Jing Bi, Qinglong Guo, Yaqi Gong, Xi Chen, Haojia Wu, Li Song, Yating Xu, Min Ou, Zhaoqin Wang, Jiean Chen, Chenran Jiang, Aimei Liu, Guobao Li, Guoliang Zhang
Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb), results in significant morbidity and mortality worldwide. Host-directed therapy (HDT), including conventional drugs, is a promising anti-TB strategy that shows synergistic antibacterial effects when combined with anti-TB drugs. Here, the mycobactericidal effect of three anti-diabetic drugs was examined. Of these, only Troglitazone (Trog) enhanced the antimycobacterial effect in vitro and in vivo. This was due to Trog-mediated autophagy activation. Moreover, a knock-down experiment revealed that Trog activated autophagy and exhibited antimycobacterial activity through the LKB1-AMPK signaling pathway. Molecular docking and co-immunoprecipitation experiments demonstrated that Trog promoted LKB1 phosphorylation and activation by targeting STRADA. Finally, we found that Trog inhibited the intracellular survival of clinical isoniazid (INH)-resistant Mtb, and the combination of Trog and INH showed additive antibacterial effects against Mtb H37Rv. Taken together, anti-diabetic Trog may be repurposed as an HDT candidate and combined with first-line anti-TB drugs.
{"title":"Troglitazone reduces intracellular Mycobacterium tuberculosis survival via macrophage autophagy through LKB1-AMPKα signaling","authors":"Jing Bi, Qinglong Guo, Yaqi Gong, Xi Chen, Haojia Wu, Li Song, Yating Xu, Min Ou, Zhaoqin Wang, Jiean Chen, Chenran Jiang, Aimei Liu, Guobao Li, Guoliang Zhang","doi":"10.1093/infdis/jiae523","DOIUrl":"https://doi.org/10.1093/infdis/jiae523","url":null,"abstract":"Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb), results in significant morbidity and mortality worldwide. Host-directed therapy (HDT), including conventional drugs, is a promising anti-TB strategy that shows synergistic antibacterial effects when combined with anti-TB drugs. Here, the mycobactericidal effect of three anti-diabetic drugs was examined. Of these, only Troglitazone (Trog) enhanced the antimycobacterial effect in vitro and in vivo. This was due to Trog-mediated autophagy activation. Moreover, a knock-down experiment revealed that Trog activated autophagy and exhibited antimycobacterial activity through the LKB1-AMPK signaling pathway. Molecular docking and co-immunoprecipitation experiments demonstrated that Trog promoted LKB1 phosphorylation and activation by targeting STRADA. Finally, we found that Trog inhibited the intracellular survival of clinical isoniazid (INH)-resistant Mtb, and the combination of Trog and INH showed additive antibacterial effects against Mtb H37Rv. Taken together, anti-diabetic Trog may be repurposed as an HDT candidate and combined with first-line anti-TB drugs.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"60 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490445","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}
Keon-Woong Yoon, Ki Back Chu, Gi-Deok Eom, Jie Mao, Eun-Kyung Moon, Sung Soo Kim, Fu-Shi Quan
Visceral leishmaniasis (VL) poses a significant public health challenge due to the lack of an approved human vaccine. We attempted to enhance the efficacy of virus-like particle vaccines expressing the Leishmania donovani promastigote surface antigen (LdPSA-VLP) by adjuvanting with CpG oligodeoxynucleotide (CpG-ODN). Here, adjuvanted vaccine-induced immune responses and their efficacies in mice challenged with mCherry-expressing L. donovani promastigotes were evaluated. Adjuvanted LdPSA-VLP vaccination significantly elevated parasite-specific IgG, IgG1, IgG2a, and IgG2b serum antibody levels. Additionally, vaccinated mice exhibited enhanced germinal center B cells and splenic T cell activities, compared to unimmunized mice. Importantly, adjuvanted LdPSA-VLPs reduced the levels of inflammatory cytokines IFN-γ and IL-6 in visceral organs, leading to decreased total parasite burden and protection against L. donovani challenge. Our findings indicate that CpG-ODN enhanced the protection conferred by LdPSA-VLPs, offering a promising step toward effective VL vaccine development.
