Stephanie L Rolsma, Andrew Sokolow, Pratish C Patel, Katherine Sokolow, Natalia Jimenez-Truque, William H Fissell, Vivian Ryan, Carl M Kirkpatrick, Roger L Nation, Kenan Gu, Mary Teresi, Nicholas Fishbane, Marissa Kontos, Guohua An, Patricia Winokur, Cornelia B Landersdorfer, C Buddy Creech
Background Patients with cystic fibrosis (CF) experience recurrent bacterial pulmonary exacerbations. Management of these infections is increasingly challenging due to decreased antimicrobial susceptibility to beta-lactam antibiotics. The pharmacokinetics of these agents are inadequately characterized in patients with CF. Methods One hundred fifty-five pediatric and adult participants with CF receiving cefepime (n=82), meropenem (n=42), or piperacillin-tazobactam (n=31) were enrolled. Opportunistic blood samples were obtained during hospitalization. Population PK analysis was conducted using nonlinear mixed-effects modeling. Clinical and demographic characteristics were evaluated as potential covariates. Monte Carlo simulations were performed to evaluate probability of target attainment (PTA) for different dosing regimens. Results Estimated creatinine clearance, and total or lean body weight, affected the pharmacokinetics of cefepime and meropenem. No covariates were identified for piperacillin and tazobactam. In the cefepime group, a 3-h infusion achieved higher PTA than a 0.5-h infusion for all participants. Estimated breakpoints (the respective minimum inhibitory concentration (MIC) up to which ≥90% of patients are predicted to reach a PK/PD target) were two- to four-fold higher in pediatric participants receiving a 3-h vs. 0.5-h infusion. In the meropenem group, increased creatinine clearance led to reduced PTA. In the piperacillin-tazobactam group, total daily dose and mode of administration were principal drivers of PTA. Conclusions Standard dosing regimens fail to achieve specific MIC targets in patients with CF. Therefore, clinicians should incorporate local antibiograms and PK models to determine optimal dosing. Further PK optimization to account for interindividual differences could be achieved by real-time beta-lactam therapeutic drug monitoring.
{"title":"Population Pharmacokinetic Modeling of Cefepime, Meropenem, and Piperacillin-Tazobactam in Patients with Cystic Fibrosis","authors":"Stephanie L Rolsma, Andrew Sokolow, Pratish C Patel, Katherine Sokolow, Natalia Jimenez-Truque, William H Fissell, Vivian Ryan, Carl M Kirkpatrick, Roger L Nation, Kenan Gu, Mary Teresi, Nicholas Fishbane, Marissa Kontos, Guohua An, Patricia Winokur, Cornelia B Landersdorfer, C Buddy Creech","doi":"10.1093/infdis/jiae451","DOIUrl":"https://doi.org/10.1093/infdis/jiae451","url":null,"abstract":"Background Patients with cystic fibrosis (CF) experience recurrent bacterial pulmonary exacerbations. Management of these infections is increasingly challenging due to decreased antimicrobial susceptibility to beta-lactam antibiotics. The pharmacokinetics of these agents are inadequately characterized in patients with CF. Methods One hundred fifty-five pediatric and adult participants with CF receiving cefepime (n=82), meropenem (n=42), or piperacillin-tazobactam (n=31) were enrolled. Opportunistic blood samples were obtained during hospitalization. Population PK analysis was conducted using nonlinear mixed-effects modeling. Clinical and demographic characteristics were evaluated as potential covariates. Monte Carlo simulations were performed to evaluate probability of target attainment (PTA) for different dosing regimens. Results Estimated creatinine clearance, and total or lean body weight, affected the pharmacokinetics of cefepime and meropenem. No covariates were identified for piperacillin and tazobactam. In the cefepime group, a 3-h infusion achieved higher PTA than a 0.5-h infusion for all participants. Estimated breakpoints (the respective minimum inhibitory concentration (MIC) up to which ≥90% of patients are predicted to reach a PK/PD target) were two- to four-fold higher in pediatric participants receiving a 3-h vs. 0.5-h infusion. In the meropenem group, increased creatinine clearance led to reduced PTA. In the piperacillin-tazobactam group, total daily dose and mode of administration were principal drivers of PTA. Conclusions Standard dosing regimens fail to achieve specific MIC targets in patients with CF. Therefore, clinicians should incorporate local antibiograms and PK models to determine optimal dosing. Further PK optimization to account for interindividual differences could be achieved by real-time beta-lactam therapeutic drug monitoring.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Thaís M M Barreto, Roberta S Souza, Raquel B São Pedro, Isadora M Paiva, Andréia S Silva, Ana L Nogueira, Ana P N Bellinat, Nathália L S Dias, Sara Nunes, Gabriela S G Britto, Edson H B Amaral, Gabriela D Rocha, Carolina Silva-Carvalho, Ricardo Lyra, Fernanda S G Kehdy, Túlio L Campos, Patrícia M M F Moura, Eduardo Tarazona-Santos, Thiago M Cunha, Natália M Tavares, Marcus V B Oliveira-Sá, Regina C F Ramos, Rodrigo F Carmo, Luydson R S Vasconcelos, Pablo R S Oliveira
