pathogen interactions, with a focus on fungal evasion strategies. We also discuss recent approaches to targeting intraphagosomal pathogens, including the redirection of phagosomes towards degradative pathways for fungal pathogen eradication. In this Review, the authors discuss fungal pathogen–host interactions with a focus on phagocytosis and intracellular processing of pathogens within phagosomes. They also outline potential therapeutic approaches for targeting intraphagosomal pathogens.
{"title":"Manipulation of host phagocytosis by fungal pathogens and therapeutic opportunities","authors":"Lei-Jie Jia, Katherine González, Thomas Orasch, Franziska Schmidt, Axel A. Brakhage","doi":"10.1038/s41564-024-01780-0","DOIUrl":"10.1038/s41564-024-01780-0","url":null,"abstract":"An important host defence mechanism against pathogens is intracellular killing, which is achieved through phagocytosis, a cellular process for engulfing and neutralizing extracellular particles. Phagocytosis results in the formation of matured phagolysosomes, which are specialized compartments that provide a hostile environment and are considered the end point of the degradative pathway. However, all fungal pathogens studied to date have developed strategies to manipulate phagosomal function directly and also indirectly by redirecting phagosomes from the degradative pathway to a non-degradative pathway with the expulsion and even transfer of pathogens between cells. Here, using the major human fungal pathogens Aspergillus fumigatus, Candida albicans, Cryptococcus neoformans and Histoplasma capsulatum as examples, we discuss the processes involved in host phagosome–fungal pathogen interactions, with a focus on fungal evasion strategies. We also discuss recent approaches to targeting intraphagosomal pathogens, including the redirection of phagosomes towards degradative pathways for fungal pathogen eradication. In this Review, the authors discuss fungal pathogen–host interactions with a focus on phagocytosis and intracellular processing of pathogens within phagosomes. They also outline potential therapeutic approaches for targeting intraphagosomal pathogens.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"9 9","pages":"2216-2231"},"PeriodicalIF":20.5,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142073306","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}
Pub Date : 2024-08-23DOI: 10.1038/s41564-024-01786-8
Jacob Class, Lacy M. Simons, Ramon Lorenzo-Redondo, Jazmin Galván Achi, Laura Cooper, Tanushree Dangi, Pablo Penaloza-MacMaster, Egon A. Ozer, Sarah E. Lutz, Lijun Rong, Judd F. Hultquist, Justin M. Richner
Severe coronavirus disease 2019 and post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are associated with neurological complications that may be linked to direct infection of the central nervous system (CNS), but the selective pressures ruling neuroinvasion are poorly defined. Here we assessed SARS-CoV-2 evolution in the lung versus CNS of infected mice. Higher levels of viral divergence were observed in the CNS than the lung after intranasal challenge with a high frequency of mutations in the spike furin cleavage site (FCS). Deletion of the FCS significantly attenuated virulence after intranasal challenge, with lower viral titres and decreased morbidity compared with the wild-type virus. Intracranial inoculation of the FCS-deleted virus, however, was sufficient to restore virulence. After intracranial inoculation, both viruses established infection in the lung, but dissemination from the CNS to the lung required the intact FCS. Cumulatively, these data suggest a critical role for the FCS in determining SARS-CoV-2 tropism and compartmentalization. SARS-CoV-2 replication in the murine lung requires the spike furin cleavage site, which is then lost during divergence in the brain.