由于缺乏已获批准的人类疫苗，内脏利什曼病（VL）对公共卫生构成了重大挑战。我们试图通过CpG寡脱氧核苷酸（CpG-ODN）佐剂来提高表达唐氏利什曼原虫表面抗原的病毒样颗粒疫苗（LdPSA-VLP）的效力。在此，我们评估了佐剂疫苗诱导的免疫反应及其在小鼠体内对表达 mCherry 的唐诺瓦尼原鞭毛虫的免疫效果。佐剂 LdPSA-VLP 疫苗接种能显著提高寄生虫特异性 IgG、IgG1、IgG2a 和 IgG2b 血清抗体水平。此外，与未接种疫苗的小鼠相比，接种疫苗的小鼠生殖中心 B 细胞和脾脏 T 细胞活性增强。重要的是，佐剂 LdPSA-VLPs 降低了内脏器官中炎症细胞因子 IFN-γ 和 IL-6 的水平，从而减少了寄生虫的总负荷，保护小鼠免受唐诺瓦尼氏菌的侵袭。我们的研究结果表明，CpG-ODN增强了LdPSA-VLPs的保护作用，为有效开发VL疫苗迈出了充满希望的一步。
{"title":"CpG-adjuvanted virus-like particle vaccine induces protective immunity against Leishmania donovani infection","authors":"Keon-Woong Yoon, Ki Back Chu, Gi-Deok Eom, Jie Mao, Eun-Kyung Moon, Sung Soo Kim, Fu-Shi Quan","doi":"10.1093/infdis/jiae526","DOIUrl":"https://doi.org/10.1093/infdis/jiae526","url":null,"abstract":"Visceral leishmaniasis (VL) poses a significant public health challenge due to the lack of an approved human vaccine. We attempted to enhance the efficacy of virus-like particle vaccines expressing the Leishmania donovani promastigote surface antigen (LdPSA-VLP) by adjuvanting with CpG oligodeoxynucleotide (CpG-ODN). Here, adjuvanted vaccine-induced immune responses and their efficacies in mice challenged with mCherry-expressing L. donovani promastigotes were evaluated. Adjuvanted LdPSA-VLP vaccination significantly elevated parasite-specific IgG, IgG1, IgG2a, and IgG2b serum antibody levels. Additionally, vaccinated mice exhibited enhanced germinal center B cells and splenic T cell activities, compared to unimmunized mice. Importantly, adjuvanted LdPSA-VLPs reduced the levels of inflammatory cytokines IFN-γ and IL-6 in visceral organs, leading to decreased total parasite burden and protection against L. donovani challenge. Our findings indicate that CpG-ODN enhanced the protection conferred by LdPSA-VLPs, offering a promising step toward effective VL vaccine development.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"110 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489578","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}
Isabel Leroux-Roels, Azhar Alhatemi, Magalie Caubet, Fien De Boever, Bertrand de Wergifosse, Mohamed El Idrissi, Guilherme S Ferreira, Bart Jacobs, Axel Lambert, Sandra Morel, Charlotte Servais, Juan Pablo Yarzabal
Background This study investigated the safety, reactogenicity, and immunogenicity in healthy subjects of a Clostridioides difficile vaccine candidate with/without adjuvant, targeting toxins A and B. Methods In this first-in-human, phase 1, observer-blind study, subjects aged 18–45 years were randomized to receive F2 antigen (n = 10) or placebo (n = 10), and subjects aged 50–70 years to receive F2 antigen plus AS01 adjuvant (n = 45), F2 antigen (n = 45), or placebo (n = 30) in 2 doses 1 month apart. A subcohort (n = 40) received a third dose 15 months later. Solicited adverse events (AEs) were recorded for 7 days and unsolicited AEs for 30 days after each dose. Immunogenicity was assessed at baseline and after each dose. Results Solicited AEs were transient and most frequent in subjects receiving F2 antigen plus AS01. No serious AEs were considered related to study vaccine. Immunogenicity was substantially higher in subjects receiving F2 antigen plus AS01 than subjects receiving F2 antigen alone. A third dose increased the immune response in subjects with baseline neutralization titers below the assay lower limit of quantitation. Conclusions The GSK C. difficile vaccine candidate was immunogenic, especially when given with AS01, and was well tolerated with an acceptable safety profile. Clinical Trial Registration NCT04026009.