Multisystem Inflammatory Syndrome in Children (MIS-C) is a rare, potentially fatal complication of SARS-CoV-2 infection. Genetic defects in inflammation-related pathways have been linked to MIS-C, but additional research is needed, especially in diverse ethnic groups. The present study aimed to identify genetic variants underlying MIS-C in Brazilian patients. Whole-exome sequencing was performed, focusing on genes involved in the host immune response to SARS-CoV-2. Functional assays assessed the impact of selected variants on NF-κB signaling. Nine rare, potentially deleterious variants were found in eight of 21 patients, located in IL17RC, IFNA10, or NLRP12 genes. Unlike the wild-type NLRP12 protein, which inhibits NF-κB activation in HEK 293T cells, the mutant NLRP12 proteins have significantly reduced inhibitory properties. In conclusion, our results indicate that rare autosomal variants in immune-related genes may underlie MIS-C, highlighting the potential role of NLRP12 in its predisposition. These findings provide new insights for the appropriate management of MIS-C.
{"title":"Rare genetic variants of NLRP12 in Admixed Latino-American Children with SARS-CoV-2-related Multisystem Inflammatory Syndrome","authors":"Thaís M M Barreto, Roberta S Souza, Raquel B São Pedro, Isadora M Paiva, Andréia S Silva, Ana L Nogueira, Ana P N Bellinat, Nathália L S Dias, Sara Nunes, Gabriela S G Britto, Edson H B Amaral, Gabriela D Rocha, Carolina Silva-Carvalho, Ricardo Lyra, Fernanda S G Kehdy, Túlio L Campos, Patrícia M M F Moura, Eduardo Tarazona-Santos, Thiago M Cunha, Natália M Tavares, Marcus V B Oliveira-Sá, Regina C F Ramos, Rodrigo F Carmo, Luydson R S Vasconcelos, Pablo R S Oliveira","doi":"10.1093/infdis/jiae480","DOIUrl":"https://doi.org/10.1093/infdis/jiae480","url":null,"abstract":"Multisystem Inflammatory Syndrome in Children (MIS-C) is a rare, potentially fatal complication of SARS-CoV-2 infection. Genetic defects in inflammation-related pathways have been linked to MIS-C, but additional research is needed, especially in diverse ethnic groups. The present study aimed to identify genetic variants underlying MIS-C in Brazilian patients. Whole-exome sequencing was performed, focusing on genes involved in the host immune response to SARS-CoV-2. Functional assays assessed the impact of selected variants on NF-κB signaling. Nine rare, potentially deleterious variants were found in eight of 21 patients, located in IL17RC, IFNA10, or NLRP12 genes. Unlike the wild-type NLRP12 protein, which inhibits NF-κB activation in HEK 293T cells, the mutant NLRP12 proteins have significantly reduced inhibitory properties. In conclusion, our results indicate that rare autosomal variants in immune-related genes may underlie MIS-C, highlighting the potential role of NLRP12 in its predisposition. These findings provide new insights for the appropriate management of MIS-C.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142325598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
V Murugaiah, S J Watson, R F Cunliffe, N J Temperton, S T Reece, P Kellam, J S Tregoning
The development of a universal influenza vaccine likely requires an understanding of previous exposure to influenza virus (through vaccination or infection) and how that shapes the antibody repertoire to vaccination, sometimes called Original Antigenic Sin or antigenic imprinting. Whilst animal models can have a much more defined exposure history, they lack a human B cell repertoire. Transgenic mice with the complete human immunoglobulin locus enable studies of controlled infection history leading to human-like antibody evolution. Here we evaluated responses to influenza in the Intelliselect Transgenic mouse (the Kymouse). We show the Kymouse is susceptible to disease following infection with either H1N1, H3N2 or B/Yam influenza viruses and that it induces a robust binding and neutralising antibody response to all three strains of influenza virus. This study demonstrates that human B cell repertoire mice can be used for influenza virus studies, providing a tool for further interrogation of the antibody response.
