Pub Date : 2024-09-18DOI: 10.1038/s41564-024-01807-6
Yushan Xia, Xueying Wei, Peng Gao, Chenyuan Wang, Anne de Jong, Jonathan Hon Kwan Chen, María José Rodríguez-Sánchez, Alba Rodríguez-Nogales, Patricia Diez-Echave, Julio Gálvez, Federico García, Weihui Wu, Richard Yi-Tsun Kao, Hongyan Li, Rubén Cebrián, Oscar P. Kuipers, Hongzhe Sun
Pseudomonas aeruginosa infections are difficult to treat due to rapid development of antibiotic drug resistance. The synergistic combination of already-in-use drugs is an alternative to developing new antibiotics to combat antibiotic-resistant bacteria. Here we demonstrate that bismuth-based drugs (bismuth subsalicylate, colloidal bismuth subcitrate) in combination with different classes of antibiotics (tetracyclines, macrolides, quinolones, rifamycins and so on) can eliminate multidrug-resistant P. aeruginosa and do not induce development of antibiotic resistance. Bismuth disrupts iron homeostasis by binding to P. aeruginosa siderophores. Inside cells, bismuth inhibits the electron transport chain, dissipates the proton motive force and impairs efflux pump activity by disrupting iron–sulfur cluster-containing enzymes, including respiration complexes. As a result, bismuth facilitates antibiotic accumulation inside bacteria, enhancing their efficacy. The combination therapy shows potent antibacterial efficacy and low toxicity in an ex vivo bacteraemia model and increases the survival rate of mice in in vivo mouse lung-infection models. Our findings highlight the potential of bismuth-based drugs to be repurposed to combat P. aeruginosa infections in combination with clinically used antibiotics. Bismuth-based drugs combined with antibiotics enhance efficacy against multidrug-resistant Pseudomonas aeruginosa by disrupting bacterial iron homeostasis and electron transport.
{"title":"Bismuth-based drugs sensitize Pseudomonas aeruginosa to multiple antibiotics by disrupting iron homeostasis","authors":"Yushan Xia, Xueying Wei, Peng Gao, Chenyuan Wang, Anne de Jong, Jonathan Hon Kwan Chen, María José Rodríguez-Sánchez, Alba Rodríguez-Nogales, Patricia Diez-Echave, Julio Gálvez, Federico García, Weihui Wu, Richard Yi-Tsun Kao, Hongyan Li, Rubén Cebrián, Oscar P. Kuipers, Hongzhe Sun","doi":"10.1038/s41564-024-01807-6","DOIUrl":"10.1038/s41564-024-01807-6","url":null,"abstract":"Pseudomonas aeruginosa infections are difficult to treat due to rapid development of antibiotic drug resistance. The synergistic combination of already-in-use drugs is an alternative to developing new antibiotics to combat antibiotic-resistant bacteria. Here we demonstrate that bismuth-based drugs (bismuth subsalicylate, colloidal bismuth subcitrate) in combination with different classes of antibiotics (tetracyclines, macrolides, quinolones, rifamycins and so on) can eliminate multidrug-resistant P. aeruginosa and do not induce development of antibiotic resistance. Bismuth disrupts iron homeostasis by binding to P. aeruginosa siderophores. Inside cells, bismuth inhibits the electron transport chain, dissipates the proton motive force and impairs efflux pump activity by disrupting iron–sulfur cluster-containing enzymes, including respiration complexes. As a result, bismuth facilitates antibiotic accumulation inside bacteria, enhancing their efficacy. The combination therapy shows potent antibacterial efficacy and low toxicity in an ex vivo bacteraemia model and increases the survival rate of mice in in vivo mouse lung-infection models. Our findings highlight the potential of bismuth-based drugs to be repurposed to combat P. aeruginosa infections in combination with clinically used antibiotics. Bismuth-based drugs combined with antibiotics enhance efficacy against multidrug-resistant Pseudomonas aeruginosa by disrupting bacterial iron homeostasis and electron transport.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"9 10","pages":"2600-2613"},"PeriodicalIF":20.5,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236274","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 : 2024-09-18DOI: 10.1038/s41564-024-01801-y
Xiaojie Zheng, Yunfa Zhang, Lingyu Zhang, Tong Yang, Faxue Zhang, Xi Wang, Shu Jeffrey Zhu, Ning Cui, Hongdi Lv, Xiaoai Zhang, Hao Li, Wei Liu
Bile acids are microbial metabolites that can impact infection of enteric and hepatitis viruses, but their functions during systemic viral infection remain unclear. Here we show that elevated levels of the secondary bile acid taurolithocholic acid (TLCA) are associated with reduced fatality rates and suppressed viraemia in patients infected with severe fever with thrombocytopenia syndrome virus (SFTSV), an emerging tick-borne haemorrhagic fever virus. TLCA inhibits viral replication and mitigates host inflammation during SFTSV infection in vitro, and indirectly suppresses SFTSV-mediated induction of ferroptosis by upregulating fatty acid desaturase 2 via the TGR5–PI3K/AKT–SREBP2 axis. High iron and ferritin serum levels during early infection were correlated with decreased TLCA levels and fatal outcomes in SFTSV-infected patients, indicating potential biomarkers. Furthermore, treatment with either ferroptosis inhibitors or TLCA protected mice from lethal SFTSV infection. Our findings highlight the therapeutic potential of bile acids to treat haemorrhagic fever viral infection. A microbially derived bile acid, taurolithocholic acid, limits viral replication, host inflammation and ferroptosis during infection with severe fever with thrombocytopenia syndrome virus, an emerging tick-borne haemorrhagic fever virus.