{"title":"Safety and Immunogenicity of an Adjuvanted Clostridioides difficile Vaccine Candidate in Healthy Adults: A Randomized Placebo-Controlled Phase 1 Study","authors":"Isabel Leroux-Roels, Azhar Alhatemi, Magalie Caubet, Fien De Boever, Bertrand de Wergifosse, Mohamed El Idrissi, Guilherme S Ferreira, Bart Jacobs, Axel Lambert, Sandra Morel, Charlotte Servais, Juan Pablo Yarzabal","doi":"10.1093/infdis/jiae466","DOIUrl":"https://doi.org/10.1093/infdis/jiae466","url":null,"abstract":"Background This study investigated the safety, reactogenicity, and immunogenicity in healthy subjects of a Clostridioides difficile vaccine candidate with/without adjuvant, targeting toxins A and B. Methods In this first-in-human, phase 1, observer-blind study, subjects aged 18–45 years were randomized to receive F2 antigen (n = 10) or placebo (n = 10), and subjects aged 50–70 years to receive F2 antigen plus AS01 adjuvant (n = 45), F2 antigen (n = 45), or placebo (n = 30) in 2 doses 1 month apart. A subcohort (n = 40) received a third dose 15 months later. Solicited adverse events (AEs) were recorded for 7 days and unsolicited AEs for 30 days after each dose. Immunogenicity was assessed at baseline and after each dose. Results Solicited AEs were transient and most frequent in subjects receiving F2 antigen plus AS01. No serious AEs were considered related to study vaccine. Immunogenicity was substantially higher in subjects receiving F2 antigen plus AS01 than subjects receiving F2 antigen alone. A third dose increased the immune response in subjects with baseline neutralization titers below the assay lower limit of quantitation. Conclusions The GSK C. difficile vaccine candidate was immunogenic, especially when given with AS01, and was well tolerated with an acceptable safety profile. Clinical Trial Registration NCT04026009.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489579","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}
Background The interaction between antibodies and Fc gamma receptors (FcγRs) plays a critical role in regulating immune responses to Plasmodium falciparum. Polymorphisms in genes encoding FcγRs influence the host's capacity to control parasite infection. This study investigates whether non-coding variants influencing FcγR expression are associated with anti-malarial immunization and infection traits. Methods We utilized eQTL databases and functional annotations to identify non-coding variants, specifically rs1771575, rs2099684, and rs6700241, within the FCGR gene cluster. In addition, we examined the coding variants rs1801274 (p.His167Arg) and rs1050501 (p.Ile231Thr), which affect the affinity of FcγRIIa and FcγRIIb for IgG. These variants were genotyped in 163 individuals from Burkinabe families. Family-based linear mixed regression and Quantitative Transmission Disequilibrium Tests (QTDT) analyses were performed to assess associations with IgG levels and malaria infection, accounting for relevant covariates. Results Linear mixed models identified rs1771575 as associated with total IgG levels, while both rs1771575 and rs1801274 were linked to IgG2, and rs1050501 to IgG1 levels. A haplotype combining rs2099684 and rs6700241 was positively associated with IgG1. The rs1771575-CC and rs1050501-TT genotypes correlated with higher infection levels in children. QTDT models confirmed the association of rs1771575 with IgG2 and infection in children. Conclusions Our findings suggest that the intergenic variant rs1771575 serves as an independent marker for IgG levels and blood infection in children. This highlights the interplay between regulatory variants and coding mutations in FCGR, which may influence immune function and antibody production. These results underscore the potential for personalized strategies to monitor humoral responses in malaria-endemic regions.
