Karen Sauve, Aubrey Watson, Jun T Oh, Steven Swift, Xavier Vila-Farres, Wessam Abdelhady, Yan Q Xiong, Dario LeHoux, Gary Woodnutt, Arnold S Bayer, Raymond Schuch
Background: Lysins (cell wall hydrolases) targeting gram-negative organisms require engineering to permeabilize the outer membrane and access subjacent peptidoglycan to facilitate killing. In the current study, the potential clinical utility for the engineered lysin CF-370 was examined in vitro and in vivo against gram-negative pathogens important in human infections.
Methods: Minimum inhibitory concentration (MICs) and bactericidal activity were determined using standard methods. An in vivo proof-of-concept efficacy study was conducted using a rabbit acute pneumonia model caused by Pseudomonas aeruginosa.
Results: CF-370 exhibited potent antimicrobial activity, with MIC50/90 values (in µg/mL) for: P aeruginosa, 1/2; Acinetobacter baumannii, 1/1; Escherichia coli, 0.25/1; Klebsiella pneumoniae, 2/4; Enterobacter cloacae 1/4; and Stenotrophomonas maltophilia 2/8. CF-370 furthermore demonstrated bactericidal activity, activity in serum, a low propensity for resistance, anti-biofilm activity, and synergy with antibiotics. In the pneumonia model, CF-370 alone decreased bacterial densities in lungs, kidneys, and spleen versus vehicle control, and demonstrated significantly increased efficacy when combined with meropenem (vs either agent alone).
Conclusions: CF-370 is the first engineered lysin described with potent broad-spectrum in vitro activity against multiple clinically relevant gram-negative pathogens, as well as potent in vivo efficacy in an animal model of severe invasive multisystem infection.
背景:针对革兰氏阴性菌的溶菌素(细胞壁水解酶)需要经过工程改造才能使外膜渗透,并进入邻近的肽聚糖以促进杀灭。本研究在体外和体内检测了工程溶菌素 CF-370 对人类感染中重要的革兰氏阴性病原体的潜在临床用途:方法:采用标准方法测定 MIC 和杀菌活性。方法:采用标准方法测定 MIC 和杀菌活性,并利用铜绿假单胞菌引起的兔急性肺炎模型进行了体内疗效验证研究:结果:CF-370 具有很强的抗菌活性,对铜绿假单胞菌的 MIC50/90 值(微克/毫升)为1/2;鲍曼不动杆菌(Acinetobacter baumannii),1/1;大肠埃希菌(Escherichia coli),0.25/1;肺炎克雷伯菌(Klebsiella pneumoniae),2/4;泄殖腔肠杆菌(Enterobacter cloacae),1/4;嗜麦芽血单胞菌(Stenotrophomonas maltophilia),2/8。CF-370 还表现出:i)杀菌活性;ii)血清活性;iii)低耐药性倾向;iv)抗生物膜活性;v)与抗生素的协同作用。在肺炎模型中,与药物对照组相比,CF-370 单独使用可降低肺、肾和脾中的细菌密度,与美罗培南(与单独使用其中一种药物相比)联合使用时,疗效显著提高:结论:CF-370 是第一种针对多种临床相关革兰氏阴性病原体具有强效广谱体外活性的工程溶菌素,在严重侵袭性多系统感染动物模型中也具有强效体内疗效。
{"title":"The Engineered Lysin CF-370 Is Active Against Antibiotic-Resistant Gram-Negative Pathogens In Vitro and Synergizes With Meropenem in Experimental Pseudomonas aeruginosa Pneumonia.","authors":"Karen Sauve, Aubrey Watson, Jun T Oh, Steven Swift, Xavier Vila-Farres, Wessam Abdelhady, Yan Q Xiong, Dario LeHoux, Gary Woodnutt, Arnold S Bayer, Raymond Schuch","doi":"10.1093/infdis/jiae027","DOIUrl":"10.1093/infdis/jiae027","url":null,"abstract":"<p><strong>Background: </strong>Lysins (cell wall hydrolases) targeting gram-negative organisms require engineering to permeabilize the outer membrane and access subjacent peptidoglycan to facilitate killing. In the current study, the potential clinical utility for the engineered lysin CF-370 was examined in vitro and in vivo against gram-negative pathogens important in human infections.</p><p><strong>Methods: </strong>Minimum inhibitory concentration (MICs) and bactericidal activity were determined using standard methods. An in vivo proof-of-concept efficacy study was conducted using a rabbit acute pneumonia model caused by Pseudomonas aeruginosa.</p><p><strong>Results: </strong>CF-370 exhibited potent antimicrobial activity, with MIC50/90 values (in µg/mL) for: P aeruginosa, 1/2; Acinetobacter baumannii, 1/1; Escherichia coli, 0.25/1; Klebsiella pneumoniae, 2/4; Enterobacter cloacae 1/4; and Stenotrophomonas maltophilia 2/8. CF-370 furthermore demonstrated bactericidal activity, activity in serum, a low propensity for resistance, anti-biofilm activity, and synergy with antibiotics. In the pneumonia model, CF-370 alone decreased bacterial densities in lungs, kidneys, and spleen versus vehicle control, and demonstrated significantly increased efficacy when combined with meropenem (vs either agent alone).</p><p><strong>Conclusions: </strong>CF-370 is the first engineered lysin described with potent broad-spectrum in vitro activity against multiple clinically relevant gram-negative pathogens, as well as potent in vivo efficacy in an animal model of severe invasive multisystem infection.