Pub Date : 2024-09-10DOI: 10.1016/j.ebiom.2024.105317
Asia-Sophia Wolf,Kristin H Bjørlykke,Hilde S Ørbo,Sabin Bhandari,Guri Solum,Ingrid Fadum Kjønstad,Ingrid Jyssum,Unni C Nygaard,Anja Bråthen Kristoffersen,Ingrid E Christensen,Sarah E Josefsson,Katrine Persgård Lund,Adity Chopra,Julie Røkke Osen,Viktoriia Chaban,Anne T Tveter,Joseph Sexton,Tore K Kvien,Jørgen Jahnsen,Espen A Haavardsholm,Gunnveig Grødeland,John Torgils Vaage,Sella A Provan,Hassen Kared,Fridtjof Lund-Johansen,Ludvig A Munthe,Silje Watterdal Syversen,Guro Løvik Goll,Kristin Kaasen Jørgensen,Siri Mjaaland
BACKGROUNDUnderstanding cellular responses to SARS-CoV-2 immunisations is important for informing vaccine recommendations in patients with inflammatory bowel disease (IBD) and other vulnerable patients on immunosuppressive therapies. This study investigated the magnitude and quality of T cell responses after multiple SARS-CoV-2 vaccine doses and COVID-19 breakthrough infection.METHODSThis prospective, observational study included patients with IBD and arthritis on tumour necrosis factor inhibitors (TNFi) receiving up to four SARS-CoV-2 vaccine doses. T cell responses to SARS-CoV-2 peptides were measured by flow cytometry before and 2-4 weeks after vaccinations and breakthrough infection to assess the frequency and polyfunctionality of responding cells, along with receptor-binding domain (anti-RBD) antibodies.FINDINGSBetween March 2, 2021, and December 20, 2022, 143 patients (118 IBD, 25 arthritis) and 73 healthy controls were included. In patients with either IBD or arthritis, humoral immunity was attenuated compared to healthy controls (median anti-RBD levels 3391 vs. 6280 BAU/ml, p = 0.008) after three SARS-CoV-2 vaccine doses. Patients with IBD had comparable quantities (median CD4 0.11% vs. 0.11%, p = 0.26, CD8 0.031% vs. 0.047%, p = 0.33) and quality (polyfunctionality score: 0.403 vs. 0.371, p = 0.39; 0.105 vs. 0.101, p = 0.87) of spike-specific T cells to healthy controls. Patients with arthritis had lower frequencies but comparable quality of responding T cells to controls. Breakthrough infection increased spike-specific CD8 T cell quality and T cell responses against non-spike peptides.INTERPRETATIONPatients with IBD on TNFi have T cell responses comparable to healthy controls despite attenuated humoral responses following three vaccine doses. Repeated vaccination and breakthrough infection increased the quality of T cell responses. Our study adds evidence that, in the absence of other risk factors, this group may in future be able to follow the general recommendations for COVID-19 vaccines.FUNDINGSouth-Eastern Norway Regional Health Authority, Coalition for Epidemic Preparedness Innovations (CEPI), Norwegian Institute of Public Health, Akershus University Hospital, Diakonhjemmet Hospital.
{"title":"T cell responses to repeated SARS-CoV-2 vaccination and breakthrough infections in patients on TNF inhibitor treatment: a prospective cohort study.","authors":"Asia-Sophia Wolf,Kristin H Bjørlykke,Hilde S Ørbo,Sabin Bhandari,Guri Solum,Ingrid Fadum Kjønstad,Ingrid Jyssum,Unni C Nygaard,Anja Bråthen Kristoffersen,Ingrid E Christensen,Sarah E Josefsson,Katrine Persgård Lund,Adity Chopra,Julie Røkke Osen,Viktoriia Chaban,Anne T Tveter,Joseph Sexton,Tore K Kvien,Jørgen Jahnsen,Espen A Haavardsholm,Gunnveig Grødeland,John Torgils Vaage,Sella A Provan,Hassen Kared,Fridtjof Lund-Johansen,Ludvig A Munthe,Silje Watterdal Syversen,Guro Løvik Goll,Kristin Kaasen Jørgensen,Siri Mjaaland","doi":"10.1016/j.ebiom.2024.105317","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105317","url":null,"abstract":"BACKGROUNDUnderstanding cellular responses to SARS-CoV-2 immunisations is important for informing vaccine recommendations in patients with inflammatory bowel disease (IBD) and other vulnerable patients on immunosuppressive therapies. This study investigated the magnitude and quality of T cell responses after multiple SARS-CoV-2 vaccine doses and COVID-19 breakthrough infection.METHODSThis prospective, observational study included patients with IBD and arthritis on tumour necrosis factor inhibitors (TNFi) receiving up to four SARS-CoV-2 vaccine doses. T cell responses to SARS-CoV-2 peptides were measured by flow cytometry before and 2-4 weeks after vaccinations and breakthrough infection to assess the frequency and polyfunctionality of responding cells, along with receptor-binding domain (anti-RBD) antibodies.FINDINGSBetween March 2, 2021, and December 20, 2022, 143 patients (118 IBD, 25 arthritis) and 73 healthy controls were included. In patients with either IBD or arthritis, humoral immunity was attenuated compared to healthy controls (median anti-RBD levels 3391 vs. 6280 BAU/ml, p = 0.008) after three SARS-CoV-2 vaccine doses. Patients with IBD had comparable quantities (median CD4 0.11% vs. 0.11%, p = 0.26, CD8 0.031% vs. 0.047%, p = 0.33) and quality (polyfunctionality score: 0.403 vs. 0.371, p = 0.39; 0.105 vs. 0.101, p = 0.87) of spike-specific T cells to healthy controls. Patients with arthritis had lower frequencies but comparable quality of responding T cells to controls. Breakthrough infection increased spike-specific CD8 T cell quality and T cell responses against non-spike peptides.INTERPRETATIONPatients with IBD on TNFi have T cell responses comparable to healthy controls despite attenuated humoral responses following three vaccine doses. Repeated vaccination and breakthrough infection increased the quality of T cell responses. Our study adds evidence that, in the absence of other risk factors, this group may in future be able to follow the general recommendations for COVID-19 vaccines.FUNDINGSouth-Eastern Norway Regional Health Authority, Coalition for Epidemic Preparedness Innovations (CEPI), Norwegian Institute of Public Health, Akershus University Hospital, Diakonhjemmet Hospital.","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":11.1,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142215959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BACKGROUNDThe global spread of the plasmid-mediated mcr (mobilized colistin resistance) gene family presents a significant threat to the efficacy of colistin, a last-line defense against numerous Gram-negative pathogens. The mcr-9 is the second most prevalent variant after mcr-1.METHODSA dataset of 698 mcr-9-positive isolates from 44 countries is compiled. The historical trajectory of the mcr-9 gene is reconstructed using Bayesian analysis. The effective reproduction number is used innovatively to study the transmission dynamics of this mobile-drug-resistant gene.FINDINGSOur investigation traces the origins of mcr-9 back to the 1960s, revealing a subsequent expansion from Western Europe to the America and East Asia in the late 20th century. Currently, its transmissibility remains high in Western Europe. Intriguingly, mcr-9 likely emerged from human-associated Salmonella and exhibits a unique propensity for transmission within the Enterobacter. Our research provides a new perspective that this host preference may be driven by codon usage biases in plasmids. Specifically, mcr-9-carrying plasmids prefer the nucleotide C over T compared to mcr-1-carrying plasmids among synonymous codons. The same bias is seen in Enterobacter compared to Escherichia (respectively as their most dominant genus). Furthermore, we uncovered fascinating patterns of coexistence between different mcr-9 subtypes and other resistance genes. Characterized by its low colistin resistance, mcr-9 has used this seemingly benign feature to silently circumnavigate the globe, evading conventional detection methods. However, colistin-resistant Enterobacter strains with high mcr-9 expression have emerged clinically, implying a strong risk of mcr-9 evolving into a global "true-resistance-gene".INTERPRETATIONThis study explores the mcr-9 gene, emphasizing its origin, adaptability, and dissemination potential. Given the high mcr-9 expression colistin-resistant strains was observed in clinically the prevalence of mcr-9 poses a significant challenge to drug resistance prevention and control within the One Health framework.FUNDINGThis work was partially supported by the National Natural Science Foundation of China (Grant No. 32141001 and 81991533).