{"title":"An Expression Quantitative Trait Locus of Fc Gamma Receptor Genes is Associated with Anti-Malarial IgG Responses and Infection Levels in Burkinabe Families","authors":"Christelle Dieppois, Mathieu Adjemout, Jules Cretin, Frederic Gallardo, Magali Torres, Christophe Picard, Serge Aimé Sawadogo, Pascal Rihet, Pascale Paul","doi":"10.1093/infdis/jiae528","DOIUrl":"https://doi.org/10.1093/infdis/jiae528","url":null,"abstract":"Background The interaction between antibodies and Fc gamma receptors (FcγRs) plays a critical role in regulating immune responses to Plasmodium falciparum. Polymorphisms in genes encoding FcγRs influence the host's capacity to control parasite infection. This study investigates whether non-coding variants influencing FcγR expression are associated with anti-malarial immunization and infection traits. Methods We utilized eQTL databases and functional annotations to identify non-coding variants, specifically rs1771575, rs2099684, and rs6700241, within the FCGR gene cluster. In addition, we examined the coding variants rs1801274 (p.His167Arg) and rs1050501 (p.Ile231Thr), which affect the affinity of FcγRIIa and FcγRIIb for IgG. These variants were genotyped in 163 individuals from Burkinabe families. Family-based linear mixed regression and Quantitative Transmission Disequilibrium Tests (QTDT) analyses were performed to assess associations with IgG levels and malaria infection, accounting for relevant covariates. Results Linear mixed models identified rs1771575 as associated with total IgG levels, while both rs1771575 and rs1801274 were linked to IgG2, and rs1050501 to IgG1 levels. A haplotype combining rs2099684 and rs6700241 was positively associated with IgG1. The rs1771575-CC and rs1050501-TT genotypes correlated with higher infection levels in children. QTDT models confirmed the association of rs1771575 with IgG2 and infection in children. Conclusions Our findings suggest that the intergenic variant rs1771575 serves as an independent marker for IgG levels and blood infection in children. This highlights the interplay between regulatory variants and coding mutations in FCGR, which may influence immune function and antibody production. These results underscore the potential for personalized strategies to monitor humoral responses in malaria-endemic regions.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"54 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490543","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}
Marie Høst Pahus,Yu Zheng,Maxine Olefsky,Jesper Damsgaard Gunst,Pablo Tebas,Babafemi Taiwo,Ole S Søgaard,Michael J Peluso,Yolanda Lie,Jacqueline D Reeves,Christos J Petropoulos,Marina Caskey,Katharine J Bar
BACKGROUNDDevelopment of a screening assay for the clinical use of broadly neutralizing antibodies (bnAbs) is a priority for HIV therapy and cure initiatives.METHODSWe assessed the PhenoSense Monoclonal Antibody (mAb) Assay (Labcorp-Monogram Biosciences) which is CLIA-validated and has been used prospectively and retrospectively in multiple recent bnAb clinical trials.RESULTSWhen performed on pre-ART plasma and on-ART longitudinal PBMC samples sourced from a recent clinical trial, the PhenoSense mAb Assay produced robust reproducibility, concordance across sample types, and expected ranges in the susceptibility measures of bnAbs in clinical development. PhenoSense mAb applied retrospectively to baseline samples from three recent studies correlated with published laboratory-based study evaluations, but baseline bnAb susceptibility was not consistently predictive of durable virus suppression. Assessment of the feasibility of the assay in four recent clinical studies provides estimates of assay success rate and processing time.CONCLUSIONSThe PhenoSense mAb Assay provides reproducible bnAb susceptibility measurements across relevant sample types yet was not consistently predictive of virus suppression. Logistical and operational assay requirements can impact timely clinical trial conduct. These results inform bnAb studies in development.
