Pub Date : 2024-08-07DOI: 10.1016/j.lanmic.2024.07.006
Xinyao Liu, Zihan Zhao, Zhiyong Zong
{"title":"Precise geographical distribution and call for accurate identification of histoplasmosis cases in China.","authors":"Xinyao Liu, Zihan Zhao, Zhiyong Zong","doi":"10.1016/j.lanmic.2024.07.006","DOIUrl":"https://doi.org/10.1016/j.lanmic.2024.07.006","url":null,"abstract":"","PeriodicalId":46633,"journal":{"name":"Lancet Microbe","volume":null,"pages":null},"PeriodicalIF":20.9,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141914237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-05DOI: 10.1016/S2666-5247(24)00138-1
Christine Chevillon, Benoît de Thoisy, Alex W Rakestraw, Kayla M Fast, Jennifer L Pechal, Sophie Picq, Loïc Epelboin, Paul Le Turnier, Magdalene Dogbe, Heather R Jordan, Michael W Sandel, Mark Eric Benbow, Jean-François Guégan
Predicting the outbreak of infectious diseases and designing appropriate preventive health actions require interdisciplinary research into the processes that drive exposure to and transmission of disease agents. In the case of mycobacterial diseases, the epidemiological understanding of the scientific community hitherto was based on the clinical studies of infections in vertebrates. To evaluate the information gained by comprehensively accounting for the ecological and evolutionary constraints, we conducted literature searches assessing the role of mycobacteria interactions with non-vertebrate species in the origin of their pathogenicity and variations in disease risk. The reviewed literature challenges the current theory of person-to-person transmission for several mycobacterial infections. Furthermore, the findings suggest that diverse non-vertebrate organisms influence virulence, mediate transmission, and contribute to pathogen abundance in relation to vertebrate exposure. We advocate that an ecological and evolutionary framework provides novel insights to support a more comprehensive understanding of the prevention and management of diseases in vertebrates.
{"title":"Ecological and evolutionary perspectives advance understanding of mycobacterial diseases.","authors":"Christine Chevillon, Benoît de Thoisy, Alex W Rakestraw, Kayla M Fast, Jennifer L Pechal, Sophie Picq, Loïc Epelboin, Paul Le Turnier, Magdalene Dogbe, Heather R Jordan, Michael W Sandel, Mark Eric Benbow, Jean-François Guégan","doi":"10.1016/S2666-5247(24)00138-1","DOIUrl":"https://doi.org/10.1016/S2666-5247(24)00138-1","url":null,"abstract":"<p><p>Predicting the outbreak of infectious diseases and designing appropriate preventive health actions require interdisciplinary research into the processes that drive exposure to and transmission of disease agents. In the case of mycobacterial diseases, the epidemiological understanding of the scientific community hitherto was based on the clinical studies of infections in vertebrates. To evaluate the information gained by comprehensively accounting for the ecological and evolutionary constraints, we conducted literature searches assessing the role of mycobacteria interactions with non-vertebrate species in the origin of their pathogenicity and variations in disease risk. The reviewed literature challenges the current theory of person-to-person transmission for several mycobacterial infections. Furthermore, the findings suggest that diverse non-vertebrate organisms influence virulence, mediate transmission, and contribute to pathogen abundance in relation to vertebrate exposure. We advocate that an ecological and evolutionary framework provides novel insights to support a more comprehensive understanding of the prevention and management of diseases in vertebrates.</p>","PeriodicalId":46633,"journal":{"name":"Lancet Microbe","volume":null,"pages":null},"PeriodicalIF":20.9,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141907971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-05DOI: 10.1016/S2666-5247(24)00112-5
Biana Bernshtein, Meagan Kelly, Deniz Cizmeci, Julia A Zhiteneva, Ryan Macvicar, Mohammad Kamruzzaman, Taufiqur R Bhuiyan, Fahima Chowdhury, Ashraful Islam Khan, Firdausi Qadri, Richelle C Charles, Peng Xu, Pavol Kováč, Kristen A Clarkson, Robert W Kaminski, Galit Alter, Edward T Ryan
Background: Shigella is the third leading global cause of moderate or severe diarrhoea among children younger than 5 years globally, and is the leading cause in children aged 24-59 months. The mechanism of protection against Shigella infection and disease in endemic areas is uncertain. We aimed to compare the Shigella-specific antibody responses in individuals living in Shigella-endemic and non-endemic areas, and to identify correlates of protection in a Shigella-endemic location.