{"title":"Evolution of SARS-CoV-2 in the murine central nervous system drives viral diversification","authors":"Jacob Class, Lacy M. Simons, Ramon Lorenzo-Redondo, Jazmin Galván Achi, Laura Cooper, Tanushree Dangi, Pablo Penaloza-MacMaster, Egon A. Ozer, Sarah E. Lutz, Lijun Rong, Judd F. Hultquist, Justin M. Richner","doi":"10.1038/s41564-024-01786-8","DOIUrl":"10.1038/s41564-024-01786-8","url":null,"abstract":"Severe coronavirus disease 2019 and post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are associated with neurological complications that may be linked to direct infection of the central nervous system (CNS), but the selective pressures ruling neuroinvasion are poorly defined. Here we assessed SARS-CoV-2 evolution in the lung versus CNS of infected mice. Higher levels of viral divergence were observed in the CNS than the lung after intranasal challenge with a high frequency of mutations in the spike furin cleavage site (FCS). Deletion of the FCS significantly attenuated virulence after intranasal challenge, with lower viral titres and decreased morbidity compared with the wild-type virus. Intracranial inoculation of the FCS-deleted virus, however, was sufficient to restore virulence. After intracranial inoculation, both viruses established infection in the lung, but dissemination from the CNS to the lung required the intact FCS. Cumulatively, these data suggest a critical role for the FCS in determining SARS-CoV-2 tropism and compartmentalization. SARS-CoV-2 replication in the murine lung requires the spike furin cleavage site, which is then lost during divergence in the brain.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"9 9","pages":"2383-2394"},"PeriodicalIF":20.5,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142042608","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}
Pub Date : 2024-08-22DOI: 10.1038/s41564-024-01777-9
Edward B. Irvine, Angel Nikolov, Mehak Z. Khan, Joshua M. Peters, Richard Lu, Jaimie Sixsmith, Aaron Wallace, Esther van Woudenbergh, Sally Shin, Wiktor Karpinski, Jeff C. Hsiao, Arturo Casadevall, Bryan D. Bryson, Lisa Cavacini, Patricia S. Grace, Galit Alter, Sarah M. Fortune
Mounting evidence indicates that antibodies can contribute towards control of tuberculosis (TB). However, the underlying mechanisms of humoral immune protection and whether antibodies can be exploited in therapeutic strategies to combat TB are relatively understudied. Here we engineered the receptor-binding Fc (fragment crystallizable) region of an antibody recognizing the Mycobacterium tuberculosis (Mtb) capsule, to define antibody Fc-mediated mechanism(s) of Mtb restriction. We generated 52 Fc variants that either promote or inhibit specific antibody effector functions, rationally building antibodies with enhanced capacity to promote Mtb restriction in a human whole-blood model of infection. While there is likely no singular Fc profile that universally drives control of Mtb, here we found that several Fc-engineered antibodies drove Mtb restriction in a neutrophil-dependent manner. Single-cell RNA sequencing analysis showed that a restrictive Fc-engineered antibody promoted neutrophil survival and expression of cell-intrinsic antimicrobial programs. These data show the potential of Fc-engineered antibodies as therapeutics able to harness the protective functions of neutrophils to promote control of TB. Fc engineering of a capsule-specific antibody identifies Fc variants which augment effector function and promote neutrophil-dependent control of Mycobacterium tuberculosis.
越来越多的证据表明，抗体有助于控制结核病（TB）。然而，人们对体液免疫保护的基本机制以及抗体是否可用于结核病治疗策略的研究相对不足。在这里，我们设计了一种能识别结核分枝杆菌（Mtb）包囊的抗体的受体结合 Fc（可结晶片段）区域，以确定抗体 Fc 介导的 Mtb 限制机制。我们生成了 52 个 Fc 变体，它们可以促进或抑制特定的抗体效应器功能，从而在人类全血感染模型中合理地构建了具有更强抑制 Mtb 能力的抗体。虽然很可能没有一种单一的 Fc 配置文件能普遍驱动对 Mtb 的控制，但我们在这里发现，几种 Fc 工程抗体能以中性粒细胞依赖的方式驱动 Mtb 限制。单细胞 RNA 测序分析表明，一种限制性 Fc 工程抗体能促进中性粒细胞的存活和细胞内在抗微生物程序的表达。这些数据显示了 Fc 工程抗体作为治疗药物的潜力，它能够利用中性粒细胞的保护功能来促进结核病的控制。