{"title":"Decoding the origins, spread, and global risks of mcr-9 gene.","authors":"Kaiwen Song,Longyang Jin,Meng Cai,Qi Wang,Xingyu Wu,Shuyi Wang,Shijun Sun,Ruobing Wang,Fengning Chen,Hui Wang","doi":"10.1016/j.ebiom.2024.105326","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105326","url":null,"abstract":"BACKGROUNDThe global spread of the plasmid-mediated mcr (mobilized colistin resistance) gene family presents a significant threat to the efficacy of colistin, a last-line defense against numerous Gram-negative pathogens. The mcr-9 is the second most prevalent variant after mcr-1.METHODSA dataset of 698 mcr-9-positive isolates from 44 countries is compiled. The historical trajectory of the mcr-9 gene is reconstructed using Bayesian analysis. The effective reproduction number is used innovatively to study the transmission dynamics of this mobile-drug-resistant gene.FINDINGSOur investigation traces the origins of mcr-9 back to the 1960s, revealing a subsequent expansion from Western Europe to the America and East Asia in the late 20th century. Currently, its transmissibility remains high in Western Europe. Intriguingly, mcr-9 likely emerged from human-associated Salmonella and exhibits a unique propensity for transmission within the Enterobacter. Our research provides a new perspective that this host preference may be driven by codon usage biases in plasmids. Specifically, mcr-9-carrying plasmids prefer the nucleotide C over T compared to mcr-1-carrying plasmids among synonymous codons. The same bias is seen in Enterobacter compared to Escherichia (respectively as their most dominant genus). Furthermore, we uncovered fascinating patterns of coexistence between different mcr-9 subtypes and other resistance genes. Characterized by its low colistin resistance, mcr-9 has used this seemingly benign feature to silently circumnavigate the globe, evading conventional detection methods. However, colistin-resistant Enterobacter strains with high mcr-9 expression have emerged clinically, implying a strong risk of mcr-9 evolving into a global \"true-resistance-gene\".INTERPRETATIONThis study explores the mcr-9 gene, emphasizing its origin, adaptability, and dissemination potential. Given the high mcr-9 expression colistin-resistant strains was observed in clinically the prevalence of mcr-9 poses a significant challenge to drug resistance prevention and control within the One Health framework.FUNDINGThis work was partially supported by the National Natural Science Foundation of China (Grant No. 32141001 and 81991533).","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":11.1,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142216087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BACKGROUNDDepressive symptoms are rising in the general population, but their associated factors are unclear. Although the link between sleep disturbances and depressive symptoms severity (DSS) is reported, the predictive role of sleep on DSS and the impact of anxiety and the brain on their relationship remained obscure.METHODSUsing three population-based datasets (N = 1813), we trained the machine learning models in the primary dataset (N = 1101) to assess the predictive role of sleep quality, anxiety problems, and brain structural (and functional) measurements on DSS, then we tested our models' performance in two independent datasets (N = 378, N = 334) to test the generalizability of our findings. Furthermore, we applied our model to a smaller longitudinal subsample (N = 66). In addition, we performed a mediation analysis to identify the role of anxiety and brain measurements on the sleep quality and DSS association.FINDINGSSleep quality could predict individual DSS (r = 0.43, R2 = 0.18, rMSE = 2.73), and adding anxiety, contrary to brain measurements, strengthened its prediction performance (r = 0.67, R2 = 0.45, rMSE = 2.25). Importantly, out-of-cohort validations in other cross-sectional datasets and a longitudinal subsample provided robust similar results. Furthermore, anxiety scores, contrary to brain measurements, mediated the association between sleep quality and DSS.INTERPRETATIONPoor sleep quality could predict DSS at the individual subject level across three datasets. Anxiety scores not only increased the predictive model's performance but also mediated the link between sleep quality and DSS.FUNDINGThe study is supported by Helmholtz Imaging Platform grant (NimRLS, ZTI-PF-4-010), the Deutsche Forschungsgemeinschaft (DFG, GE 2835/2-1, GE 2835/4-1), the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)-Project-ID 431549029-SFB 1451, the programme "Profilbildung 2020" (grant no. PROFILNRW-2020-107-A), an initiative of the Ministry of Culture and Science of the State of Northrhine Westphalia.