</p>","PeriodicalId":50179,"journal":{"name":"Journal of Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11326841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139747693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The family Borreliaceae contains arthropod-borne spirochetes that cause two widespread human diseases, Lyme disease and relapsing fever. Lyme disease is a subacute, progressive illness with variable stage and tissue manifestations. Relapsing fever is an acute febrile illness with prominent bacteremia that may recur and disseminate, particularly to the nervous system. Clinical heterogeneity is a hallmark of both diseases. While human clinical manifestations are influenced by a wide variety of factors, including immune status and host genetic susceptibility, there is evidence that Borreliaceae microbial factors influence the clinical manifestations of human disease caused by this family of spirochetes. Despite these associations, the spirochete genes that influence the severity and manifestations of human disease are, for the most part, unknown. Recent work has identified lineage-specific expansions of lipoproteome-rich accessory genome elements in virulent clones of Borrelia burgdorferi. Using publicly available genome assemblies, it is shown that all Borreliaceae lineages for which sufficient sequence data are available harbor a similar pattern of strongly structured, lineage-specific expansions in their accessory genomes, particularly among lipoproteins, and that this pattern holds across phylogenetic scales including genera, species, and genotypes. The relationships among pangenome elements suggest that infrequent episodes of marked genomic change followed by clonal expansion in geographically and enzootically structured populations may account for the unique lineage structure of Borreliaceae. This analysis informs future genotype-phenotype studies among Borreliaceae and lays a foundation for studies of individual gene function guided by phylogenetic patterns of conservation, diversification, gain, and/or loss.
{"title":"Analysis of the Borreliaceae Pangenome Reveals a Distinct Genomic Architecture Conserved Across Phylogenetic Scales.","authors":"Jacob E Lemieux","doi":"10.1093/infdis/jiae256","DOIUrl":"https://doi.org/10.1093/infdis/jiae256","url":null,"abstract":"<p><p>The family Borreliaceae contains arthropod-borne spirochetes that cause two widespread human diseases, Lyme disease and relapsing fever. Lyme disease is a subacute, progressive illness with variable stage and tissue manifestations. Relapsing fever is an acute febrile illness with prominent bacteremia that may recur and disseminate, particularly to the nervous system. Clinical heterogeneity is a hallmark of both diseases. While human clinical manifestations are influenced by a wide variety of factors, including immune status and host genetic susceptibility, there is evidence that Borreliaceae microbial factors influence the clinical manifestations of human disease caused by this family of spirochetes. Despite these associations, the spirochete genes that influence the severity and manifestations of human disease are, for the most part, unknown. Recent work has identified lineage-specific expansions of lipoproteome-rich accessory genome elements in virulent clones of Borrelia burgdorferi. Using publicly available genome assemblies, it is shown that all Borreliaceae lineages for which sufficient sequence data are available harbor a similar pattern of strongly structured, lineage-specific expansions in their accessory genomes, particularly among lipoproteins, and that this pattern holds across phylogenetic scales including genera, species, and genotypes. The relationships among pangenome elements suggest that infrequent episodes of marked genomic change followed by clonal expansion in geographically and enzootically structured populations may account for the unique lineage structure of Borreliaceae. This analysis informs future genotype-phenotype studies among Borreliaceae and lays a foundation for studies of individual gene function guided by phylogenetic patterns of conservation, diversification, gain, and/or loss.</p>","PeriodicalId":50179,"journal":{"name":"Journal of Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141977089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rebecca Danner, Lauren M Prochniak, Michaela Pereckas, Joseph R Rouse, Amanda Wahhab, Lauren G Hackner, Robert B Lochhead
Background: During infection with the Lyme arthritis (LA) pathogen Borrelia burgdorferi, T-cell responses to both host and pathogen are dysregulated, resulting in chronic infection and frequent development of autoimmunity.