{"title":"Taurolithocholic acid protects against viral haemorrhagic fever via inhibition of ferroptosis","authors":"Xiaojie Zheng, Yunfa Zhang, Lingyu Zhang, Tong Yang, Faxue Zhang, Xi Wang, Shu Jeffrey Zhu, Ning Cui, Hongdi Lv, Xiaoai Zhang, Hao Li, Wei Liu","doi":"10.1038/s41564-024-01801-y","DOIUrl":"10.1038/s41564-024-01801-y","url":null,"abstract":"Bile acids are microbial metabolites that can impact infection of enteric and hepatitis viruses, but their functions during systemic viral infection remain unclear. Here we show that elevated levels of the secondary bile acid taurolithocholic acid (TLCA) are associated with reduced fatality rates and suppressed viraemia in patients infected with severe fever with thrombocytopenia syndrome virus (SFTSV), an emerging tick-borne haemorrhagic fever virus. TLCA inhibits viral replication and mitigates host inflammation during SFTSV infection in vitro, and indirectly suppresses SFTSV-mediated induction of ferroptosis by upregulating fatty acid desaturase 2 via the TGR5–PI3K/AKT–SREBP2 axis. High iron and ferritin serum levels during early infection were correlated with decreased TLCA levels and fatal outcomes in SFTSV-infected patients, indicating potential biomarkers. Furthermore, treatment with either ferroptosis inhibitors or TLCA protected mice from lethal SFTSV infection. Our findings highlight the therapeutic potential of bile acids to treat haemorrhagic fever viral infection. A microbially derived bile acid, taurolithocholic acid, limits viral replication, host inflammation and ferroptosis during infection with severe fever with thrombocytopenia syndrome virus, an emerging tick-borne haemorrhagic fever virus.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"9 10","pages":"2583-2599"},"PeriodicalIF":20.5,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236277","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 : 2024-09-18DOI: 10.1038/s41564-024-01817-4
Elodie Ghedin, Megan R. Hockman
Sequencing data reveal highly diverse viromes associated with clinically important parasitic nematodes. Serological data suggest that this ongoing relationship could impact disease.
{"title":"The host–parasite–virus triad","authors":"Elodie Ghedin, Megan R. Hockman","doi":"10.1038/s41564-024-01817-4","DOIUrl":"10.1038/s41564-024-01817-4","url":null,"abstract":"Sequencing data reveal highly diverse viromes associated with clinically important parasitic nematodes. Serological data suggest that this ongoing relationship could impact disease.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"9 10","pages":"2473-2474"},"PeriodicalIF":20.5,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236273","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 : 2024-09-18DOI: 10.1038/s41564-024-01791-x
Ian R. Humphreys, Jing Zhang, Minkyung Baek, Yaxi Wang, Aditya Krishnakumar, Jimin Pei, Ivan Anishchenko, Catherine A. Tower, Blake A. Jackson, Thulasi Warrier, Deborah T. Hung, S. Brook Peterson, Joseph D. Mougous, Qian Cong, David Baker
Identification of bacterial protein–protein interactions and predicting the structures of these complexes could aid in the understanding of pathogenicity mechanisms and developing treatments for infectious diseases. Here we developed RoseTTAFold2-Lite, a rapid deep learning model that leverages residue–residue coevolution and protein structure prediction to systematically identify and structurally characterize protein–protein interactions at the proteome-wide scale. Using this pipeline, we searched through 78 million pairs of proteins across 19 human bacterial pathogens and identified 1,923 confidently predicted complexes involving essential genes and 256 involving virulence factors. Many of these complexes were not previously known; we experimentally tested 12 such predictions, and half of them were validated. The predicted interactions span core metabolic and virulence pathways ranging from post-transcriptional modification to acid neutralization to outer-membrane machinery and should contribute to our understanding of the biology of these important pathogens and the design of drugs to combat them. RoseTTAFold2-Lite uses residue–residue coevolution and protein structure prediction to identify and structurally characterize protein–protein interactions in bacterial pathogens.