{"title":"Prediction of depressive symptoms severity based on sleep quality, anxiety, and gray matter volume: a generalizable machine learning approach across three datasets.","authors":"Mahnaz Olfati,Fateme Samea,Shahrooz Faghihroohi,Somayeh Maleki Balajoo,Vincent Küppers,Sarah Genon,Kaustubh Patil,Simon B Eickhoff,Masoud Tahmasian","doi":"10.1016/j.ebiom.2024.105313","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105313","url":null,"abstract":"BACKGROUNDDepressive symptoms are rising in the general population, but their associated factors are unclear. Although the link between sleep disturbances and depressive symptoms severity (DSS) is reported, the predictive role of sleep on DSS and the impact of anxiety and the brain on their relationship remained obscure.METHODSUsing three population-based datasets (N = 1813), we trained the machine learning models in the primary dataset (N = 1101) to assess the predictive role of sleep quality, anxiety problems, and brain structural (and functional) measurements on DSS, then we tested our models' performance in two independent datasets (N = 378, N = 334) to test the generalizability of our findings. Furthermore, we applied our model to a smaller longitudinal subsample (N = 66). In addition, we performed a mediation analysis to identify the role of anxiety and brain measurements on the sleep quality and DSS association.FINDINGSSleep quality could predict individual DSS (r = 0.43, R2 = 0.18, rMSE = 2.73), and adding anxiety, contrary to brain measurements, strengthened its prediction performance (r = 0.67, R2 = 0.45, rMSE = 2.25). Importantly, out-of-cohort validations in other cross-sectional datasets and a longitudinal subsample provided robust similar results. Furthermore, anxiety scores, contrary to brain measurements, mediated the association between sleep quality and DSS.INTERPRETATIONPoor sleep quality could predict DSS at the individual subject level across three datasets. Anxiety scores not only increased the predictive model's performance but also mediated the link between sleep quality and DSS.FUNDINGThe study is supported by Helmholtz Imaging Platform grant (NimRLS, ZTI-PF-4-010), the Deutsche Forschungsgemeinschaft (DFG, GE 2835/2-1, GE 2835/4-1), the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)-Project-ID 431549029-SFB 1451, the programme \"Profilbildung 2020\" (grant no. PROFILNRW-2020-107-A), an initiative of the Ministry of Culture and Science of the State of Northrhine Westphalia.","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":11.1,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142215960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-04DOI: 10.1016/j.ebiom.2024.105324
Peng Luo, Zi-Wei Ye, Shuofeng Yuan
{"title":"Bridging gaps: a neural network approach for cross-species scRNA-seq analysis in COVID-19.","authors":"Peng Luo, Zi-Wei Ye, Shuofeng Yuan","doi":"10.1016/j.ebiom.2024.105324","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105324","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-04DOI: 10.1016/j.ebiom.2024.105320
Avi Kenny, Janine van Duijn, One Dintwe, Jack Heptinstall, Randy Burnham, Sheetal Sawant, Lu Zhang, Dieter Mielke, Sharon Khuzwayo, Faatima Laher Omar, Sherry Stanfield-Oakley, Taylor Keyes, Brooke Dunn, Derrick Goodman, Youyi Fong, David Benkeser, Rodger Zou, John Hural, Ollivier Hyrien, Michal Juraska, Alex Luedtke, Lars van der Laan, Elena E Giorgi, Craig Magaret, Lindsay N Carpp, Laura Pattacini, Tom van de Kerkhof, Bette Korber, Wouter Willems, Leigh H Fisher, Hanneke Schuitemaker, Edith Swann, James G Kublin, Maria G Pau, Susan Buchbinder, Frank Tomaka, Steven Nijs, Ludo Lavreys, Huub C Gelderblom, Lawrence Corey, Kathryn Mngadi, Glenda E Gray, Erica Borducchi, Jenny Hendriks, Kelly E Seaton, Susan Zolla-Pazner, Dan H Barouch, Guido Ferrari, Stephen C De Rosa, M Juliana McElrath, Erica Andersen-Nissen, Daniel J Stieh, Georgia D Tomaras, Peter B Gilbert
Background: The HVTN 705 Imbokodo trial of 2636 people without HIV and assigned female sex at birth, conducted in southern Africa, evaluated a heterologous HIV-1 vaccine regimen: mosaic adenovirus 26-based vaccine (Ad26.Mos4.HIV) at Months 0, 3, 6, 12 and alum-adjuvanted clade C gp140 at Months 6, 12. Per-protocol vaccine efficacy (VE) against HIV-1 diagnosis from seven to 24 months was 14.1% (95% CI: -22.0% to 39.5%). Immune correlates analysis was performed for markers selected based on prior evidence in efficacy trials and/or nonhuman primate models.
Methods: Humoral and cellular immune response markers at Month 7 were evaluated as immune correlates of risk and of protection in a breakthrough case-control cohort (n = 52 cases, 246 non-cases). Primary markers were IgG binding to vaccine-strain gp140, IgG3 binding to diverse Env antigens (IgG3 Env breadth), IgG3 binding to diverse V1V2 antigens (IgG3 V1V2 breadth), antibody-dependent phagocytosis against the vaccine-strain gp140, Env-specific CD4+ and CD8+ T-cell responses, and multi-epitope functions.
Findings: No immune markers were statistically significant correlates of risk. IgG3 V1V2 breadth trended toward an inverse association: hazard ratio 0.70 (95% CI: 0.36 to 1.35; p = 0.29) per 10-fold increase and 0.51 (95% CI: 0.21 to 1.24; p = 0.14) in a Cox model with all primary markers. The VE estimate was 11.8% (95% CI: -17.9% to 34.0%) at all IgG3 V1V2 breadth values below 667 weighted geometric mean net MFI; just above this value, the VE estimate sharply increased to 62.6% (95% CI: -17.9% to 89.6%), and further increased to 80.9% (95% CI: -17.9% to 99.5%) at 1471 MFI, the 95th percentile of the marker distribution. Mediation analysis yielded a VE of 35.7% (95% CI: 15.0% to 51.3%) attributable to the vaccine's impact on this marker.
Interpretation: The trend in association of greater IgG3 V1V2 antibody breadth with lower likelihood of HIV acquisition is consistent with the identification of antibodies against V1V2 as immune correlates in three other HIV vaccine efficacy trials and suggests that a greater emphasis should be placed on studying this region in the HIV-1 envelope as a vaccine immunogen.
Funding: National Institute of Allergy and Infectious Diseases and Janssen Vaccines & Prevention BV.