Methods: We applied a systems approach to retrospectively analyse serological responses to Shigella across endemic and non-endemic populations. We profiled serum samples collected from 44 individuals from the USA without previous exposure to Shigella and who were experimentally challenged with Shigella sonnei (non-endemic setting), and serum samples collected from 55 Peruvian army recruits (endemic setting). In the endemic setting, a subset of 37 samples collected from individuals infected with culture-confirmed Shigella flexneri 2a were divided into two groups: susceptible, which included individuals infected within 90 days of entering the camp (n=29); or resistant, which included individuals infected later than 90 days after entering the camp (n=8). We analysed Shigella-specific antibody isotype, subclass, and Fc receptor binding profiles across IpaB, IpaC, IpaD, and lipopolysaccharide from S flexneri 2a, 3a, and 6, and S sonnei, and O-specific polysaccharide (OSP) from S flexneri 2a and 3a and S sonnei. We also evaluated antibody-mediated complement deposition and innate immune cell activation. The main outcome of interest was the detection of antibody markers and functionality associated with protection against shigellosis in a high-burden endemic setting.
Findings: Adults with endemic exposure to Shigella possessed broad and functional antibody responses across polysaccharide, glycolipid, and protein antigens compared with individuals from non-endemic regions. In a setting with high Shigella burden, elevated levels of OSP-specific Fcα receptor (FcαR) binding antibodies were associated with resistance to shigellosis, whereas total OSP-specific IgA was not, suggesting a potentially unique functionality. OSP-specific FcαR binding IgA found in resistant individuals activated bactericidal neutrophil functions including phagocytosis, degranulation, and production of reactive oxygen species. Moreover, IgA depletion from resistant serum significantly reduced binding of OSP-specific antibodies to FcαR and antibody-mediated activation of neutrophils and monocytes.
Interpretation: Our findings suggest that OSP-specific functional IgA responses contribute to protective immunity against Shigella infection in a high-burden setting. These findings will assist in the development and evaluation of Shigella vaccines.
Funding: US National Institutes of Health.
背景：志贺氏菌是导致全球 5 岁以下儿童中度或重度腹泻的第三大原因，也是导致 24-59 个月儿童腹泻的主要原因。在志贺氏杆菌流行地区，预防志贺氏杆菌感染和疾病的机制尚不确定。我们的目的是比较生活在志贺氏杆菌流行地区和非流行地区的人的志贺氏杆菌特异性抗体反应，并确定在志贺氏杆菌流行地区保护的相关因素：我们采用了一种系统方法，对志贺氏杆菌流行区和非流行区人群的血清反应进行了回顾性分析。我们分析了从美国 44 名以前未接触过志贺氏杆菌、但在实验中感染了松内志贺氏菌（非地方病）的人身上采集的血清样本，以及从 55 名秘鲁新兵（地方病）身上采集的血清样本。在地方病环境中，从感染了经培养证实的柔性志贺氏菌 2a 的个体中采集的 37 份样本被分为两组：易感组，包括进入营地后 90 天内感染的个体（29 人）；耐受组，包括进入营地后 90 天后感染的个体（8 人）。我们分析了志贺氏杆菌特异性抗体的同型、亚类和 Fc 受体结合情况，包括 IpaB、IpaC、IpaD 和来自 S flexneri 2a、3a 和 6 以及 S sonnei 的脂多糖，以及来自 S flexneri 2a 和 3a 以及 S sonnei 的 O 特异性多糖 (OSP)。我们还评估了抗体介导的补体沉积和先天性免疫细胞活化。我们感兴趣的主要结果是，在高负担地方病环境中检测与志贺氏杆菌病保护相关的抗体标记物和功能：研究结果：与来自非志贺氏杆菌流行地区的个体相比，接触过志贺氏杆菌的成年人对多糖、糖脂和蛋白质抗原具有广泛的功能性抗体反应。在志贺氏杆菌负担较重的环境中，OSP特异性Fcα受体（FcαR）结合抗体水平的升高与志贺氏杆菌病的抵抗力有关，而OSP特异性IgA总量却与之无关，这表明OSP特异性IgA可能具有独特的功能。在耐药个体中发现的 OSP 特异性 FcαR 结合 IgA 激活了中性粒细胞的杀菌功能，包括吞噬、脱颗粒和产生活性氧。此外，从耐药血清中清除 IgA 能显著减少 OSP 特异性抗体与 FcαR 的结合以及抗体介导的中性粒细胞和单核细胞活化：我们的研究结果表明，OSP特异性功能性IgA反应有助于在高负担环境中对志贺氏杆菌感染产生保护性免疫。这些发现将有助于志贺氏杆菌疫苗的开发和评估：美国国立卫生研究院。