开发通用流感疫苗可能需要了解以前接触流感病毒的情况（通过接种疫苗或感染），以及这种情况如何形成接种疫苗后的抗体库，有时也称为 "原始抗原罪 "或 "抗原印记"。虽然动物模型可以有更明确的接触史，但它们缺乏人类 B 细胞群。具有完整人类免疫球蛋白基因座的转基因小鼠可用于研究受控感染史导致的类人抗体进化。在这里，我们评估了 Intelliselect 转基因小鼠（Kymouse）对流感的反应。我们的研究表明，Kymouse 感染 H1N1、H3N2 或 B/Yam 流感病毒后易发病，并能诱导出对所有三种流感病毒株的强结合和中和抗体反应。这项研究表明，人类 B 细胞谱系小鼠可用于流感病毒研究，为进一步研究抗体反应提供了工具。
{"title":"A transgenic mouse with a humanised B cell repertoire mounts an antibody response to influenza infection and vaccination","authors":"V Murugaiah, S J Watson, R F Cunliffe, N J Temperton, S T Reece, P Kellam, J S Tregoning","doi":"10.1093/infdis/jiae472","DOIUrl":"https://doi.org/10.1093/infdis/jiae472","url":null,"abstract":"The development of a universal influenza vaccine likely requires an understanding of previous exposure to influenza virus (through vaccination or infection) and how that shapes the antibody repertoire to vaccination, sometimes called Original Antigenic Sin or antigenic imprinting. Whilst animal models can have a much more defined exposure history, they lack a human B cell repertoire. Transgenic mice with the complete human immunoglobulin locus enable studies of controlled infection history leading to human-like antibody evolution. Here we evaluated responses to influenza in the Intelliselect Transgenic mouse (the Kymouse). We show the Kymouse is susceptible to disease following infection with either H1N1, H3N2 or B/Yam influenza viruses and that it induces a robust binding and neutralising antibody response to all three strains of influenza virus. This study demonstrates that human B cell repertoire mice can be used for influenza virus studies, providing a tool for further interrogation of the antibody response.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Linda Niemetz, Bianca S Bodmer, Catherine Olal, Beatriz Escudero-Pérez, Katharina Hoehn, András Bencsik, Molly A Vickers, Estefanía Rodríguez, Lisa Oestereich, Thomas Hoenen, César Muñoz-Fontela
Background Previous studies have described that Ebola virus (EBOV) infection of human monocyte–derived dendritic cells (moDCs) inhibits dendritic cell (DC) maturation, resulting in poor T-cell activation. However, it is unknown how other DC subsets distinct from moDCs respond to EBOV infection. Methods To better understand how DCs initiate T-cell activation during EBOV infection, we assessed the response of conventional mouse DCs (cDCs) to EBOV infection utilizing a recombinant EBOV expressing the model antigen ovalbumin. Results In contrast to moDCs, mouse cDC2s and cDC1s were poorly infected with EBOV but were highly activated. DCs were able to prime CD8 T cells via cross-presentation of antigens obtained from cell debris of EBOV-infected cells. EBOV infection further enhanced DC cross-presentation. Conclusions Our findings indicate that EBOV infection of cDCs results in activation rather than inhibition, leading to high levels of T-cell activation. With that we propose a mechanistic explanation for the excess T-cell activation observed in human Ebola virus disease.