{"title":"Immune correlates analysis of the Imbokodo (HVTN 705/HPX2008) efficacy trial of a mosaic HIV-1 vaccine regimen evaluated in Southern African people assigned female sex at birth: a two-phase case-control study.","authors":"Avi Kenny, Janine van Duijn, One Dintwe, Jack Heptinstall, Randy Burnham, Sheetal Sawant, Lu Zhang, Dieter Mielke, Sharon Khuzwayo, Faatima Laher Omar, Sherry Stanfield-Oakley, Taylor Keyes, Brooke Dunn, Derrick Goodman, Youyi Fong, David Benkeser, Rodger Zou, John Hural, Ollivier Hyrien, Michal Juraska, Alex Luedtke, Lars van der Laan, Elena E Giorgi, Craig Magaret, Lindsay N Carpp, Laura Pattacini, Tom van de Kerkhof, Bette Korber, Wouter Willems, Leigh H Fisher, Hanneke Schuitemaker, Edith Swann, James G Kublin, Maria G Pau, Susan Buchbinder, Frank Tomaka, Steven Nijs, Ludo Lavreys, Huub C Gelderblom, Lawrence Corey, Kathryn Mngadi, Glenda E Gray, Erica Borducchi, Jenny Hendriks, Kelly E Seaton, Susan Zolla-Pazner, Dan H Barouch, Guido Ferrari, Stephen C De Rosa, M Juliana McElrath, Erica Andersen-Nissen, Daniel J Stieh, Georgia D Tomaras, Peter B Gilbert","doi":"10.1016/j.ebiom.2024.105320","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105320","url":null,"abstract":"<p><strong>Background: </strong>The HVTN 705 Imbokodo trial of 2636 people without HIV and assigned female sex at birth, conducted in southern Africa, evaluated a heterologous HIV-1 vaccine regimen: mosaic adenovirus 26-based vaccine (Ad26.Mos4.HIV) at Months 0, 3, 6, 12 and alum-adjuvanted clade C gp140 at Months 6, 12. Per-protocol vaccine efficacy (VE) against HIV-1 diagnosis from seven to 24 months was 14.1% (95% CI: -22.0% to 39.5%). Immune correlates analysis was performed for markers selected based on prior evidence in efficacy trials and/or nonhuman primate models.</p><p><strong>Methods: </strong>Humoral and cellular immune response markers at Month 7 were evaluated as immune correlates of risk and of protection in a breakthrough case-control cohort (n = 52 cases, 246 non-cases). Primary markers were IgG binding to vaccine-strain gp140, IgG3 binding to diverse Env antigens (IgG3 Env breadth), IgG3 binding to diverse V1V2 antigens (IgG3 V1V2 breadth), antibody-dependent phagocytosis against the vaccine-strain gp140, Env-specific CD4+ and CD8+ T-cell responses, and multi-epitope functions.</p><p><strong>Findings: </strong>No immune markers were statistically significant correlates of risk. IgG3 V1V2 breadth trended toward an inverse association: hazard ratio 0.70 (95% CI: 0.36 to 1.35; p = 0.29) per 10-fold increase and 0.51 (95% CI: 0.21 to 1.24; p = 0.14) in a Cox model with all primary markers. The VE estimate was 11.8% (95% CI: -17.9% to 34.0%) at all IgG3 V1V2 breadth values below 667 weighted geometric mean net MFI; just above this value, the VE estimate sharply increased to 62.6% (95% CI: -17.9% to 89.6%), and further increased to 80.9% (95% CI: -17.9% to 99.5%) at 1471 MFI, the 95th percentile of the marker distribution. Mediation analysis yielded a VE of 35.7% (95% CI: 15.0% to 51.3%) attributable to the vaccine's impact on this marker.</p><p><strong>Interpretation: </strong>The trend in association of greater IgG3 V1V2 antibody breadth with lower likelihood of HIV acquisition is consistent with the identification of antibodies against V1V2 as immune correlates in three other HIV vaccine efficacy trials and suggests that a greater emphasis should be placed on studying this region in the HIV-1 envelope as a vaccine immunogen.</p><p><strong>Funding: </strong>National Institute of Allergy and Infectious Diseases and Janssen Vaccines & Prevention BV.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-03DOI: 10.1016/j.ebiom.2024.105325
Ole Vidhammer Bjørnstad, Manuel Carrasco, Kenneth Finne, Vandana Ardawatia, Ingeborg Winge, Cecilie Askeland, Jarle B Arnes, Gøril Knutsvik, Dimitrios Kleftogiannis, Joao A Paulo, Lars A Akslen, Heidrun Vethe
Background: Presence of nerves in tumours, by axonogenesis and neurogenesis, is gaining increased attention for its impact on cancer initiation and development, and the new field of cancer neuroscience is emerging. A recent study in prostate cancer suggested that the tumour microenvironment may influence cancer progression by recruitment of Doublecortin (DCX)-expressing neural progenitor cells (NPCs). However, the presence of such cells in human breast tumours has not been comprehensively explored.
Methods: Here, we investigate the presence of DCX-expressing cells in breast cancer stromal tissue from patients using Imaging Mass Cytometry. Single-cell analysis of 372,468 cells across histopathological images of 107 breast cancers enabled spatial resolution of neural elements in the stromal compartment in correlation with clinicopathological features of these tumours. In parallel, we established a 3D in vitro model mimicking breast cancer neural progenitor-innervation and examined the two cell types as they co-evolved in co-culture by using mass spectrometry-based global proteomics.
Findings: Stromal presence of DCX + cells is associated with tumours of higher histological grade, a basal-like phenotype, and shorter patient survival in tumour tissue from patients with breast cancer. Global proteomics analysis revealed significant changes in the proteomic landscape of both breast cancer cells and neural progenitors in co-culture.
Interpretation: These results support that neural involvement plays an active role in breast cancer and warrants further studies on the relevance of nerve elements for tumour progression.
Funding: This work was supported by the Research Council of Norway through its Centre of Excellence funding scheme, project number 223250 (to L.A.A), the Norwegian Cancer Society (to L.A.A. and H.V.), the Regional Health Trust Western Norway (Helse Vest) (to L.A.A.), the Meltzer Research Fund (to H.V.) and the National Institutes of Health (NIH)/NIGMS grant R01 GM132129 (to J.A.P.).