{"title":"Protein interactions in human pathogens revealed through deep learning","authors":"Ian R. Humphreys, Jing Zhang, Minkyung Baek, Yaxi Wang, Aditya Krishnakumar, Jimin Pei, Ivan Anishchenko, Catherine A. Tower, Blake A. Jackson, Thulasi Warrier, Deborah T. Hung, S. Brook Peterson, Joseph D. Mougous, Qian Cong, David Baker","doi":"10.1038/s41564-024-01791-x","DOIUrl":"10.1038/s41564-024-01791-x","url":null,"abstract":"Identification of bacterial protein–protein interactions and predicting the structures of these complexes could aid in the understanding of pathogenicity mechanisms and developing treatments for infectious diseases. Here we developed RoseTTAFold2-Lite, a rapid deep learning model that leverages residue–residue coevolution and protein structure prediction to systematically identify and structurally characterize protein–protein interactions at the proteome-wide scale. Using this pipeline, we searched through 78 million pairs of proteins across 19 human bacterial pathogens and identified 1,923 confidently predicted complexes involving essential genes and 256 involving virulence factors. Many of these complexes were not previously known; we experimentally tested 12 such predictions, and half of them were validated. The predicted interactions span core metabolic and virulence pathways ranging from post-transcriptional modification to acid neutralization to outer-membrane machinery and should contribute to our understanding of the biology of these important pathogens and the design of drugs to combat them. RoseTTAFold2-Lite uses residue–residue coevolution and protein structure prediction to identify and structurally characterize protein–protein interactions in bacterial pathogens.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"9 10","pages":"2642-2652"},"PeriodicalIF":20.5,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41564-024-01791-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236275","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 : 2024-09-17DOI: 10.1038/s41564-024-01816-5
Julia Prigann, Rubens Tavora, Robert L. Furler O’Brien, Ursula Schulze-Gahmen, Daniela Boehm, Nadia R. Roan, Douglas F. Nixon, Lishomwa C. Ndhlovu, Susana Valente, Melanie Ott
Persistence of the transcriptionally active HIV reservoir has important implications for people living with HIV, including chronic immune activation and inflammation. Supplementing antiretroviral therapy with transcriptional inhibitors could overcome this by silencing the transcriptionally active HIV reservoir.
{"title":"Silencing the transcriptionally active HIV reservoir to improve treatment outcomes","authors":"Julia Prigann, Rubens Tavora, Robert L. Furler O’Brien, Ursula Schulze-Gahmen, Daniela Boehm, Nadia R. Roan, Douglas F. Nixon, Lishomwa C. Ndhlovu, Susana Valente, Melanie Ott","doi":"10.1038/s41564-024-01816-5","DOIUrl":"10.1038/s41564-024-01816-5","url":null,"abstract":"Persistence of the transcriptionally active HIV reservoir has important implications for people living with HIV, including chronic immune activation and inflammation. Supplementing antiretroviral therapy with transcriptional inhibitors could overcome this by silencing the transcriptionally active HIV reservoir.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"9 10","pages":"2470-2472"},"PeriodicalIF":20.5,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142235100","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 : 2024-09-17DOI: 10.1038/s41564-024-01815-6
Julie Chih-yu Chen
Julie Chih-yu Chen is the head of Data Sciences at the National Microbiology Laboratory, Public Health Agency of Canada, and an Assistant Professor at the University of Manitoba, Canada. She develops and applies statistical and machine learning techniques to diverse omics data related to infectious disease.