{"title":"Fc-engineered antibodies promote neutrophil-dependent control of Mycobacterium tuberculosis","authors":"Edward B. Irvine, Angel Nikolov, Mehak Z. Khan, Joshua M. Peters, Richard Lu, Jaimie Sixsmith, Aaron Wallace, Esther van Woudenbergh, Sally Shin, Wiktor Karpinski, Jeff C. Hsiao, Arturo Casadevall, Bryan D. Bryson, Lisa Cavacini, Patricia S. Grace, Galit Alter, Sarah M. Fortune","doi":"10.1038/s41564-024-01777-9","DOIUrl":"10.1038/s41564-024-01777-9","url":null,"abstract":"Mounting evidence indicates that antibodies can contribute towards control of tuberculosis (TB). However, the underlying mechanisms of humoral immune protection and whether antibodies can be exploited in therapeutic strategies to combat TB are relatively understudied. Here we engineered the receptor-binding Fc (fragment crystallizable) region of an antibody recognizing the Mycobacterium tuberculosis (Mtb) capsule, to define antibody Fc-mediated mechanism(s) of Mtb restriction. We generated 52 Fc variants that either promote or inhibit specific antibody effector functions, rationally building antibodies with enhanced capacity to promote Mtb restriction in a human whole-blood model of infection. While there is likely no singular Fc profile that universally drives control of Mtb, here we found that several Fc-engineered antibodies drove Mtb restriction in a neutrophil-dependent manner. Single-cell RNA sequencing analysis showed that a restrictive Fc-engineered antibody promoted neutrophil survival and expression of cell-intrinsic antimicrobial programs. These data show the potential of Fc-engineered antibodies as therapeutics able to harness the protective functions of neutrophils to promote control of TB. Fc engineering of a capsule-specific antibody identifies Fc variants which augment effector function and promote neutrophil-dependent control of Mycobacterium tuberculosis.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"9 9","pages":"2369-2382"},"PeriodicalIF":20.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41564-024-01777-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142022070","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}
Fusobacterium nucleatum can bind to host cells and potentiate intestinal tumorigenesis. Here we used a genome-wide screen to identify an adhesin, RadD, which facilitates the attachment of F. nucleatum to colorectal cancer (CRC) cells in vitro. RadD directly binds to CD147, a receptor overexpressed on CRC cell surfaces, which initiated a PI3K–AKT–NF–κB–MMP9 cascade, subsequently enhancing tumorigenesis in mice. Clinical specimen analysis showed that elevated radD gene levels in CRC tissues correlated positively with activated oncogenic signalling and poor patient outcomes. Finally, blockade of the interaction between RadD and CD147 in mice effectively impaired F. nucleatum attachment and attenuated F. nucleatum-induced oncogenic response. Together, our study provides insights into an oncogenic mechanism driven by F. nucleatum RadD and suggests that the RadD–CD147 interaction could be a potential therapeutic target for CRC. The bacterial adhesin, RadD, enhances the ability of Fusobacterium nucleatum to interact with colorectal cancer cells and promote tumour development in mice.
核叉杆菌能与宿主细胞结合并促进肠道肿瘤发生。在这里，我们利用全基因组筛选确定了一种粘附素 RadD，它能在体外促进 F. nucleatum 与结直肠癌（CRC）细胞的粘附。RadD直接与CD147结合，CD147是一种在CRC细胞表面过度表达的受体，它启动了PI3K-AKT-NF-κB-MMP9级联反应，随后增强了小鼠的肿瘤发生。临床标本分析表明，CRC 组织中 radD 基因水平的升高与激活的致癌信号和患者的不良预后呈正相关。最后，在小鼠体内阻断 RadD 与 CD147 之间的相互作用可有效抑制 F. nucleatum 的附着并减轻 F. nucleatum 诱导的致癌反应。总之，我们的研究深入揭示了由F. nucleatum RadD驱动的致癌机制，并表明RadD与CD147的相互作用可能是治疗CRC的潜在靶点。