方法我们评估了 PhenoSense 单克隆抗体（mAb）检测试剂盒（Labcorp-Monogram Biosciences），该试剂盒已通过 CLIA 认证，并已在最近的多个 bnAb 临床试验中进行了前瞻性和回顾性使用。结果PhenoSense mAb 检测试剂盒对来自近期临床试验的抗逆转录病毒治疗前血浆和抗逆转录病毒治疗期间纵向 PBMC 样本进行检测时，在临床开发中的 bnAbs 易感性测量中，PhenoSense mAb 检测试剂盒的重现性、跨样本类型的一致性和预期范围都很好。将 PhenoSense mAb 回溯应用于最近三项研究的基线样本与已发表的基于实验室的研究评估结果相关联，但基线 bnAb 药敏性并不能持续预测病毒的持久抑制。结论：PhenoSense mAb 检测法可对相关样本类型进行可重复的 bnAb 药敏测定，但不能持续预测病毒抑制效果。后勤和操作测定要求会影响临床试验的及时进行。这些结果为开发中的 bnAb 研究提供了参考。
{"title":"Evaluation and real-world experience of a neutralization susceptibility screening assay for broadly neutralizing anti-HIV-1 antibodies.","authors":"Marie Høst Pahus,Yu Zheng,Maxine Olefsky,Jesper Damsgaard Gunst,Pablo Tebas,Babafemi Taiwo,Ole S Søgaard,Michael J Peluso,Yolanda Lie,Jacqueline D Reeves,Christos J Petropoulos,Marina Caskey,Katharine J Bar","doi":"10.1093/infdis/jiae486","DOIUrl":"https://doi.org/10.1093/infdis/jiae486","url":null,"abstract":"BACKGROUNDDevelopment of a screening assay for the clinical use of broadly neutralizing antibodies (bnAbs) is a priority for HIV therapy and cure initiatives.METHODSWe assessed the PhenoSense Monoclonal Antibody (mAb) Assay (Labcorp-Monogram Biosciences) which is CLIA-validated and has been used prospectively and retrospectively in multiple recent bnAb clinical trials.RESULTSWhen performed on pre-ART plasma and on-ART longitudinal PBMC samples sourced from a recent clinical trial, the PhenoSense mAb Assay produced robust reproducibility, concordance across sample types, and expected ranges in the susceptibility measures of bnAbs in clinical development. PhenoSense mAb applied retrospectively to baseline samples from three recent studies correlated with published laboratory-based study evaluations, but baseline bnAb susceptibility was not consistently predictive of durable virus suppression. Assessment of the feasibility of the assay in four recent clinical studies provides estimates of assay success rate and processing time.CONCLUSIONSThe PhenoSense mAb Assay provides reproducible bnAb susceptibility measurements across relevant sample types yet was not consistently predictive of virus suppression. Logistical and operational assay requirements can impact timely clinical trial conduct. These results inform bnAb studies in development.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"194 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488190","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}
Nathan A Ledeboer,Jane M Caldwell,Bobby L Boyanton
Pharyngitis is an inflammatory condition of the pharynx and/or tonsils commonly seen in both children and adults. Viruses and bacteria represent the most common encountered etiologic agents-yeast/fungi and parasites are infrequently implicated. Some of these are predominantly observed in unique populations (eg, immunocompromised or unvaccinated individuals). This manuscript (part 3 of 3) summarizes the current state of biomarker diagnostic testing and highlights the expanding role they will likely play in the expedited diagnosis and management of patients with acute pharyngitis. Biomarkers, in conjunction with rapid antigen and/or nucleic acid amplification testing, will likely become the standard of care to accurately diagnose the etiologic agent(s) of pharyngitis. This novel testing paradigm has the potential to guide appropriate patient management and antibiotic stewardship by accurately determining if the cause of pharyngitis is due to a viral or bacterial etiology.