{"title":"Lessons from a data scientist during COVID-19","authors":"Julie Chih-yu Chen","doi":"10.1038/s41564-024-01815-6","DOIUrl":"10.1038/s41564-024-01815-6","url":null,"abstract":"Julie Chih-yu Chen is the head of Data Sciences at the National Microbiology Laboratory, Public Health Agency of Canada, and an Assistant Professor at the University of Manitoba, Canada. She develops and applies statistical and machine learning techniques to diverse omics data related to infectious disease.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"9 10","pages":"2466-2467"},"PeriodicalIF":20.5,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142235099","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 : 2024-09-17DOI: 10.1038/s41564-024-01814-7
Thomas C. Mettenleiter
Thomas Mettenleiter was president of the Friedrich-Loeffler-Institut for 27 years and retired in June 2023. Looking back, he reflects on events around and following the reunification of Germany that changed his career path.
{"title":"A ‘Wende’ for virology in Germany","authors":"Thomas C. Mettenleiter","doi":"10.1038/s41564-024-01814-7","DOIUrl":"10.1038/s41564-024-01814-7","url":null,"abstract":"Thomas Mettenleiter was president of the Friedrich-Loeffler-Institut for 27 years and retired in June 2023. Looking back, he reflects on events around and following the reunification of Germany that changed his career path.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"9 10","pages":"2468-2469"},"PeriodicalIF":20.5,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142235098","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 : 2024-09-16DOI: 10.1038/s41564-024-01794-8
Jianfeng Lin, Jian Miao, Katherine G. Schaefer, Charles M. Russell, Robert J. Pyron, Fuming Zhang, Quynh T. Phan, Norma V. Solis, Hong Liu, Masato Tashiro, Jonathan S. Dordick, Robert J. Linhardt, Michael R. Yeaman, Gavin M. King, Francisco N. Barrera, Brian M. Peters, Scott G. Filler
Candidalysin, a cytolytic peptide produced by the fungal pathogen Candida albicans, is a key virulence factor. However, its host cell targets remain elusive. Here we performed a genome-wide loss-of-function CRISPR screen in the TR146 human oral epithelial cell line and identified that disruption of genes (XYLT2, B3GALT6 and B3GAT3) in glycosaminoglycan (GAG) biosynthesis conferred resistance to damage induced by candidalysin and live C. albicans. Surface plasmon resonance and atomic force and electron microscopy indicated that candidalysin binds to sulfated GAGs, facilitating its enrichment on the host cell surface. Adding exogenous sulfated GAGs or the analogue dextran sulfate protected cells against candidalysin-induced damage. Dextran sulfate also inhibited C. albicans invasion and fungal-induced epithelial cell cytokine production. In mice with vulvovaginal candidiasis, topical dextran sulfate administration reduced intravaginal tissue damage and inflammation. Collectively, sulfated GAGs are epithelial cell targets of candidalysin and can be used therapeutically to protect cells from candidalysin-induced damage. Sulfated glycosaminoglycans are host cell targets of candidalysin, a cytolytic toxin of the fungal pathogen Candida albicans.
{"title":"Sulfated glycosaminoglycans are host epithelial cell targets of the Candida albicans toxin candidalysin","authors":"Jianfeng Lin, Jian Miao, Katherine G. Schaefer, Charles M. Russell, Robert J. Pyron, Fuming Zhang, Quynh T. Phan, Norma V. Solis, Hong Liu, Masato Tashiro, Jonathan S. Dordick, Robert J. Linhardt, Michael R. Yeaman, Gavin M. King, Francisco N. Barrera, Brian M. Peters, Scott G. Filler","doi":"10.1038/s41564-024-01794-8","DOIUrl":"10.1038/s41564-024-01794-8","url":null,"abstract":"Candidalysin, a cytolytic peptide produced by the fungal pathogen Candida albicans, is a key virulence factor. However, its host cell targets remain elusive. Here we performed a genome-wide loss-of-function CRISPR screen in the TR146 human oral epithelial cell line and identified that disruption of genes (XYLT2, B3GALT6 and B3GAT3) in glycosaminoglycan (GAG) biosynthesis conferred resistance to damage induced by candidalysin and live C. albicans. Surface plasmon resonance and atomic force and electron microscopy indicated that candidalysin binds to sulfated GAGs, facilitating its enrichment on the host cell surface. Adding exogenous sulfated GAGs or the analogue dextran sulfate protected cells against candidalysin-induced damage. Dextran sulfate also inhibited C. albicans invasion and fungal-induced epithelial cell cytokine production. In mice with vulvovaginal candidiasis, topical dextran sulfate administration reduced intravaginal tissue damage and inflammation. Collectively, sulfated GAGs are epithelial cell targets of candidalysin and can be used therapeutically to protect cells from candidalysin-induced damage. Sulfated glycosaminoglycans are host cell targets of candidalysin, a cytolytic toxin of the fungal pathogen Candida albicans.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"9 10","pages":"2553-2569"},"PeriodicalIF":20.5,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142234449","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 : 2024-09-11DOI: 10.1038/s41564-024-01802-x