Methods: To assess CD4+ T-cell epitopes presented during development of LA, we used an unbiased, immunopeptidomics approach to characterize the major histocompatibility complex (MHC) class II immunopeptidome in B burgdorferi-infected C57BL/6 (B6) mice, which develop mild, self-limiting LA, and infected B6 Il10-/- mice, which develop severe, persistent LA at 0, 4, and 16 weeks postinfection (22-23 mice per group).
Results: Peptides derived from proteins involved in adaptive T- and B-cell responses and cholesterol metabolism, including human Lyme autoantigen apolipoprotein B-100 (apoB-100), were enriched in infected Il10-/- mice; whereas peptides derived from proteins involved in neutrophil extracellular net formation were enriched in infected B6 mice. Presentation of apoB-100 peptides showed evidence of epitope expansion during infection. Of several identified B burgdorferi peptides, only 1, a methyl-accepting chemotaxis protein peptide Mcp4442-462, was immunogenic.
Conclusions: ApoB-100, a human Lyme autoantigen, undergoes marked epitope expansion during LA development. The paucity of immunogenic B burgdorferi epitopes supports previous findings suggesting CD4+ T-cell responses are suppressed in murine LA.
背景:在感染莱姆关节炎(LA)病原体鲍瑞氏菌(Borrelia burgdorferi)期间,宿主和病原体的T细胞反应失调,导致慢性感染和自身免疫的频繁发生:为了评估在LA发展过程中出现的CD4+ T细胞表位,我们使用了一种无偏见的免疫肽组学方法来描述Burgdorferi感染的C57BL/6(B6)小鼠和感染的B6 Il10-/-小鼠(每组22-23只小鼠)的主要组织相容性复合体(MHC)II类免疫肽组(前者在感染后0、4和16周出现轻度、自限性LA,后者则出现重度、持续性LA):结果:受感染的Il10-/-小鼠体内富集了来自参与适应性T细胞和B细胞反应及胆固醇代谢的蛋白质的肽,包括人类莱姆自身抗原载脂蛋白B-100(apoB-100);而受感染的B6小鼠体内富集了来自参与中性粒细胞胞外网形成的蛋白质的肽。在感染过程中,apoB-100多肽的表达显示了表位扩展的证据。在几种已确定的B burgdorferi肽中,只有1种(甲基接受趋化蛋白肽Mcp4442-462)具有免疫原性:结论:ApoB-100是人类莱姆自身抗原,在LA发育过程中会出现明显的表位扩展。免疫原 B burgdorferi 表位的缺乏支持了之前的研究结果,即 CD4+ T 细胞反应在小鼠 LA 中受到抑制。
{"title":"Identification of Major Histocompatibility Complex Class II Epitopes From Lyme Autoantigen Apolipoprotein B-100 and Borrelia burgdorferi Mcp4 in Murine Lyme Arthritis.","authors":"Rebecca Danner, Lauren M Prochniak, Michaela Pereckas, Joseph R Rouse, Amanda Wahhab, Lauren G Hackner, Robert B Lochhead","doi":"10.1093/infdis/jiae324","DOIUrl":"10.1093/infdis/jiae324","url":null,"abstract":"<p><strong>Background: </strong>During infection with the Lyme arthritis (LA) pathogen Borrelia burgdorferi, T-cell responses to both host and pathogen are dysregulated, resulting in chronic infection and frequent development of autoimmunity.</p><p><strong>Methods: </strong>To assess CD4+ T-cell epitopes presented during development of LA, we used an unbiased, immunopeptidomics approach to characterize the major histocompatibility complex (MHC) class II immunopeptidome in B burgdorferi-infected C57BL/6 (B6) mice, which develop mild, self-limiting LA, and infected B6 Il10-/- mice, which develop severe, persistent LA at 0, 4, and 16 weeks postinfection (22-23 mice per group).</p><p><strong>Results: </strong>Peptides derived from proteins involved in adaptive T- and B-cell responses and cholesterol metabolism, including human Lyme autoantigen apolipoprotein B-100 (apoB-100), were enriched in infected Il10-/- mice; whereas peptides derived from proteins involved in neutrophil extracellular net formation were enriched in infected B6 mice. Presentation of apoB-100 peptides showed evidence of epitope expansion during infection. Of several identified B burgdorferi peptides, only 1, a methyl-accepting chemotaxis protein peptide Mcp4442-462, was immunogenic.</p><p><strong>Conclusions: </strong>ApoB-100, a human Lyme autoantigen, undergoes marked epitope expansion during LA development. The paucity of immunogenic B burgdorferi epitopes supports previous findings suggesting CD4+ T-cell responses are suppressed in murine LA.</p>","PeriodicalId":50179,"journal":{"name":"Journal of Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11322890/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141977091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dylan Ehrbar, Sheila L Arvikar, Katherine B Sulka, Geena Chiumento, Nicole L J Nelson, Sergio A Hernandez, Morgan A Williams, Franc Strle, Allen C Steere, Klemen Strle
Background: Postinfectious Lyme arthritis (LA) is associated with dysregulated immunity and autoreactive T- and B-cell responses in joints. Here we explored the role of host genetic variation in this outcome.