{"title":"The adhesin RadD enhances Fusobacterium nucleatum tumour colonization and colorectal carcinogenesis","authors":"Lu Zhang, Xiao-Xu Leng, Jianxun Qi, Ni Wang, Ji-Xuan Han, Zhi-Hang Tao, Zi-Yan Zhuang, Yimeng Ren, Yi-Le Xie, Shan-Shan Jiang, Jia-Lu Li, Huimin Chen, Cheng-Bei Zhou, Yun Cui, Xiaoyu Chen, Zheng Wang, Zi-Zhen Zhang, Jie Hong, Hao-Yan Chen, Weihong Jiang, Ying-Xuan Chen, Xin Zhao, Jun Yu, Jing-Yuan Fang","doi":"10.1038/s41564-024-01784-w","DOIUrl":"10.1038/s41564-024-01784-w","url":null,"abstract":"Fusobacterium nucleatum can bind to host cells and potentiate intestinal tumorigenesis. Here we used a genome-wide screen to identify an adhesin, RadD, which facilitates the attachment of F. nucleatum to colorectal cancer (CRC) cells in vitro. RadD directly binds to CD147, a receptor overexpressed on CRC cell surfaces, which initiated a PI3K–AKT–NF–κB–MMP9 cascade, subsequently enhancing tumorigenesis in mice. Clinical specimen analysis showed that elevated radD gene levels in CRC tissues correlated positively with activated oncogenic signalling and poor patient outcomes. Finally, blockade of the interaction between RadD and CD147 in mice effectively impaired F. nucleatum attachment and attenuated F. nucleatum-induced oncogenic response. Together, our study provides insights into an oncogenic mechanism driven by F. nucleatum RadD and suggests that the RadD–CD147 interaction could be a potential therapeutic target for CRC. The bacterial adhesin, RadD, enhances the ability of Fusobacterium nucleatum to interact with colorectal cancer cells and promote tumour development in mice.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"9 9","pages":"2292-2307"},"PeriodicalIF":20.5,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142013802","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}
Pub Date : 2024-08-21DOI: 10.1038/s41564-024-01787-7
W. Robert Shaw, Flaminia Catteruccia
A metabolomics approach to study microbe–tick interactions reveals that host β-aminoisobutyric acid contributes both to tick fitness and bacterial infection.
{"title":"Bacteria induce metabolic perturbations in ticks","authors":"W. Robert Shaw, Flaminia Catteruccia","doi":"10.1038/s41564-024-01787-7","DOIUrl":"10.1038/s41564-024-01787-7","url":null,"abstract":"A metabolomics approach to study microbe–tick interactions reveals that host β-aminoisobutyric acid contributes both to tick fitness and bacterial infection.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"9 9","pages":"2206-2207"},"PeriodicalIF":20.5,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142013803","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}
Pub Date : 2024-08-20DOI: 10.1038/s41564-024-01778-8
Yaohui Sun, Fernando Ferreira, Brian Reid, Kan Zhu, Li Ma, Briana M. Young, Catherine E. Hagan, Renée M. Tsolis, Alex Mogilner, Min Zhao
Salmonella translocate to the gut epithelium via microfold cells lining the follicle-associated epithelium (FAE). How Salmonella localize to the FAE is not well characterized. Here we use live imaging and competitive assays between wild-type and chemotaxis-deficient mutants to show that Salmonella enterica serotype Typhimurium (S. Typhimurium) localize to the FAE independently of chemotaxis in an ex vivo mouse caecum infection model. Electrical recordings revealed polarized FAE with sustained outward current and small transepithelial potential, while the surrounding villus is depolarized with inward current and large transepithelial potential. The distinct electrical potentials attracted S. Typhimurium to the FAE while Escherichia coli (E. coli) localized to the villi, through a process called galvanotaxis. Chloride flux involving the cystic fibrosis transmembrane conductance regulator (CFTR) generated the ionic currents around the FAE. Pharmacological inhibition of CFTR decreased S. Typhimurium FAE localization but increased E. coli recruitment. Altogether, our findings demonstrate that bioelectric cues contribute to S. Typhimurium targeting of specific gut epithelial locations, with potential implications for other enteric bacterial infections. Gut epithelium generated electrical potentials drive differential localization of enterobacteria, promoting Salmonella tropism for the follicle-associated epithelium while Escherichia coli localize to villi.