{"title":"Review: Diagnostic Potential for Collaborative Pharyngitis Biomarkers.","authors":"Nathan A Ledeboer,Jane M Caldwell,Bobby L Boyanton","doi":"10.1093/infdis/jiae416","DOIUrl":"https://doi.org/10.1093/infdis/jiae416","url":null,"abstract":"Pharyngitis is an inflammatory condition of the pharynx and/or tonsils commonly seen in both children and adults. Viruses and bacteria represent the most common encountered etiologic agents-yeast/fungi and parasites are infrequently implicated. Some of these are predominantly observed in unique populations (eg, immunocompromised or unvaccinated individuals). This manuscript (part 3 of 3) summarizes the current state of biomarker diagnostic testing and highlights the expanding role they will likely play in the expedited diagnosis and management of patients with acute pharyngitis. Biomarkers, in conjunction with rapid antigen and/or nucleic acid amplification testing, will likely become the standard of care to accurately diagnose the etiologic agent(s) of pharyngitis. This novel testing paradigm has the potential to guide appropriate patient management and antibiotic stewardship by accurately determining if the cause of pharyngitis is due to a viral or bacterial etiology.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"43 1","pages":"S190-S196"},"PeriodicalIF":0.0,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488307","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}
Bobby L Boyanton,Jane M Caldwell,Nathan A Ledeboer
Pharyngitis is an inflammatory condition of the pharynx and/or tonsils commonly seen in both children and adults. Viruses and bacteria represent the most common encountered etiologic agents-yeast/fungi and parasites are infrequently implicated. Some of these are predominantly observed in unique populations (eg, immunocompromised or unvaccinated individuals). This manuscript (part 2 of 3) summarizes the current state of laboratory and point-of-care diagnostic testing and highlights the expanding role of nucleic acid amplification in the expedited diagnosis and management of patients with acute pharyngitis. It discusses preanalytical, analytical, and postanalytical variables that impact the performance of culture, rapid antigen, and nucleic acid amplification testing. Finally, it sets the stage for part 3, which discusses the emerging role of biomarkers in the management of individuals with acute pharyngitis.
{"title":"Review: Current Laboratory and Point-of-Care Pharyngitis Diagnostic Testing and Knowledge Gaps.","authors":"Bobby L Boyanton,Jane M Caldwell,Nathan A Ledeboer","doi":"10.1093/infdis/jiae415","DOIUrl":"https://doi.org/10.1093/infdis/jiae415","url":null,"abstract":"Pharyngitis is an inflammatory condition of the pharynx and/or tonsils commonly seen in both children and adults. Viruses and bacteria represent the most common encountered etiologic agents-yeast/fungi and parasites are infrequently implicated. Some of these are predominantly observed in unique populations (eg, immunocompromised or unvaccinated individuals). This manuscript (part 2 of 3) summarizes the current state of laboratory and point-of-care diagnostic testing and highlights the expanding role of nucleic acid amplification in the expedited diagnosis and management of patients with acute pharyngitis. It discusses preanalytical, analytical, and postanalytical variables that impact the performance of culture, rapid antigen, and nucleic acid amplification testing. Finally, it sets the stage for part 3, which discusses the emerging role of biomarkers in the management of individuals with acute pharyngitis.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"13 1","pages":"S182-S189"},"PeriodicalIF":0.0,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488189","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}
Rachel Emily Levene,John DeVincenzo,Annie L Conery,Alaa Ahmed,Yat Sun Or,Michael H J Rhodin