Methods: The frequency of 253 702 single-nucleotide polymorphisms (SNPs) was determined in 147 patients with LA (87 with postinfectious LA and 60 with antibiotic-responsive LA), and for comparison in 90 patients with erythema migrans or the general population (n = 2504). Functional outcome of candidate SNPs was assessed by evaluating their impact on clinical outcome and on immune responses in blood and synovial fluid in patients with LA.
Results: Six SNPs associated with late cornified envelope (LCE3) genes were present at greater frequency in patients with postinfectious LA compared to those with antibiotic-responsive LA (70% vs 30%; odds ratio, 2; P < .01). These SNPs were associated with heightened levels of inflammatory Th17 cytokines in serum but lower levels of interleukin 27, a regulatory cytokine, implying that they may contribute to dysregulated Th17 immunity in blood. Moreover, in patients with postinfectious LA, the levels of these Th17 mediators correlated directly with autoantibody responses in synovial fluid, providing a possible link between LCE3 SNPs, maladaptive systemic Th17 immunity, and autoreactive responses in joints.
Conclusions: Variation in the LCE3 locus, a known genetic risk factor in psoriasis and psoriatic arthritis, is associated with dysregulated systemic Th17 immunity and heightened autoantibody responses in joints. These findings underscore the importance of host genetic predisposition and systemic Th17 immunity in the pathogenesis of postinfectious (antibiotic-refractory) Lyme arthritis.
背景:感染后莱姆关节炎(LA)与免疫失调以及关节中的自反应性T细胞和B细胞反应有关。在此,我们探讨了宿主遗传变异在这一结果中的作用:方法:我们测定了 147 名 LA 患者(87 名感染后 LA 患者和 60 名抗生素反应性 LA 患者)中 253 702 个单核苷酸多态性(SNPs)的频率,并与 90 名偏头痛红斑患者或普通人群(n = 2504)进行了比较。通过评估候选 SNP 对 LA 患者的临床结果以及血液和滑液中免疫反应的影响,对候选 SNP 的功能结果进行了评估:与抗生素反应性 LA 患者相比,感染后 LA 患者中出现频率更高的是与晚期粟粒化包膜(LCE3)基因相关的六个 SNPs(70% vs 30%;几率比,2;P < .01)。这些 SNP 与血清中 Th17 炎症细胞因子水平的升高有关,但与白细胞介素 27(一种调节性细胞因子)水平的降低有关,这意味着它们可能导致血液中 Th17 免疫失调。此外,在感染后的LA患者中,这些Th17介质的水平与滑膜液中的自身抗体反应直接相关,这说明LCE3 SNPs、不适应的全身Th17免疫和关节中的自身反应之间可能存在联系:结论:LCE3基因座的变异是银屑病和银屑病关节炎的已知遗传风险因素,它与失调的全身Th17免疫和关节中增强的自身抗体反应有关。这些发现强调了宿主遗传易感性和全身Th17免疫在感染后(抗生素难治性)莱姆关节炎发病机制中的重要性。
{"title":"Variants in the Late Cornified Envelope Gene Locus Are Associated With Elevated T-helper 17 Responses in Patients With Postinfectious Lyme Arthritis.","authors":"Dylan Ehrbar, Sheila L Arvikar, Katherine B Sulka, Geena Chiumento, Nicole L J Nelson, Sergio A Hernandez, Morgan A Williams, Franc Strle, Allen C Steere, Klemen Strle","doi":"10.1093/infdis/jiae164","DOIUrl":"10.1093/infdis/jiae164","url":null,"abstract":"<p><strong>Background: </strong>Postinfectious Lyme arthritis (LA) is associated with dysregulated immunity and autoreactive T- and B-cell responses in joints. Here we explored the role of host genetic variation in this outcome.</p><p><strong>Methods: </strong>The frequency of 253 702 single-nucleotide polymorphisms (SNPs) was determined in 147 patients with LA (87 with postinfectious LA and 60 with antibiotic-responsive LA), and for comparison in 90 patients with erythema migrans or the general population (n = 2504). Functional outcome of candidate SNPs was assessed by evaluating their impact on clinical outcome and on immune responses in blood and synovial fluid in patients with LA.</p><p><strong>Results: </strong>Six SNPs associated with late cornified envelope (LCE3) genes were present at greater frequency in patients with postinfectious LA compared to those with antibiotic-responsive LA (70% vs 30%; odds ratio, 2; P < .01). These SNPs were associated with heightened levels of inflammatory Th17 cytokines in serum but lower levels of interleukin 27, a regulatory cytokine, implying that they may contribute to dysregulated Th17 immunity in blood. Moreover, in patients with postinfectious LA, the levels of these Th17 mediators correlated directly with autoantibody responses in synovial fluid, providing a possible link between LCE3 SNPs, maladaptive systemic Th17 immunity, and autoreactive responses in joints.