背景：肿瘤中神经的轴突生成和神经发生对癌症的发生和发展的影响日益受到关注，癌症神经科学这一新领域正在兴起。最近一项关于前列腺癌的研究表明，肿瘤微环境可能会通过招募表达双皮质素（DCX）的神经祖细胞（NPCs）来影响癌症的进展。方法：在此，我们使用成像质谱细胞计数法研究了患者乳腺癌基质组织中是否存在表达 DCX 的细胞。我们对 107 例乳腺癌组织病理图像中的 372,468 个细胞进行了单细胞分析，从而获得了基质区神经元的空间分辨率以及这些肿瘤的临床病理特征。与此同时，我们建立了一个模拟乳腺癌神经祖细胞神经支配的三维体外模型，并利用基于质谱的全蛋白质组学研究了两种细胞类型在共培养过程中的共同进化：研究结果：在乳腺癌患者的肿瘤组织中，DCX +细胞基质的存在与组织学级别较高的肿瘤、基底样表型和较短的患者生存期有关。全局蛋白质组学分析表明，乳腺癌细胞和神经祖细胞在共培养过程中的蛋白质组结构发生了显著变化：这些结果支持神经参与在乳腺癌中发挥了积极作用，因此有必要进一步研究神经元素与肿瘤进展的相关性：这项工作得到了挪威研究理事会（Research Council of Norway）卓越中心资助计划（项目编号：223250，资助人：L.A.A.）、挪威癌症协会（资助人：L.A.A.和H.V.）、挪威西部地区健康信托基金（Helse Vest）（资助人：L.A.A.）、梅尔泽研究基金（资助人：H.V.）和美国国立卫生研究院（NIH）/美国国立卫生研究院（NIGMS）R01 GM132129基金（资助人：J.A.P.）的支持。
{"title":"Global and single-cell proteomics view of the co-evolution between neural progenitors and breast cancer cells in a co-culture model.","authors":"Ole Vidhammer Bjørnstad, Manuel Carrasco, Kenneth Finne, Vandana Ardawatia, Ingeborg Winge, Cecilie Askeland, Jarle B Arnes, Gøril Knutsvik, Dimitrios Kleftogiannis, Joao A Paulo, Lars A Akslen, Heidrun Vethe","doi":"10.1016/j.ebiom.2024.105325","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105325","url":null,"abstract":"<p><strong>Background: </strong>Presence of nerves in tumours, by axonogenesis and neurogenesis, is gaining increased attention for its impact on cancer initiation and development, and the new field of cancer neuroscience is emerging. A recent study in prostate cancer suggested that the tumour microenvironment may influence cancer progression by recruitment of Doublecortin (DCX)-expressing neural progenitor cells (NPCs). However, the presence of such cells in human breast tumours has not been comprehensively explored.</p><p><strong>Methods: </strong>Here, we investigate the presence of DCX-expressing cells in breast cancer stromal tissue from patients using Imaging Mass Cytometry. Single-cell analysis of 372,468 cells across histopathological images of 107 breast cancers enabled spatial resolution of neural elements in the stromal compartment in correlation with clinicopathological features of these tumours. In parallel, we established a 3D in vitro model mimicking breast cancer neural progenitor-innervation and examined the two cell types as they co-evolved in co-culture by using mass spectrometry-based global proteomics.</p><p><strong>Findings: </strong>Stromal presence of DCX + cells is associated with tumours of higher histological grade, a basal-like phenotype, and shorter patient survival in tumour tissue from patients with breast cancer. Global proteomics analysis revealed significant changes in the proteomic landscape of both breast cancer cells and neural progenitors in co-culture.</p><p><strong>Interpretation: </strong>These results support that neural involvement plays an active role in breast cancer and warrants further studies on the relevance of nerve elements for tumour progression.</p><p><strong>Funding: </strong>This work was supported by the Research Council of Norway through its Centre of Excellence funding scheme, project number 223250 (to L.A.A), the Norwegian Cancer Society (to L.A.A. and H.V.), the Regional Health Trust Western Norway (Helse Vest) (to L.A.A.), the Meltzer Research Fund (to H.V.) and the National Institutes of Health (NIH)/NIGMS grant R01 GM132129 (to J.A.P.).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142132156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-03DOI: 10.1016/j.ebiom.2024.105284
Sophia Lengsfeld, Leila Probst, Yara Emara, Laura Werlen, Deborah R Vogt, Cemile Bathelt, Fabienne Baur, Brida Caviezel, Tanja Vukajlovic, Manuel Fischer, Bettina Winzeler
Background: The reward-regulatory properties of GLP-1 are attracting increasing interest. Animal studies show that GLP-1 receptor agonists not only reduce consumption of addictive substances, but also influence sexual behaviour. We aimed to investigate the effect of dulaglutide versus placebo on sexual desire in humans.
Methods: In this randomised, double-blind, placebo-controlled crossover trial, healthy eugonadal men of normal weight, aged 18-50 years with active and satisfactory sex lifes were (1:1) randomly allocated to dulaglutide or placebo for four weeks. We assessed sexual desire (Massachusetts General Hospital-Sexual Functioning Questionnaire [MGH-SFQ]), hormones of the hypothalamic-pituitary-gonadal axis (total testosterone, follicle-stimulating hormone [FSH], luteinizing hormone [LH]) and sperm parameters. Changes in these parameters were compared under dulaglutide versus placebo using paired t-tests.
Findings: 24 out of 26 randomised participants completed the study (13 participants randomised to dulaglutide first and 13 to placebo first). No change in the MGH-SFQ was observed after four weeks of dulaglutide versus placebo (estimated difference 0.58 [95% CI -0.83 to 2.00], p-value = 0.402). Hormones of the hypothalamic-pituitary-gonadal axis (estimated differences: total testosterone (nmol/l) 0.9 [95% CI -1.5 to 3.3], FSH (IU/l) -0.2 [95% CI -0.3 to 0.0] and LH (IU/l) -0.8 [95% CI -1.5 to 0.0]) as well as sperm parameters all remained in the normal range without significant differences between the treatments. No severe adverse events occurred.
Interpretation: In this study of healthy men, we found no evidence of negative impacts of a four-week treatment with the widely used GLP-1 receptor agonist dulaglutide on sexual desire, hypothalamic-pituitary-gonadal axis hormones or sperm parameters.
Funding: Swiss National Science Foundation (PZ00P3_193206), Gottfried and Julia Bangerter-Rhyner Foundation, Goldschmidt-Jacobson Foundation, Swiss Academy of Medical Sciences.