背景 以前的研究表明，埃博拉病毒（EBOV）感染人类单核细胞衍生树突状细胞（moDCs）会抑制树突状细胞（DC）成熟，导致 T 细胞活化不良。然而，与moDCs不同的其他DC亚群如何应对EBOV感染尚不清楚。方法 为了更好地了解DC如何在EBOV感染期间启动T细胞活化，我们利用表达模式抗原卵清蛋白的重组EBOV评估了常规小鼠DC（cDCs）对EBOV感染的反应。结果 与 moDCs 相反，小鼠 cDC2s 和 cDC1s 感染 EBOV 后的活化程度很低。DC能够通过交叉呈递从EBOV感染细胞的细胞碎片中获得的抗原来激活CD8 T细胞。EBOV 感染进一步增强了 DC 的交叉呈递能力。结论 我们的研究结果表明，EBOV 感染 cDCs 会导致活化而非抑制，从而导致高水平的 T 细胞活化。因此，我们提出了在人类埃博拉病毒疾病中观察到的T细胞过度活化的机理解释。
{"title":"Ebola Virus Infection of Flt3-Dependent, Conventional Dendritic Cells and Antigen Cross-presentation Leads to High Levels of T-Cell Activation","authors":"Linda Niemetz, Bianca S Bodmer, Catherine Olal, Beatriz Escudero-Pérez, Katharina Hoehn, András Bencsik, Molly A Vickers, Estefanía Rodríguez, Lisa Oestereich, Thomas Hoenen, César Muñoz-Fontela","doi":"10.1093/infdis/jiae441","DOIUrl":"https://doi.org/10.1093/infdis/jiae441","url":null,"abstract":"Background Previous studies have described that Ebola virus (EBOV) infection of human monocyte–derived dendritic cells (moDCs) inhibits dendritic cell (DC) maturation, resulting in poor T-cell activation. However, it is unknown how other DC subsets distinct from moDCs respond to EBOV infection. Methods To better understand how DCs initiate T-cell activation during EBOV infection, we assessed the response of conventional mouse DCs (cDCs) to EBOV infection utilizing a recombinant EBOV expressing the model antigen ovalbumin. Results In contrast to moDCs, mouse cDC2s and cDC1s were poorly infected with EBOV but were highly activated. DCs were able to prime CD8 T cells via cross-presentation of antigens obtained from cell debris of EBOV-infected cells. EBOV infection further enhanced DC cross-presentation. Conclusions Our findings indicate that EBOV infection of cDCs results in activation rather than inhibition, leading to high levels of T-cell activation. With that we propose a mechanistic explanation for the excess T-cell activation observed in human Ebola virus disease.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142321389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sahera Dirajlal-Fargo, Melica Nikahd, Kate Ailstock, Manjunath Manubolu, Victor Musiime, Cissy Kityo, Grace A McComsey, Nicholas T Funderburg
This study examined the changes in the lipidome and associations with immune activation and cardiovascular disease markers in youth living with perinatally acquired HIV (YPHIV). The serum lipidome was measured in ART-treated YPHIV (n=100) and HIV- Ugandan children (n=98) Plasma markers of systemic inflammation, monocyte activation, gut integrity, T cell activation, as well as and common carotid artery intima-media thickness (IMT) and pulse wave velocity (PWV) were evaluated at baseline and 96 weeks. Overall, median age was 12 years,52% were females. Total cholesterol, LDL, and HDL were similar between the groups, however, the concentrations of ceramides, diacylglycerols, free fatty acids, lysophysophatidylcholines and phosphatidylcholines, were higher in YPHIV (P≤0.03). Increases in phosphatidylethanolamine (16:0 and 18:0) correlated with increases in sCD163, OxLDL, CRP, IFAB and PWV in PHIV (r≥0.3). YPHIV, successfully suppressed on ART, have elevated lipid species that are associated with CVD, specificallypalmitic acid (C16:0) and stearic acid (C18:0).