</p><p><strong>Conclusions: </strong>Variation in the LCE3 locus, a known genetic risk factor in psoriasis and psoriatic arthritis, is associated with dysregulated systemic Th17 immunity and heightened autoantibody responses in joints. These findings underscore the importance of host genetic predisposition and systemic Th17 immunity in the pathogenesis of postinfectious (antibiotic-refractory) Lyme arthritis.</p>","PeriodicalId":50179,"journal":{"name":"Journal of Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11322884/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141977098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lyme disease is a zoonotic infection due to Ixodes tick-transmitted Borrelia burgdorferi sensu lato spirochetes and the most common vector-borne disease in the Northern Hemisphere. Despite nearly 50 years of investigation, the pathogenesis of this infection and its 2 main adverse outcomes-postinfectious Lyme arthritis and posttreatment Lyme disease syndrome-are incompletely understood. Advancement in sequencing and mass spectrometry have led to the rapid expansion of high-throughput omics technologies, including transcriptomics, metabolomics, and proteomics, which are now being applied to human diseases. This review summarizes findings of omics studies conducted on blood and tissue samples of people with acute Lyme disease and its postinfectious outcomes.
{"title":"Insights From Omics in Lyme Disease.","authors":"Linda K Bockenstedt, Alexia A Belperron","doi":"10.1093/infdis/jiae250","DOIUrl":"https://doi.org/10.1093/infdis/jiae250","url":null,"abstract":"<p><p>Lyme disease is a zoonotic infection due to Ixodes tick-transmitted Borrelia burgdorferi sensu lato spirochetes and the most common vector-borne disease in the Northern Hemisphere. Despite nearly 50 years of investigation, the pathogenesis of this infection and its 2 main adverse outcomes-postinfectious Lyme arthritis and posttreatment Lyme disease syndrome-are incompletely understood. Advancement in sequencing and mass spectrometry have led to the rapid expansion of high-throughput omics technologies, including transcriptomics, metabolomics, and proteomics, which are now being applied to human diseases. This review summarizes findings of omics studies conducted on blood and tissue samples of people with acute Lyme disease and its postinfectious outcomes.</p>","PeriodicalId":50179,"journal":{"name":"Journal of Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141977092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Persistent symptoms after an infection have been described for a number of infectious diseases, including Lyme disease. Studies have confirmed a moderate but consistent increase in the prevalence of such symptoms after Lyme disease, though the risk increase varies dependent on study design and the definition of persistent symptoms. Various possible predictors have been proposed, including a dysregulation of the immune system, metabolic changes, increased sensitization to pain signals, cognitive-behavioral factors, or-controversially-the persistence of the causative Borrelia bacteria or remnants thereof. Research on the precise roles of any of these factors is still ongoing. The lack of biological underpinning also makes it difficult to assess with certainty which patients' (generally nonspecific) persistent symptoms are etiologically related to the previous Lyme disease episode and which are not, particularly as these symptoms occur in the general population relatively frequently. The diagnostic criteria for posttreatment Lyme disease syndrome have shown their usefulness in both clinical and research settings but leave out a number of patients whose symptoms may fall just outside said criteria. Though the relationship between these symptoms and the previous Lyme disease episode may be very uncertain, we would argue that a uniform description and classification of these patients will aid in future research and patient management, regardless of the eventual underlying cause. Thus, we argue for an inclusive classification system for all persistent symptoms attributed to Lyme disease in order to promote validation of patient experiences and perspectives, while also maintaining scientific nuance regarding the very uncertain etiology of these patients' symptoms.