背景：GLP-1 的奖赏调节特性正引起越来越多的关注。动物实验表明，GLP-1 受体激动剂不仅能减少成瘾物质的消耗，还能影响性行为。我们旨在研究度拉鲁肽与安慰剂相比对人类性欲的影响：在这项随机、双盲、安慰剂对照交叉试验中，体重正常、年龄在 18-50 岁之间、性生活活跃且令人满意的健康男性（1:1）被随机分配到度拉鲁肽或安慰剂中，为期四周。我们评估了性欲（麻省总医院性功能问卷[MGH-SFQ]）、下丘脑-垂体-性腺轴激素（总睾酮、促卵泡激素[FSH]、促黄体生成素[LH]）和精子参数。研究结果：26 名随机参与者中有 24 人完成了研究（13 人先随机接受度拉鲁肽治疗，13 人先接受安慰剂治疗）。服用度拉鲁肽四周后，MGH-SFQ与安慰剂相比没有变化（估计差异为0.58 [95% CI -0.83 至 2.00]，P值= 0.402）。下丘脑-垂体-性腺轴激素（估计差异：总睾酮（nmol/l）0.9 [95% CI -1.5 至 3.3]，FSH（IU/l）-0.2 [95% CI -0.3 至 0.0]，LH（IU/l）-0.8 [95% CI -1.5 至 0.0]）以及精子参数均保持在正常范围，治疗之间无显著差异。没有发生严重的不良反应：在这项针对健康男性的研究中，我们没有发现证据表明使用广泛使用的GLP-1受体激动剂度拉鲁肽进行为期四周的治疗会对性欲、下丘脑-垂体-性腺轴激素或精子参数产生负面影响：瑞士国家科学基金会（PZ00P3_193206）、戈特弗里德和朱莉娅-班格特-莱纳基金会、戈尔德施密特-雅各布森基金会、瑞士医学科学院。
{"title":"Effects of the glucagon-like peptide-1 receptor agonist dulaglutide on sexuality in healthy men: a randomised, double-blind, placebo-controlled crossover study.","authors":"Sophia Lengsfeld, Leila Probst, Yara Emara, Laura Werlen, Deborah R Vogt, Cemile Bathelt, Fabienne Baur, Brida Caviezel, Tanja Vukajlovic, Manuel Fischer, Bettina Winzeler","doi":"10.1016/j.ebiom.2024.105284","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105284","url":null,"abstract":"<p><strong>Background: </strong>The reward-regulatory properties of GLP-1 are attracting increasing interest. Animal studies show that GLP-1 receptor agonists not only reduce consumption of addictive substances, but also influence sexual behaviour. We aimed to investigate the effect of dulaglutide versus placebo on sexual desire in humans.</p><p><strong>Methods: </strong>In this randomised, double-blind, placebo-controlled crossover trial, healthy eugonadal men of normal weight, aged 18-50 years with active and satisfactory sex lifes were (1:1) randomly allocated to dulaglutide or placebo for four weeks. We assessed sexual desire (Massachusetts General Hospital-Sexual Functioning Questionnaire [MGH-SFQ]), hormones of the hypothalamic-pituitary-gonadal axis (total testosterone, follicle-stimulating hormone [FSH], luteinizing hormone [LH]) and sperm parameters. Changes in these parameters were compared under dulaglutide versus placebo using paired t-tests.</p><p><strong>Findings: </strong>24 out of 26 randomised participants completed the study (13 participants randomised to dulaglutide first and 13 to placebo first). No change in the MGH-SFQ was observed after four weeks of dulaglutide versus placebo (estimated difference 0.58 [95% CI -0.83 to 2.00], p-value = 0.402). Hormones of the hypothalamic-pituitary-gonadal axis (estimated differences: total testosterone (nmol/l) 0.9 [95% CI -1.5 to 3.3], FSH (IU/l) -0.2 [95% CI -0.3 to 0.0] and LH (IU/l) -0.8 [95% CI -1.5 to 0.0]) as well as sperm parameters all remained in the normal range without significant differences between the treatments. No severe adverse events occurred.</p><p><strong>Interpretation: </strong>In this study of healthy men, we found no evidence of negative impacts of a four-week treatment with the widely used GLP-1 receptor agonist dulaglutide on sexual desire, hypothalamic-pituitary-gonadal axis hormones or sperm parameters.</p><p><strong>Funding: </strong>Swiss National Science Foundation (PZ00P3_193206), Gottfried and Julia Bangerter-Rhyner Foundation, Goldschmidt-Jacobson Foundation, Swiss Academy of Medical Sciences.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142132154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-03DOI: 10.1016/j.ebiom.2024.105319
Eric J Nilles, Kathryn Roberts, Michael de St Aubin, Helen Mayfield, Angela Cadavid Restrepo, Salome Garnier, Gabriela Abdalla, Marie Caroline Etienne, William Duke, Devan Dumas, Petr Jarolim, Timothy Oasan, Farah Peña, Beatriz Lopez, Lucia de la Cruz, Isaac Miguel Sanchez, Kristy Murray, Margaret Baldwin, Ronald Skewes-Ramm, Cecilia Then Paulino, Colleen L Lau, Adam Kucharski
Background: Individual immune responses to SARS-CoV-2 are well-studied, while the combined effect of these responses on population-level immune dynamics remains poorly understood. Given the key role of population immunity on pathogen transmission, delineation of the factors that drive population immune evolution has critical public health implications.
Methods: We enrolled individuals 5 years and older selected using a multistage cluster survey approach in the Northwest and Southeast of the Dominican Republic. Paired blood samples were collected mid-pandemic (Aug 2021) and late pandemic (Nov 2022). We measured serum pan-immunoglobulin antibodies against the SARS-CoV-2 spike protein. Generalized Additive Models (GAMs) and random forest models were used to analyze the relationship between changes in antibody levels and various predictor variables. Principal component analysis and partial dependence plots further explored the relationships between predictors and antibody changes.
Findings: We found a transformation in the distribution of antibody levels from an irregular to a normalized single peak Gaussian distribution that was driven by titre-dependent boosting. This led to the convergence of antibody levels around a common immune setpoint, irrespective of baseline titres and vaccination profile.
Interpretation: Our results suggest that titre-dependent kinetics driven by widespread transmission direct the evolution of population immunity in a consistent manner. These findings have implications for targeted vaccination strategies and improved modeling of future transmission, providing a preliminary blueprint for understanding population immune dynamics that could guide public health and vaccine policy for SARS-CoV-2 and potentially other pathogens.
Funding: The study was primarily funded by the Centers for Disease Control and Prevention grant U01GH002238 (EN). Salary support was provided by Wellcome Trust grant 206250/Z/17/Z (AK) and the Australian National Health and Medical Research Council Investigator grant APP1158469 (CLL).