{"title":"Changes in the lipidome are associated with immune activation and subclinical vascular disease in youth with HIV in Uganda","authors":"Sahera Dirajlal-Fargo, Melica Nikahd, Kate Ailstock, Manjunath Manubolu, Victor Musiime, Cissy Kityo, Grace A McComsey, Nicholas T Funderburg","doi":"10.1093/infdis/jiae461","DOIUrl":"https://doi.org/10.1093/infdis/jiae461","url":null,"abstract":"This study examined the changes in the lipidome and associations with immune activation and cardiovascular disease markers in youth living with perinatally acquired HIV (YPHIV). The serum lipidome was measured in ART-treated YPHIV (n=100) and HIV- Ugandan children (n=98) Plasma markers of systemic inflammation, monocyte activation, gut integrity, T cell activation, as well as and common carotid artery intima-media thickness (IMT) and pulse wave velocity (PWV) were evaluated at baseline and 96 weeks. Overall, median age was 12 years,52% were females. Total cholesterol, LDL, and HDL were similar between the groups, however, the concentrations of ceramides, diacylglycerols, free fatty acids, lysophysophatidylcholines and phosphatidylcholines, were higher in YPHIV (P≤0.03). Increases in phosphatidylethanolamine (16:0 and 18:0) correlated with increases in sCD163, OxLDL, CRP, IFAB and PWV in PHIV (r≥0.3). YPHIV, successfully suppressed on ART, have elevated lipid species that are associated with CVD, specificallypalmitic acid (C16:0) and stearic acid (C18:0).","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142328909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sofia Bartholdsson, Maria-Pia Hergens, Karin E Hansson, Josef Ragnarsson, Peter Hodosi, Ismail Kus, Mona Insulander, Sirkka Vene, Lars Lindquist, Helena H Askling, Sara Gredmark-Russ
Background The incidence of Tick-borne encephalitis (TBE) has increased during the last decades in Europe. Our aim was to assess the clinical characteristics and outcome of TBE patients in Region Stockholm, as a high-risk area in Sweden. Methods The notification database at the regional Department of Communicable Disease Control and Prevention was used to identify TBE cases during 2006-2015. Clinical data was retrieved from the included patients’ medical records. The associations of specific variables to predefined outcomes of disease severity were evaluated with multivariate logistic regression models. Results Of 1004 identified TBE cases, 703 adult patients were included. Sixty-one percent were men, and the median age was 50 years (range 18-94). The majority were non-vaccinated. Comorbidity was present in 34%, and 4% had immunomodulatory therapy. Seventy-five percent were hospitalised, and 11% had severe disease. More than 70% of the 79 patients followed up for more than 6 months had persisting symptoms. The case fatality rate was 1.4%, with 15% in the group with immunomodulatory treatment. In the multivariate analysis, severe disease was associated with underlying comorbidities, age ≥50 years, and previous complete TBE vaccination. Conclusion This is the largest cohort of TBE patients in Scandinavia. Our findings of a more severe course of disease in patients of older age, with immunomodulatory therapy, with comorbidities, and vaccination breakthrough infections must be interpreted in the context of hospitalised patients. Optimised prevention is needed for patients with immunomodulatory therapy, given the considerable case fatality rate. Follow-up visits and rehabilitation should be better standardised.