{"title":"Persistent Symptoms After Lyme Disease: Clinical Characteristics, Predictors, and Classification.","authors":"M E Baarsma, Joppe W Hovius","doi":"10.1093/infdis/jiae203","DOIUrl":"https://doi.org/10.1093/infdis/jiae203","url":null,"abstract":"<p><p>Persistent symptoms after an infection have been described for a number of infectious diseases, including Lyme disease. Studies have confirmed a moderate but consistent increase in the prevalence of such symptoms after Lyme disease, though the risk increase varies dependent on study design and the definition of persistent symptoms. Various possible predictors have been proposed, including a dysregulation of the immune system, metabolic changes, increased sensitization to pain signals, cognitive-behavioral factors, or-controversially-the persistence of the causative Borrelia bacteria or remnants thereof. Research on the precise roles of any of these factors is still ongoing. The lack of biological underpinning also makes it difficult to assess with certainty which patients' (generally nonspecific) persistent symptoms are etiologically related to the previous Lyme disease episode and which are not, particularly as these symptoms occur in the general population relatively frequently. The diagnostic criteria for posttreatment Lyme disease syndrome have shown their usefulness in both clinical and research settings but leave out a number of patients whose symptoms may fall just outside said criteria. Though the relationship between these symptoms and the previous Lyme disease episode may be very uncertain, we would argue that a uniform description and classification of these patients will aid in future research and patient management, regardless of the eventual underlying cause. Thus, we argue for an inclusive classification system for all persistent symptoms attributed to Lyme disease in order to promote validation of patient experiences and perspectives, while also maintaining scientific nuance regarding the very uncertain etiology of these patients' symptoms.</p>","PeriodicalId":50179,"journal":{"name":"Journal of Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141977096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Powassan virus is a tick-borne flavivirus that can cause severe neuroinvasive disease, with areas of endemicity in the Northeast and Midwest United States, Canada, and Russia. Diagnosis is challenging and relies on a high index of suspicion and choosing the right test based on duration of infection and the patient's immune status. This review covers laboratory testing for Powassan virus, including historical considerations, modern options, and methods being developed in the research space.
{"title":"Laboratory Testing for Powassan Virus: Past, Present, and Future.","authors":"Erik H Klontz, Navid Chowdhury, John A Branda","doi":"10.1093/infdis/jiae197","DOIUrl":"https://doi.org/10.1093/infdis/jiae197","url":null,"abstract":"<p><p>Powassan virus is a tick-borne flavivirus that can cause severe neuroinvasive disease, with areas of endemicity in the Northeast and Midwest United States, Canada, and Russia. Diagnosis is challenging and relies on a high index of suspicion and choosing the right test based on duration of infection and the patient's immune status. This review covers laboratory testing for Powassan virus, including historical considerations, modern options, and methods being developed in the research space.</p>","PeriodicalId":50179,"journal":{"name":"Journal of Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141977093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In the 40 years since Steere and colleagues first described Lyme disease, the illness has increased in incidence and distribution to become the most common vector-borne disease in the United States. Public health officials have developed, implemented, and revised surveillance systems to describe and monitor the condition. Much has been learned about the epidemiology of the illness, despite practical and logistical constraints that have encumbered the collection and interpretation of surveillance data. Future development of automated data collection from electronic health records as a source of surveillance and clinical information will address practical challenges and help answer ongoing questions about complications and persistent symptoms. Robust surveillance will be essential to monitor the effectiveness and safety of future vaccines and other preventive measures.