背景：对SARS-CoV-2的个体免疫反应进行了深入研究，但对这些反应对群体免疫动态的综合影响仍知之甚少。鉴于群体免疫在病原体传播中的关键作用，确定推动群体免疫演变的因素对公共卫生具有重要意义：我们在多米尼加共和国西北部和东南部采用多阶段群组调查法选取了 5 岁及以上的人群。在大流行中期（2021 年 8 月）和大流行后期（2022 年 11 月）采集了配对血样。我们测定了血清中针对 SARS-CoV-2 尖峰蛋白的泛免疫球蛋白抗体。我们使用了广义加性模型（GAMs）和随机森林模型来分析抗体水平变化与各种预测变量之间的关系。主成分分析和偏倚图进一步探讨了预测变量与抗体变化之间的关系：我们发现抗体水平的分布从不规则分布转变为归一化的单峰高斯分布，这种转变是由滴度依赖性增强驱动的。无论基线滴度和疫苗接种情况如何，这都会导致抗体水平趋同于一个共同的免疫设定点：我们的研究结果表明，广泛传播驱动的滴度依赖性动力学以一致的方式指导着群体免疫力的演变。这些发现对有针对性的疫苗接种策略和改进未来传播的建模具有重要意义，为了解人群免疫动态提供了初步蓝图，可以指导针对 SARS-CoV-2 和其他潜在病原体的公共卫生和疫苗政策：本研究主要由美国疾病控制和预防中心（Centers for Disease Control and Prevention）的 U01GH002238 (EN) 基金资助。威康信托基金206250/Z/17/Z（AK）和澳大利亚国家健康与医学研究委员会研究员基金APP1158469（CLL）提供了薪金支持。
{"title":"Convergence of SARS-CoV-2 spike antibody levels to a population immune setpoint.","authors":"Eric J Nilles, Kathryn Roberts, Michael de St Aubin, Helen Mayfield, Angela Cadavid Restrepo, Salome Garnier, Gabriela Abdalla, Marie Caroline Etienne, William Duke, Devan Dumas, Petr Jarolim, Timothy Oasan, Farah Peña, Beatriz Lopez, Lucia de la Cruz, Isaac Miguel Sanchez, Kristy Murray, Margaret Baldwin, Ronald Skewes-Ramm, Cecilia Then Paulino, Colleen L Lau, Adam Kucharski","doi":"10.1016/j.ebiom.2024.105319","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105319","url":null,"abstract":"<p><strong>Background: </strong>Individual immune responses to SARS-CoV-2 are well-studied, while the combined effect of these responses on population-level immune dynamics remains poorly understood. Given the key role of population immunity on pathogen transmission, delineation of the factors that drive population immune evolution has critical public health implications.</p><p><strong>Methods: </strong>We enrolled individuals 5 years and older selected using a multistage cluster survey approach in the Northwest and Southeast of the Dominican Republic. Paired blood samples were collected mid-pandemic (Aug 2021) and late pandemic (Nov 2022). We measured serum pan-immunoglobulin antibodies against the SARS-CoV-2 spike protein. Generalized Additive Models (GAMs) and random forest models were used to analyze the relationship between changes in antibody levels and various predictor variables. Principal component analysis and partial dependence plots further explored the relationships between predictors and antibody changes.</p><p><strong>Findings: </strong>We found a transformation in the distribution of antibody levels from an irregular to a normalized single peak Gaussian distribution that was driven by titre-dependent boosting. This led to the convergence of antibody levels around a common immune setpoint, irrespective of baseline titres and vaccination profile.</p><p><strong>Interpretation: </strong>Our results suggest that titre-dependent kinetics driven by widespread transmission direct the evolution of population immunity in a consistent manner. These findings have implications for targeted vaccination strategies and improved modeling of future transmission, providing a preliminary blueprint for understanding population immune dynamics that could guide public health and vaccine policy for SARS-CoV-2 and potentially other pathogens.</p><p><strong>Funding: </strong>The study was primarily funded by the Centers for Disease Control and Prevention grant U01GH002238 (EN). Salary support was provided by Wellcome Trust grant 206250/Z/17/Z (AK) and the Australian National Health and Medical Research Council Investigator grant APP1158469 (CLL).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142132155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-02DOI: 10.1016/j.ebiom.2024.105277
Therese Yien May Lim, Chaitanya K Jaladanki, Yi Hao Wong, Thinesshwary Yogarajah, Hao Fan, Justin Jang Hann Chu
Background: Global cyclical outbreaks of human enterovirus infections has positioned human enterovirus A71 (EV-A71) as a neurotropic virus of clinical importance. However, there remains a scarcity of internationally approved antivirals and vaccines.
Methods: In pursuit of repurposing drugs for combating human enteroviruses, we employed a comprehensive pharmacophore- and molecular docking-based virtual screen targeting EV-A71 capsid protein VP1-4, 3C protease, and 3D polymerase proteins. Among 15 shortlisted ligand candidates, we dissected the inhibitory mechanism of Tanomastat in cell-based studies and evaluated its in vivo efficacy in an EV-A71-infected murine model.
Findings: We demonstrated that Tanomastat exerts dose-dependent inhibition on EV-A71 replication, with comparable efficacy profiles in enterovirus species A, B, C, and D in vitro. Time-course studies suggested that Tanomastat predominantly disrupts early process(es) of the EV-A71 replication cycle. Mechanistically, live virus particle tracking and docking predictions revealed that Tanomastat specifically impedes viral capsid dissociation, potentially via VP1 hydrophobic pocket binding. Bypassing its inhibition on entry stages, we utilized EV-A71 replication-competent, 3Dpol replication-defective, and bicistronic IRES reporter replicons to show that Tanomastat also inhibits viral RNA replication, but not viral IRES translation. We further showed that orally administered Tanomastat achieved 85% protective therapeutic effect and alleviated clinical symptoms in EV-A71-infected neonatal mice.
Interpretation: Our study establishes Tanomastat as a broad-spectrum anti-enterovirus candidate with promising pre-clinical efficacy, warranting further testing for potential therapeutic application.
Funding: MOE Tier 2 grants (MOE-T2EP30221-0005, R571-000-068-592, R571-000-076-515, R571-000-074-733) and A∗STARBiomedical Research Council (BMRC).
背景：全球周期性爆发的人类肠道病毒感染已使人类肠道病毒 A71（EV-A71）成为一种具有重要临床意义的神经性病毒。然而，国际上批准的抗病毒药物和疫苗仍然稀缺：方法：为寻求抗人类肠道病毒药物的再利用，我们采用了基于药理和分子对接的综合虚拟筛选方法，靶向 EV-A71 的荚膜蛋白 VP1-4、3C 蛋白酶和 3D 聚合酶蛋白。在筛选出的15种候选配体中，我们在基于细胞的研究中剖析了坦诺玛司特的抑制机制，并在EV-A71感染的小鼠模型中评估了其体内疗效：我们证明了坦诺玛司特对EV-A71复制具有剂量依赖性抑制作用，在体外对A、B、C和D型肠道病毒具有相似的疗效。时间进程研究表明，坦诺玛司特主要破坏EV-A71复制周期的早期过程。从机理上讲，活病毒粒子跟踪和对接预测显示，坦诺玛司特可能通过 VP1 疏水袋结合，特异性地阻碍病毒荚膜解离。绕过其对进入阶段的抑制作用，我们利用EV-A71复制能力强、3Dpol复制缺陷和双双子IRES报告复制子表明，坦诺玛司特也抑制病毒RNA复制，但不抑制病毒IRES翻译。我们进一步发现，口服坦诺玛司特对EV-A71感染的新生小鼠有85%的保护性治疗效果，并能缓解临床症状：我们的研究确定了坦诺玛司特是一种广谱抗肠病毒候选药物，具有良好的临床前疗效，值得进一步测试其潜在的治疗应用：教育部二级基金（MOE-T2EP30221-0005、R571-000-068-592、R571-000-076-515、R571-000-074-733）和A∗STAR生物医学研究理事会（BMRC）。