{"title":"Tick-borne Encephalitis Clinical Characteristics in Adult Patients: A 10-year Retrospective Study in Stockholm, Sweden","authors":"Sofia Bartholdsson, Maria-Pia Hergens, Karin E Hansson, Josef Ragnarsson, Peter Hodosi, Ismail Kus, Mona Insulander, Sirkka Vene, Lars Lindquist, Helena H Askling, Sara Gredmark-Russ","doi":"10.1093/infdis/jiae463","DOIUrl":"https://doi.org/10.1093/infdis/jiae463","url":null,"abstract":"Background The incidence of Tick-borne encephalitis (TBE) has increased during the last decades in Europe. Our aim was to assess the clinical characteristics and outcome of TBE patients in Region Stockholm, as a high-risk area in Sweden. Methods The notification database at the regional Department of Communicable Disease Control and Prevention was used to identify TBE cases during 2006-2015. Clinical data was retrieved from the included patients’ medical records. The associations of specific variables to predefined outcomes of disease severity were evaluated with multivariate logistic regression models. Results Of 1004 identified TBE cases, 703 adult patients were included. Sixty-one percent were men, and the median age was 50 years (range 18-94). The majority were non-vaccinated. Comorbidity was present in 34%, and 4% had immunomodulatory therapy. Seventy-five percent were hospitalised, and 11% had severe disease. More than 70% of the 79 patients followed up for more than 6 months had persisting symptoms. The case fatality rate was 1.4%, with 15% in the group with immunomodulatory treatment. In the multivariate analysis, severe disease was associated with underlying comorbidities, age ≥50 years, and previous complete TBE vaccination. Conclusion This is the largest cohort of TBE patients in Scandinavia. Our findings of a more severe course of disease in patients of older age, with immunomodulatory therapy, with comorbidities, and vaccination breakthrough infections must be interpreted in the context of hospitalised patients. Optimised prevention is needed for patients with immunomodulatory therapy, given the considerable case fatality rate. Follow-up visits and rehabilitation should be better standardised.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shanlin Ke, Javier A Villafuerte Gálvez, Zheng Sun, Yangchun Cao, Nira R Pollock, Xinhua Chen, Ciarán P Kelly, Yang-Yu Liu
Clostridioides difficile infection (CDI) is a major cause of healthcare- and antibiotic-associated diarrhea. While fecal microbiota transplantation (FMT) shows promise for recurrent CDI, its mechanisms and long-term safety are not fully understood. Live biotherapeutic products (LBPs) using pre-defined bacterial consortia offer an alternative option, but the rational designing LBPs remains challenging. Here, we employ a computational pipeline and three metagenomic datasets to identify microbial strains for LBPs targeting CDI. We constructed the CDI-related microbial genome catalog, comprising 3,741 non-redundant metagenome-assembled genomes (nrMAGs) and identified multiple potential protective nrMAGs, including strains from Dorea formicigenerans, Oscillibacter welbionis, and Faecalibacterium prausnitzii. Importantly, some of these protective nrMAGs were found to play an important role in FMT success, and most top protective nrMAGs can be validated by various previous findings. Our results demonstrate a framework for selecting microbial strains targeting CDI, paving the way for the computational design of LBPs against other enteric infections.
{"title":"Rational Design of Live Biotherapeutic Products for the Prevention of Clostridioides difficile Infection","authors":"Shanlin Ke, Javier A Villafuerte Gálvez, Zheng Sun, Yangchun Cao, Nira R Pollock, Xinhua Chen, Ciarán P Kelly, Yang-Yu Liu","doi":"10.1093/infdis/jiae470","DOIUrl":"https://doi.org/10.1093/infdis/jiae470","url":null,"abstract":"Clostridioides difficile infection (CDI) is a major cause of healthcare- and antibiotic-associated diarrhea. While fecal microbiota transplantation (FMT) shows promise for recurrent CDI, its mechanisms and long-term safety are not fully understood. Live biotherapeutic products (LBPs) using pre-defined bacterial consortia offer an alternative option, but the rational designing LBPs remains challenging. Here, we employ a computational pipeline and three metagenomic datasets to identify microbial strains for LBPs targeting CDI. We constructed the CDI-related microbial genome catalog, comprising 3,741 non-redundant metagenome-assembled genomes (nrMAGs) and identified multiple potential protective nrMAGs, including strains from Dorea formicigenerans, Oscillibacter welbionis, and Faecalibacterium prausnitzii. Importantly, some of these protective nrMAGs were found to play an important role in FMT success, and most top protective nrMAGs can be validated by various previous findings. Our results demonstrate a framework for selecting microbial strains targeting CDI, paving the way for the computational design of LBPs against other enteric infections.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Developing effective vaccines is necessary in combating new virus pandemics. For HIV and SARS-CoV-2, the induction of neutralizing antibodies (NAb) is important for vaccine protection; however, the exact mechanisms underlying protection require further study. Recent data emphasize that even Abs that do not exhibit neutralizing activity may contribute to immune defense. Abs exhibiting this function may counter virus mutations, which are acquired to escape from NAbs, and therefore, broaden the protective Ab response induced by vaccination. However, the steps leading to Ab Fc-mediated inhibition are complex. How can these functions be measured in vitro? What inhibitory assay is the most physiologically relevant at mimicking effective in vivo protection? This review provides a comprehensive update on the current knowledge gaps on the Ab Fc-mediated functions involved in HIV and SARS-CoV-2 protection. Understanding the inhibitory effects of these Abs is vital for designing the next generation of protective HIV and SARS-CoV-2 vaccines.