{"title":"Lyme Disease Surveillance and Epidemiology in the United States: A Historical Perspective.","authors":"Paul Mead, Alison Hinckley, Kiersten Kugeler","doi":"10.1093/infdis/jiae230","DOIUrl":"https://doi.org/10.1093/infdis/jiae230","url":null,"abstract":"<p><p>In the 40 years since Steere and colleagues first described Lyme disease, the illness has increased in incidence and distribution to become the most common vector-borne disease in the United States. Public health officials have developed, implemented, and revised surveillance systems to describe and monitor the condition. Much has been learned about the epidemiology of the illness, despite practical and logistical constraints that have encumbered the collection and interpretation of surveillance data. Future development of automated data collection from electronic health records as a source of surveillance and clinical information will address practical challenges and help answer ongoing questions about complications and persistent symptoms. Robust surveillance will be essential to monitor the effectiveness and safety of future vaccines and other preventive measures.</p>","PeriodicalId":50179,"journal":{"name":"Journal of Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141977095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jessica Durkee-Shock, Ariella Cohen, Naseem Maghzian, Gloria Pezzella, Mariah Jensen-Wachspress, Anna Hostal, Karenna Barton, Krista Gangler, Blachy J Dávila Saldaña, Natthawan Chaimongkol, Catherine M Bollard, Stanislav V Sosnovtsev, Jeffrey Cohen, Bianca M Nagata, Derron A Alves, Rajarshi Ghosh, Bryce A Seifert, Alexandra Freeman, Corina Gonzalez, Luigi D Notarangelo, Kim Y Green, Michael D Keller
Background: Chronic norovirus infection (CNI) causes significant morbidity in immunocompromised patients. No effective prevention or treatment currently exists.
Methods: Two patients with inborn errors of immunity, X- linked severe combined immunodeficiency (X-SCID) and DOCK8 deficiency, were followed longitudinally for clinical course, immune reconstitution, norovirus-specific T cell (NST) response, B cell reconstitution, and norovirus-specific antibody production. Samples were obtained in the peri-hematopoietic stem cell transplant setting (HSCT) before and after CNI clearance. The norovirus strain causing CNI was followed longitudinally for norovirus stool viral loads and sequencing.
Results: The noroviruses were identified as GII.4 Sydney[P4 New Orleans] in one patient and GII.17[P17] in the other. An exacerbation of diarrhea post-HSCT in the patient with X-SCID was consistent with norovirus infection but not with graft-vs-host-disease on pathologic samples. Both patients recovered polyfunctional NSTs in the CD4 and CD8 T cell compartments which recognized multiple norovirus structural and non-structural viral antigens. T cell responses were minimal during active CNI but detectable after resolution. Mapping of norovirus-specific T cell responses between the patient with DOCK8 and his matched sibling donor were nearly identical. B cell reconstitution or new endogenous antibody production for IgA or IgG were not observed.
Conclusion: This report is the first to demonstrate reconstitution of norovirus-specific T cell immunity after HSCT closely temporally aligned with clearance of CNI suggesting that cellular immunity is sufficient for norovirus clearance.
背景:慢性诺如病毒感染(CNI)会导致免疫力低下的患者严重发病。目前尚无有效的预防或治疗方法:方法:对两名患有先天性免疫缺陷(X-连锁重症联合免疫缺陷症(X-SCID)和 DOCK8 缺乏症)的患者进行了纵向随访,以了解其临床病程、免疫重建、诺如病毒特异性 T 细胞(NST)反应、B 细胞重建和诺如病毒特异性抗体产生情况。样本是在清除 CNI 之前和之后的造血干细胞移植(HSCT)环境中获得的。对引起 CNI 的诺如病毒株进行了纵向跟踪,检测诺如病毒粪便病毒载量并进行测序:结果:一名患者的诺如病毒被鉴定为 GII.4 Sydney[P4 New Orleans],另一名患者的诺如病毒被鉴定为 GII.17[P17]。X-SCID患者在接受造血干细胞移植后腹泻加重,病理样本显示与诺如病毒感染相符,但与移植物抗宿主疾病无关。两名患者的 CD4 和 CD8 T 细胞区都恢复了多功能 NST,可识别多种诺如病毒结构性和非结构性病毒抗原。在活跃的 CNI 期间,T 细胞反应微乎其微,但在病症缓解后可检测到。DOCK8 患者与其匹配的同胞供体之间的诺如病毒特异性 T 细胞反应图几乎完全相同。未观察到 B 细胞重建或产生新的 IgA 或 IgG 内源性抗体:本报告首次证明造血干细胞移植后诺如病毒特异性 T 细胞免疫的重建与 CNI 的清除在时间上密切相关,这表明细胞免疫足以清除诺如病毒。