{"title":"Tanomastat exerts multi-targeted inhibitory effects on viral capsid dissociation and RNA replication in human enteroviruses.","authors":"Therese Yien May Lim, Chaitanya K Jaladanki, Yi Hao Wong, Thinesshwary Yogarajah, Hao Fan, Justin Jang Hann Chu","doi":"10.1016/j.ebiom.2024.105277","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105277","url":null,"abstract":"<p><strong>Background: </strong>Global cyclical outbreaks of human enterovirus infections has positioned human enterovirus A71 (EV-A71) as a neurotropic virus of clinical importance. However, there remains a scarcity of internationally approved antivirals and vaccines.</p><p><strong>Methods: </strong>In pursuit of repurposing drugs for combating human enteroviruses, we employed a comprehensive pharmacophore- and molecular docking-based virtual screen targeting EV-A71 capsid protein VP1-4, 3C protease, and 3D polymerase proteins. Among 15 shortlisted ligand candidates, we dissected the inhibitory mechanism of Tanomastat in cell-based studies and evaluated its in vivo efficacy in an EV-A71-infected murine model.</p><p><strong>Findings: </strong>We demonstrated that Tanomastat exerts dose-dependent inhibition on EV-A71 replication, with comparable efficacy profiles in enterovirus species A, B, C, and D in vitro. Time-course studies suggested that Tanomastat predominantly disrupts early process(es) of the EV-A71 replication cycle. Mechanistically, live virus particle tracking and docking predictions revealed that Tanomastat specifically impedes viral capsid dissociation, potentially via VP1 hydrophobic pocket binding. Bypassing its inhibition on entry stages, we utilized EV-A71 replication-competent, 3D<sup>pol</sup> replication-defective, and bicistronic IRES reporter replicons to show that Tanomastat also inhibits viral RNA replication, but not viral IRES translation. We further showed that orally administered Tanomastat achieved 85% protective therapeutic effect and alleviated clinical symptoms in EV-A71-infected neonatal mice.</p><p><strong>Interpretation: </strong>Our study establishes Tanomastat as a broad-spectrum anti-enterovirus candidate with promising pre-clinical efficacy, warranting further testing for potential therapeutic application.</p><p><strong>Funding: </strong>MOE Tier 2 grants (MOE-T2EP30221-0005, R571-000-068-592, R571-000-076-515, R571-000-074-733) and A∗STARBiomedical Research Council (BMRC).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142125152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-02DOI: 10.1016/j.ebiom.2024.105307
Yuyao Yin, Pengyuan Zhu, Yifan Guo, Yingzhen Li, Hongbin Chen, Jun Liu, Lingxiao Sun, Shuai Ma, Chaohui Hu, Hui Wang
Background: Shotgun metagenomic next-generation sequencing (mNGS) is widely used to detect pathogens in bronchoalveolar lavage fluid (BALF). However, mNGS is complex and expensive. This study explored the feasibility of targeted next-generation sequencing (tNGS) in distinguishing lower respiratory tract infections in clinical practice.
Methods: We used 229 retrospective BALF samples to establish thresholds and diagnostic values in a prospective cohort of 251 patients. After target pathogen selection, primer and probe design, optimization experiments, and bioinformatics analysis, multiplex PCR-based tNGS (mp-tNGS) and hybrid capture-based tNGS (hc-tNGS), targeting 198 and 3060 pathogens (DNA and RNA co-detection workflow) were established and performed.
Findings: mp-tNGS and hc-tNGS took 10.3 and 16 h, respectively, with low sequencing data sizes of 0.1 M and 1 M reads, and test costs reduced to a quarter and half of mNGS. The LoDs of mp-tNGS and hc-tNGS were 50-450 CFU/mL. mp-tNGS and hc-tNGS were highly accurate, with 86.5% and 87.3% (vs. 85.5% for mNGS) sensitivities and 90.0% and 88.0% (vs. 92.1% for mNGS) specificities. tNGS detection rates for casual pathogens were 84.3% and 89.5% (vs. 88.5% for mNGS), significantly higher than conventional microbiological tests (P < 0.001). In seven samples, tNGS detected Pneumocystis jirovecii, a fungus not detected by mNGS. Whereas mNGS detected six samples with filamentous fungi (Rhizopus oryzae, Aureobasidium pullulans, Aspergillus niger complex, etc.) which missed by tNGS. The anaerobic bacteria as pathogen in eight samples was failed to detect by mp-tNGS.
Interpretation: tNGS may offer a new, broad-spectrum, rapid, accurate and cost-effective approach to diagnosing respiratory infections.
Funding: National Natural Science Foundation of China (81625014 and 82202535).
{"title":"Enhancing lower respiratory tract infection diagnosis: implementation and clinical assessment of multiplex PCR-based and hybrid capture-based targeted next-generation sequencing.","authors":"Yuyao Yin, Pengyuan Zhu, Yifan Guo, Yingzhen Li, Hongbin Chen, Jun Liu, Lingxiao Sun, Shuai Ma, Chaohui Hu, Hui Wang","doi":"10.1016/j.ebiom.2024.105307","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105307","url":null,"abstract":"<p><strong>Background: </strong>Shotgun metagenomic next-generation sequencing (mNGS) is widely used to detect pathogens in bronchoalveolar lavage fluid (BALF). However, mNGS is complex and expensive. This study explored the feasibility of targeted next-generation sequencing (tNGS) in distinguishing lower respiratory tract infections in clinical practice.</p><p><strong>Methods: </strong>We used 229 retrospective BALF samples to establish thresholds and diagnostic values in a prospective cohort of 251 patients. After target pathogen selection, primer and probe design, optimization experiments, and bioinformatics analysis, multiplex PCR-based tNGS (mp-tNGS) and hybrid capture-based tNGS (hc-tNGS), targeting 198 and 3060 pathogens (DNA and RNA co-detection workflow) were established and performed.</p><p><strong>Findings: </strong>mp-tNGS and hc-tNGS took 10.3 and 16 h, respectively, with low sequencing data sizes of 0.1 M and 1 M reads, and test costs reduced to a quarter and half of mNGS. The LoDs of mp-tNGS and hc-tNGS were 50-450 CFU/mL. mp-tNGS and hc-tNGS were highly accurate, with 86.5% and 87.3% (vs. 85.5% for mNGS) sensitivities and 90.0% and 88.0% (vs. 92.1% for mNGS) specificities. tNGS detection rates for casual pathogens were 84.3% and 89.5% (vs. 88.5% for mNGS), significantly higher than conventional microbiological tests (P < 0.001). In seven samples, tNGS detected Pneumocystis jirovecii, a fungus not detected by mNGS. Whereas mNGS detected six samples with filamentous fungi (Rhizopus oryzae, Aureobasidium pullulans, Aspergillus niger complex, etc.) which missed by tNGS. The anaerobic bacteria as pathogen in eight samples was failed to detect by mp-tNGS.</p><p><strong>Interpretation: </strong>tNGS may offer a new, broad-spectrum, rapid, accurate and cost-effective approach to diagnosing respiratory infections.</p><p><strong>Funding: </strong>National Natural Science Foundation of China (81625014 and 82202535).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142125151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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