开发有效的疫苗对于抗击新的病毒大流行十分必要。对于艾滋病毒和 SARS-CoV-2 而言，诱导中和抗体（NAb）对疫苗保护非常重要；然而，保护的确切机制还需要进一步研究。最近的数据强调，即使不表现出中和活性的 Abs 也可能有助于免疫防御。具有这种功能的抗体可对抗病毒变异，而病毒变异是为了躲避 NAb 而获得的，因此可扩大疫苗接种诱导的抗体保护反应。然而，导致抗体 Fc 介导的抑制作用的步骤非常复杂。如何在体外测量这些功能？哪种抑制试验最能模拟有效的体内保护？本综述全面更新了目前有关参与 HIV 和 SARS-CoV-2 保护的 Ab Fc 介导功能的知识缺口。了解这些抗体的抑制作用对于设计下一代保护性 HIV 和 SARS-CoV-2 疫苗至关重要。
{"title":"Unpredicted protective function of Fc-mediated inhibitory antibodies for HIV and SARS-CoV-2 vaccines.","authors":"Li-Yun Lin,Pierre Gantner,Shuang Li,Bin Su,Christiane Moog","doi":"10.1093/infdis/jiae464","DOIUrl":"https://doi.org/10.1093/infdis/jiae464","url":null,"abstract":"Developing effective vaccines is necessary in combating new virus pandemics. For HIV and SARS-CoV-2, the induction of neutralizing antibodies (NAb) is important for vaccine protection; however, the exact mechanisms underlying protection require further study. Recent data emphasize that even Abs that do not exhibit neutralizing activity may contribute to immune defense. Abs exhibiting this function may counter virus mutations, which are acquired to escape from NAbs, and therefore, broaden the protective Ab response induced by vaccination. However, the steps leading to Ab Fc-mediated inhibition are complex. How can these functions be measured in vitro? What inhibitory assay is the most physiologically relevant at mimicking effective in vivo protection? This review provides a comprehensive update on the current knowledge gaps on the Ab Fc-mediated functions involved in HIV and SARS-CoV-2 protection. Understanding the inhibitory effects of these Abs is vital for designing the next generation of protective HIV and SARS-CoV-2 vaccines.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142273556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
HTLV-1 transforms primary CD4+ T cells in vitro within a short time; however, majority of infected individuals maintain an asymptomatic condition, suggesting there is an equilibrium between the infected cells and the host immunity. In this study, we identified a variation in a major viral antigen epitope, HTLV-1 Tax301-309, in HLA-A24-positive individuals. Mismatch in A24/Tax301-309 multimers impaired detection of anti-Tax CTLs. Notably, over half of the TCRs of the anti-Tax CTLs did not recognize mismatched Tax301-309 peptides. These findings highlighted the importance of matching the viral antigen epitope type in T-cell-based immunotherapy against ATL by using viral antigen Tax.