BACKGROUNDEDP-938 is an oral once-daily RSV nucleoprotein (N) inhibitor with potent antiviral activity. In a human RSV challenge trial, EDP-938 significantly reduced viral load and symptom severity. During antiviral development, it is critical to understand the propensity for resistance to develop. In vitro studies of EDP-938 suggest a higher barrier to resistance as compared to RSV fusion inhibitors. We evaluated the development of viral resistance to EDP-938 in a human challenge trial.METHODSA subset of the 124 participants with RSV infection were chosen for genetic analysis; 159 nasal wash samples from 48 participants were analyzed using next-generation sequencing of the N gene of RSV. Of the 48 participant sampled, 37 were from EDP-938-treated and 11 were placebo-treated participants, representing 45% and 26% of the participants, respectively. The effects of treatment-emergent mutations on viral load, EDP-938 efficacy, and viral fitness were evaluated.RESULTSTwo of the 37 EDP-938-treated participants with samples sequenced had treatment-emergent mutations: N:L139I and N:E112G. From in vitro analysis, N:L139I reduced sensitivity to EDP-938 by approximately 10-fold, while N:E112G had no effect. However, N:L139I was associated with a reduction in viral fitness, suggesting clinical resistance is associated with fitness costs. Neither of these variants were associated with reduced viral clearance.CONCLUSIONSIn human RSV infections treated with EDP-938, emergence of RSV variants with reduced sensitivity to EDP-938 occurred in only 1 participant and was associated with reduced viral fitness. EDP-938's high barrier to resistance highlights its robust mechanism of action.CLINICAL TRIALS REGISTRATIONNCT03691623.
{"title":"EDP-938 Has a High Barrier to Resistance in Healthy Adults Experimentally Infected with Respiratory Syncytial Virus.","authors":"Rachel Emily Levene,John DeVincenzo,Annie L Conery,Alaa Ahmed,Yat Sun Or,Michael H J Rhodin","doi":"10.1093/infdis/jiae471","DOIUrl":"https://doi.org/10.1093/infdis/jiae471","url":null,"abstract":"BACKGROUNDEDP-938 is an oral once-daily RSV nucleoprotein (N) inhibitor with potent antiviral activity. In a human RSV challenge trial, EDP-938 significantly reduced viral load and symptom severity. During antiviral development, it is critical to understand the propensity for resistance to develop. In vitro studies of EDP-938 suggest a higher barrier to resistance as compared to RSV fusion inhibitors. We evaluated the development of viral resistance to EDP-938 in a human challenge trial.METHODSA subset of the 124 participants with RSV infection were chosen for genetic analysis; 159 nasal wash samples from 48 participants were analyzed using next-generation sequencing of the N gene of RSV. Of the 48 participant sampled, 37 were from EDP-938-treated and 11 were placebo-treated participants, representing 45% and 26% of the participants, respectively. The effects of treatment-emergent mutations on viral load, EDP-938 efficacy, and viral fitness were evaluated.RESULTSTwo of the 37 EDP-938-treated participants with samples sequenced had treatment-emergent mutations: N:L139I and N:E112G. From in vitro analysis, N:L139I reduced sensitivity to EDP-938 by approximately 10-fold, while N:E112G had no effect. However, N:L139I was associated with a reduction in viral fitness, suggesting clinical resistance is associated with fitness costs. Neither of these variants were associated with reduced viral clearance.CONCLUSIONSIn human RSV infections treated with EDP-938, emergence of RSV variants with reduced sensitivity to EDP-938 occurred in only 1 participant and was associated with reduced viral fitness. EDP-938's high barrier to resistance highlights its robust mechanism of action.CLINICAL TRIALS REGISTRATIONNCT03691623.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"30 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489794","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}
Carla N Mavian,Massimiliano S Tagliamonte,Maclean Bassett,Meer Alam,Melanie N Cash,Matt Hitchings,Rigan Louis,Alberto Riva,Kayvan Zainabadi,Marie Marcelle Deschamps,Bernard Liautaud,Vanessa Rouzier,Daniel W Fitzgerald,Jean William Pape,J Glenn Morris,Marco Salemi
We monitored SARS-CoV-2 variants in Haiti from 2020-2023. Despite Haitian COVID-19 travel restrictions and in the setting of a vaccination rate of 2.7%, the timing and lineage evolution of the Haiti epidemic mirrored what was occurring in the rest of the world. Sources for importation of lineages into Haiti were the United States (US), the Dominican Republic (DR), Europe, and Brazil, with exportation of lineages to the US, DR, Europe, and Asia. Viral load in patients infected by the Delta and Omicron BA.1 were correlated along the phylogenies, suggesting that higher viral loads have facilitated strain transmission and evolution.