{"title":"Gut epithelial electrical cues drive differential localization of enterobacteria","authors":"Yaohui Sun, Fernando Ferreira, Brian Reid, Kan Zhu, Li Ma, Briana M. Young, Catherine E. Hagan, Renée M. Tsolis, Alex Mogilner, Min Zhao","doi":"10.1038/s41564-024-01778-8","DOIUrl":"10.1038/s41564-024-01778-8","url":null,"abstract":"Salmonella translocate to the gut epithelium via microfold cells lining the follicle-associated epithelium (FAE). How Salmonella localize to the FAE is not well characterized. Here we use live imaging and competitive assays between wild-type and chemotaxis-deficient mutants to show that Salmonella enterica serotype Typhimurium (S. Typhimurium) localize to the FAE independently of chemotaxis in an ex vivo mouse caecum infection model. Electrical recordings revealed polarized FAE with sustained outward current and small transepithelial potential, while the surrounding villus is depolarized with inward current and large transepithelial potential. The distinct electrical potentials attracted S. Typhimurium to the FAE while Escherichia coli (E. coli) localized to the villi, through a process called galvanotaxis. Chloride flux involving the cystic fibrosis transmembrane conductance regulator (CFTR) generated the ionic currents around the FAE. Pharmacological inhibition of CFTR decreased S. Typhimurium FAE localization but increased E. coli recruitment. Altogether, our findings demonstrate that bioelectric cues contribute to S. Typhimurium targeting of specific gut epithelial locations, with potential implications for other enteric bacterial infections. Gut epithelium generated electrical potentials drive differential localization of enterobacteria, promoting Salmonella tropism for the follicle-associated epithelium while Escherichia coli localize to villi.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"9 10","pages":"2653-2665"},"PeriodicalIF":20.5,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41564-024-01778-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142007376","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}
Pub Date : 2024-08-19DOI: 10.1038/s41564-024-01775-x
Yassine Cherrak, Miguel Angel Salazar, Nicolas Näpflin, Lukas Malfertheiner, Mathias K.-M. Herzog, Christopher Schubert, Christian von Mering, Wolf-Dietrich Hardt
Resource competition is a driver of gut microbiota composition. Bacteria can outcompete metabolically similar rivals through the limitation of shared growth-fuelling nutrients. The mechanisms underlying this remain unclear for bacteria with identical sets of metabolic genes. Here we analysed the lactose utilization operon in the murine commensal Escherichia coli 8178. Using in vitro and in vivo approaches, we showed that translation of the lactose utilization repressor gene lacI from its native non-canonical GTG start codon increases the basal expression of the lactose utilization cluster, enhancing adaptation to lactose consumption. Consequently, a strain carrying the wild type lacI GTG start codon outperformed the lacI ATG start codon mutant in the mouse intestine. This advantage was attenuated upon limiting host lactose intake through diet shift or altering the mutant frequency, emphasizing the context-dependent effect of a single nucleotide change on the bacterial fitness of a common member of the gut microbiota. Coupled with a genomic analysis highlighting the selection of non-ATG start codons in sugar utilization regulator genes across the Enterobacteriaceae family, our data exposed an unsuspected function of non-canonical start codons in metabolic competition. Non-canonical start codons promote carbohydrate exploitation and faster metabolic adaptation, conferring growth advantages to commensal Escherichia coli in the mouse gut.
{"title":"Non-canonical start codons confer context-dependent advantages in carbohydrate utilization for commensal E. coli in the murine gut","authors":"Yassine Cherrak, Miguel Angel Salazar, Nicolas Näpflin, Lukas Malfertheiner, Mathias K.-M. Herzog, Christopher Schubert, Christian von Mering, Wolf-Dietrich Hardt","doi":"10.1038/s41564-024-01775-x","DOIUrl":"10.1038/s41564-024-01775-x","url":null,"abstract":"Resource competition is a driver of gut microbiota composition. Bacteria can outcompete metabolically similar rivals through the limitation of shared growth-fuelling nutrients. The mechanisms underlying this remain unclear for bacteria with identical sets of metabolic genes. Here we analysed the lactose utilization operon in the murine commensal Escherichia coli 8178. Using in vitro and in vivo approaches, we showed that translation of the lactose utilization repressor gene lacI from its native non-canonical GTG start codon increases the basal expression of the lactose utilization cluster, enhancing adaptation to lactose consumption. Consequently, a strain carrying the wild type lacI GTG start codon outperformed the lacI ATG start codon mutant in the mouse intestine. This advantage was attenuated upon limiting host lactose intake through diet shift or altering the mutant frequency, emphasizing the context-dependent effect of a single nucleotide change on the bacterial fitness of a common member of the gut microbiota. Coupled with a genomic analysis highlighting the selection of non-ATG start codons in sugar utilization regulator genes across the Enterobacteriaceae family, our data exposed an unsuspected function of non-canonical start codons in metabolic competition. Non-canonical start codons promote carbohydrate exploitation and faster metabolic adaptation, conferring growth advantages to commensal Escherichia coli in the mouse gut.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"9 10","pages":"2696-2709"},"PeriodicalIF":20.5,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41564-024-01775-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142002821","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}
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