{"title":"Viral antigen mismatch affects antiviral T-cell response and may impair immunotherapeutic efficacy against adult T-cell leukemia/lymphoma","authors":"Kenji Sugata, Mitsuyoshi Takatori, Omnia Reda, Benjy Jek Yang Tan, Masahito Tokunaga, Tomoo Sato, Mitsuharu Ueda, Yoshihisa Yamano, Atae Utsunomiya, Yorifumi Satou","doi":"10.1093/infdis/jiae457","DOIUrl":"https://doi.org/10.1093/infdis/jiae457","url":null,"abstract":"HTLV-1 transforms primary CD4+ T cells in vitro within a short time; however, majority of infected individuals maintain an asymptomatic condition, suggesting there is an equilibrium between the infected cells and the host immunity. In this study, we identified a variation in a major viral antigen epitope, HTLV-1 Tax301-309, in HLA-A24-positive individuals. Mismatch in A24/Tax301-309 multimers impaired detection of anti-Tax CTLs. Notably, over half of the TCRs of the anti-Tax CTLs did not recognize mismatched Tax301-309 peptides. These findings highlighted the importance of matching the viral antigen epitope type in T-cell-based immunotherapy against ATL by using viral antigen Tax.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142275610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sunwen Chou,Drew J Winston,Robin K Avery,Catherine Cordonnier,Rafael F Duarte,Shariq Haider,Johan Maertens,Karl S Peggs,Carlos Solano,Jo-Anne H Young,Joan Gu,Ginger Pocock,Genovefa A Papanicolaou
BACKGROUNDAmong 547 patients receiving maribavir or valganciclovir for first-episode cytomegalovirus infection after hematopoietic cell transplant, the treatment response rate was 69.6% and 77.4% respectively. Development of maribavir and ganciclovir resistance was compared after receiving either drug.METHODSViral mutations conferring drug resistance were analyzed in plasma DNA extracts at baseline and post-treatment.RESULTSPrior antiviral drug exposure was limited, with only 2 instances of baseline drug resistance detected. An equal number (n=241) received valganciclovir or maribavir for at least 21 days (median 55-56 days). Among them, drug resistance mutations were detected in 24 (10%) maribavir recipients at 35-125 days (median 56) after starting therapy, including in 12 of 14 who experienced a viral load rebound while on therapy. Ganciclovir resistance mutations developed in 6 (2.5%) valganciclovir recipients at 66-110 days (median 90). One maribavir recipient developed a novel UL97 gene mutation (P-loop substitution G343A) that conferred strong maribavir and ganciclovir resistance in vitro. Viral clearance was confirmed in 17 (74%) of 23 patients with emergent maribavir resistance after re-treatment with an alternative CMV antiviral drug.CONCLUSIONAfter 3-8 weeks of therapy, maribavir resistance emerged earlier and more frequently than ganciclovir resistance but was usually treatable using alternative therapy.CLINICAL TRIALS REGISTRATIONNCT02927067 (AURORA).
{"title":"Comparative Emergence of Maribavir and Ganciclovir Resistance in a Randomized Phase 3 Clinical Trial for Treatment of Cytomegalovirus Infection.","authors":"Sunwen Chou,Drew J Winston,Robin K Avery,Catherine Cordonnier,Rafael F Duarte,Shariq Haider,Johan Maertens,Karl S Peggs,Carlos Solano,Jo-Anne H Young,Joan Gu,Ginger Pocock,Genovefa A Papanicolaou","doi":"10.1093/infdis/jiae469","DOIUrl":"https://doi.org/10.1093/infdis/jiae469","url":null,"abstract":"BACKGROUNDAmong 547 patients receiving maribavir or valganciclovir for first-episode cytomegalovirus infection after hematopoietic cell transplant, the treatment response rate was 69.6% and 77.4% respectively. Development of maribavir and ganciclovir resistance was compared after receiving either drug.METHODSViral mutations conferring drug resistance were analyzed in plasma DNA extracts at baseline and post-treatment.RESULTSPrior antiviral drug exposure was limited, with only 2 instances of baseline drug resistance detected. An equal number (n=241) received valganciclovir or maribavir for at least 21 days (median 55-56 days). Among them, drug resistance mutations were detected in 24 (10%) maribavir recipients at 35-125 days (median 56) after starting therapy, including in 12 of 14 who experienced a viral load rebound while on therapy. Ganciclovir resistance mutations developed in 6 (2.5%) valganciclovir recipients at 66-110 days (median 90). One maribavir recipient developed a novel UL97 gene mutation (P-loop substitution G343A) that conferred strong maribavir and ganciclovir resistance in vitro. Viral clearance was confirmed in 17 (74%) of 23 patients with emergent maribavir resistance after re-treatment with an alternative CMV antiviral drug.CONCLUSIONAfter 3-8 weeks of therapy, maribavir resistance emerged earlier and more frequently than ganciclovir resistance but was usually treatable using alternative therapy.CLINICAL TRIALS REGISTRATIONNCT02927067 (AURORA).","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142275333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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