{"title":"COVID-19 lineages in a minimally vaccinated island population: Genomic epidemiology of SARS-CoV-2 in Haiti.","authors":"Carla N Mavian,Massimiliano S Tagliamonte,Maclean Bassett,Meer Alam,Melanie N Cash,Matt Hitchings,Rigan Louis,Alberto Riva,Kayvan Zainabadi,Marie Marcelle Deschamps,Bernard Liautaud,Vanessa Rouzier,Daniel W Fitzgerald,Jean William Pape,J Glenn Morris,Marco Salemi","doi":"10.1093/infdis/jiae520","DOIUrl":"https://doi.org/10.1093/infdis/jiae520","url":null,"abstract":"We monitored SARS-CoV-2 variants in Haiti from 2020-2023. Despite Haitian COVID-19 travel restrictions and in the setting of a vaccination rate of 2.7%, the timing and lineage evolution of the Haiti epidemic mirrored what was occurring in the rest of the world. Sources for importation of lineages into Haiti were the United States (US), the Dominican Republic (DR), Europe, and Brazil, with exportation of lineages to the US, DR, Europe, and Asia. Viral load in patients infected by the Delta and Omicron BA.1 were correlated along the phylogenies, suggesting that higher viral loads have facilitated strain transmission and evolution.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"63 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488191","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}
Jane M Caldwell,Nathan A Ledeboer,Bobby L Boyanton
Pharyngitis is an inflammatory condition of the pharynx and/or tonsils commonly seen in both children and adults. Viruses and bacteria represent the most common encountered etiologic agents-yeast/fungi and parasites are infrequently implicated. Some of these are predominantly observed in unique populations (eg, immunocompromised or unvaccinated individuals). This article (part 1 of 3) summarizes the impact of acute pharyngitis on the health care system and reviews the etiologic agents of acute pharyngitis, including both emerging and reemerging pathogens that health care providers should consider when evaluating their patients. Finally, it sets the stage for parts 2 and 3, which discuss the current and evolving state of diagnostic testing for acute pharyngitis.
{"title":"Review: Known, Emerging, and Remerging Pharyngitis Pathogens.","authors":"Jane M Caldwell,Nathan A Ledeboer,Bobby L Boyanton","doi":"10.1093/infdis/jiae391","DOIUrl":"https://doi.org/10.1093/infdis/jiae391","url":null,"abstract":"Pharyngitis is an inflammatory condition of the pharynx and/or tonsils commonly seen in both children and adults. Viruses and bacteria represent the most common encountered etiologic agents-yeast/fungi and parasites are infrequently implicated. Some of these are predominantly observed in unique populations (eg, immunocompromised or unvaccinated individuals). This article (part 1 of 3) summarizes the impact of acute pharyngitis on the health care system and reviews the etiologic agents of acute pharyngitis, including both emerging and reemerging pathogens that health care providers should consider when evaluating their patients. Finally, it sets the stage for parts 2 and 3, which discuss the current and evolving state of diagnostic testing for acute pharyngitis.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"4 1","pages":"S173-S181"},"PeriodicalIF":0.0,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488308","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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