{"title":"Reconstitution of norovirus-specific T cell responses following hematopoietic stem cell transplantation in patients with inborn errors of immunity and chronic norovirus infection.","authors":"Jessica Durkee-Shock, Ariella Cohen, Naseem Maghzian, Gloria Pezzella, Mariah Jensen-Wachspress, Anna Hostal, Karenna Barton, Krista Gangler, Blachy J Dávila Saldaña, Natthawan Chaimongkol, Catherine M Bollard, Stanislav V Sosnovtsev, Jeffrey Cohen, Bianca M Nagata, Derron A Alves, Rajarshi Ghosh, Bryce A Seifert, Alexandra Freeman, Corina Gonzalez, Luigi D Notarangelo, Kim Y Green, Michael D Keller","doi":"10.1093/infdis/jiae398","DOIUrl":"https://doi.org/10.1093/infdis/jiae398","url":null,"abstract":"<p><strong>Background: </strong>Chronic norovirus infection (CNI) causes significant morbidity in immunocompromised patients. No effective prevention or treatment currently exists.</p><p><strong>Methods: </strong>Two patients with inborn errors of immunity, X- linked severe combined immunodeficiency (X-SCID) and DOCK8 deficiency, were followed longitudinally for clinical course, immune reconstitution, norovirus-specific T cell (NST) response, B cell reconstitution, and norovirus-specific antibody production. Samples were obtained in the peri-hematopoietic stem cell transplant setting (HSCT) before and after CNI clearance. The norovirus strain causing CNI was followed longitudinally for norovirus stool viral loads and sequencing.</p><p><strong>Results: </strong>The noroviruses were identified as GII.4 Sydney[P4 New Orleans] in one patient and GII.17[P17] in the other. An exacerbation of diarrhea post-HSCT in the patient with X-SCID was consistent with norovirus infection but not with graft-vs-host-disease on pathologic samples. Both patients recovered polyfunctional NSTs in the CD4 and CD8 T cell compartments which recognized multiple norovirus structural and non-structural viral antigens. T cell responses were minimal during active CNI but detectable after resolution. Mapping of norovirus-specific T cell responses between the patient with DOCK8 and his matched sibling donor were nearly identical. B cell reconstitution or new endogenous antibody production for IgA or IgG were not observed.</p><p><strong>Conclusion: </strong>This report is the first to demonstrate reconstitution of norovirus-specific T cell immunity after HSCT closely temporally aligned with clearance of CNI suggesting that cellular immunity is sufficient for norovirus clearance.</p>","PeriodicalId":50179,"journal":{"name":"Journal of Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141977059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lyme disease is caused by the spirochete, Borrelia burgdorferi, which is transmitted by Ixodes spp ticks. The rise in Lyme disease cases since its discovery in the 1970s has reinforced the need for a vaccine. A vaccine based on B burgdorferi outer surface protein A (OspA) was approved by the Food and Drug Administration (FDA) several decades ago, but was pulled from the market a few years later, reportedly due to poor sales, despite multiple organizations concluding that it was safe and effective. Newer OspA-based vaccines are being developed and are likely to be available in the coming years. More recently, there has been a push to develop vaccines that target the tick vector instead of the pathogen to inhibit tick feeding and thus prevent transmission of tick-borne pathogens to humans and wildlife reservoirs. This review outlines the history of Lyme disease vaccines and this movement to anti-tick vaccine approaches.
{"title":"Vaccination to Prevent Lyme Disease: A Movement Towards Anti-Tick Approaches.","authors":"Emily E Johnson, Thomas M Hart, Erol Fikrig","doi":"10.1093/infdis/jiae202","DOIUrl":"10.1093/infdis/jiae202","url":null,"abstract":"<p><p>Lyme disease is caused by the spirochete, Borrelia burgdorferi, which is transmitted by Ixodes spp ticks. The rise in Lyme disease cases since its discovery in the 1970s has reinforced the need for a vaccine. A vaccine based on B burgdorferi outer surface protein A (OspA) was approved by the Food and Drug Administration (FDA) several decades ago, but was pulled from the market a few years later, reportedly due to poor sales, despite multiple organizations concluding that it was safe and effective. Newer OspA-based vaccines are being developed and are likely to be available in the coming years. More recently, there has been a push to develop vaccines that target the tick vector instead of the pathogen to inhibit tick feeding and thus prevent transmission of tick-borne pathogens to humans and wildlife reservoirs. This review outlines the history of Lyme disease vaccines and this movement to anti-tick vaccine approaches.</p>","PeriodicalId":50179,"journal":{"name":"Journal of Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11322886/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141977097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}