Man Ting Au, Junguo Ni, Kaiming Tang, Wei Wang, Lanlan Zhang, Hantang Wang, Fangyi Zhao, Zhan Li, Peng Luo, Lawrence Chun-Man Lau, Ping-Keung Chan, Cuiting Luo, Bo Zhou, Lin Zhu, Charlie Yuli Zhang, Tianshu Jiang, Marianne Lauwers, Jasper Fuk-Woo Chan, Shuofeng Yuan, Chunyi Wen
Joint pain and osteoarthritis can occur as coronavirus disease 2019 (COVID-19) sequelae after infection. However, little is known about the damage to articular cartilage. Here we illustrate knee joint damage after wild-type, Delta and Omicron variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in vivo. Rapid joint injury with cystic lesions at the osteochondral junction was observed in two patients with post-COVID osteoarthritis and recapitulated in a golden Syrian hamster model. SARS-CoV-2-activated endothelin-1 signalling increased vascular permeability and caused viral spike proteins leakage into the subchondral bone. Osteoclast activation, chondrocyte dropout and cyst formation were confirmed histologically. The US Food and Drug Administration-approved endothelin receptor antagonist, macitentan, mitigated cystic lesions and preserved chondrocyte number in the acute phase of viral infection in hamsters. Delayed macitentan treatment at post-acute infection phase alleviated chondrocyte senescence and restored subchondral bone loss. It is worth noting that it could also attenuate viral spike-induced joint pain. Our work suggests endothelin receptor blockade as a novel therapeutic strategy for post-COVID arthritis. Endothelin-1 activation after SARS-CoV-2 infection leads to vascular permeability, chondrocyte senescence, osteoclast activation and cyst formation in affected joints of hamsters, which can be alleviated using macitentan. Joint injury was also seen in two patients after COVID-19 infection.
{"title":"Blockade of endothelin receptors mitigates SARS-CoV-2-induced osteoarthritis","authors":"Man Ting Au, Junguo Ni, Kaiming Tang, Wei Wang, Lanlan Zhang, Hantang Wang, Fangyi Zhao, Zhan Li, Peng Luo, Lawrence Chun-Man Lau, Ping-Keung Chan, Cuiting Luo, Bo Zhou, Lin Zhu, Charlie Yuli Zhang, Tianshu Jiang, Marianne Lauwers, Jasper Fuk-Woo Chan, Shuofeng Yuan, Chunyi Wen","doi":"10.1038/s41564-024-01802-x","DOIUrl":"10.1038/s41564-024-01802-x","url":null,"abstract":"Joint pain and osteoarthritis can occur as coronavirus disease 2019 (COVID-19) sequelae after infection. However, little is known about the damage to articular cartilage. Here we illustrate knee joint damage after wild-type, Delta and Omicron variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in vivo. Rapid joint injury with cystic lesions at the osteochondral junction was observed in two patients with post-COVID osteoarthritis and recapitulated in a golden Syrian hamster model. SARS-CoV-2-activated endothelin-1 signalling increased vascular permeability and caused viral spike proteins leakage into the subchondral bone. Osteoclast activation, chondrocyte dropout and cyst formation were confirmed histologically. The US Food and Drug Administration-approved endothelin receptor antagonist, macitentan, mitigated cystic lesions and preserved chondrocyte number in the acute phase of viral infection in hamsters. Delayed macitentan treatment at post-acute infection phase alleviated chondrocyte senescence and restored subchondral bone loss. It is worth noting that it could also attenuate viral spike-induced joint pain. Our work suggests endothelin receptor blockade as a novel therapeutic strategy for post-COVID arthritis. Endothelin-1 activation after SARS-CoV-2 infection leads to vascular permeability, chondrocyte senescence, osteoclast activation and cyst formation in affected joints of hamsters, which can be alleviated using macitentan. Joint injury was also seen in two patients after COVID-19 infection.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"9 10","pages":"2538-2552"},"PeriodicalIF":20.5,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142166299","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}
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