{"title":"Determinants of immune responses predictive of protection against shigellosis in an endemic zone: a systems analysis of antibody profiles and function.","authors":"Biana Bernshtein, Meagan Kelly, Deniz Cizmeci, Julia A Zhiteneva, Ryan Macvicar, Mohammad Kamruzzaman, Taufiqur R Bhuiyan, Fahima Chowdhury, Ashraful Islam Khan, Firdausi Qadri, Richelle C Charles, Peng Xu, Pavol Kováč, Kristen A Clarkson, Robert W Kaminski, Galit Alter, Edward T Ryan","doi":"10.1016/S2666-5247(24)00112-5","DOIUrl":"https://doi.org/10.1016/S2666-5247(24)00112-5","url":null,"abstract":"<p><strong>Background: </strong>Shigella is the third leading global cause of moderate or severe diarrhoea among children younger than 5 years globally, and is the leading cause in children aged 24-59 months. The mechanism of protection against Shigella infection and disease in endemic areas is uncertain. We aimed to compare the Shigella-specific antibody responses in individuals living in Shigella-endemic and non-endemic areas, and to identify correlates of protection in a Shigella-endemic location.</p><p><strong>Methods: </strong>We applied a systems approach to retrospectively analyse serological responses to Shigella across endemic and non-endemic populations. We profiled serum samples collected from 44 individuals from the USA without previous exposure to Shigella and who were experimentally challenged with Shigella sonnei (non-endemic setting), and serum samples collected from 55 Peruvian army recruits (endemic setting). In the endemic setting, a subset of 37 samples collected from individuals infected with culture-confirmed Shigella flexneri 2a were divided into two groups: susceptible, which included individuals infected within 90 days of entering the camp (n=29); or resistant, which included individuals infected later than 90 days after entering the camp (n=8). We analysed Shigella-specific antibody isotype, subclass, and Fc receptor binding profiles across IpaB, IpaC, IpaD, and lipopolysaccharide from S flexneri 2a, 3a, and 6, and S sonnei, and O-specific polysaccharide (OSP) from S flexneri 2a and 3a and S sonnei. We also evaluated antibody-mediated complement deposition and innate immune cell activation. The main outcome of interest was the detection of antibody markers and functionality associated with protection against shigellosis in a high-burden endemic setting.</p><p><strong>Findings: </strong>Adults with endemic exposure to Shigella possessed broad and functional antibody responses across polysaccharide, glycolipid, and protein antigens compared with individuals from non-endemic regions. In a setting with high Shigella burden, elevated levels of OSP-specific Fcα receptor (FcαR) binding antibodies were associated with resistance to shigellosis, whereas total OSP-specific IgA was not, suggesting a potentially unique functionality. OSP-specific FcαR binding IgA found in resistant individuals activated bactericidal neutrophil functions including phagocytosis, degranulation, and production of reactive oxygen species. Moreover, IgA depletion from resistant serum significantly reduced binding of OSP-specific antibodies to FcαR and antibody-mediated activation of neutrophils and monocytes.</p><p><strong>Interpretation: </strong>Our findings suggest that OSP-specific functional IgA responses contribute to protective immunity against Shigella infection in a high-burden setting. These findings will assist in the development and evaluation of Shigella vaccines.</p><p><strong>Funding: </strong>US National Institutes of Health.</p>","PeriodicalId":46633,"journal":{"name":"Lancet Microbe","volume":null,"pages":null},"PeriodicalIF":20.9,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141907970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-03DOI: 10.1016/j.lanmic.2024.07.013
Man Sun, Huan Zhou
{"title":"Enhancing public health strategies for dengue control: insights and recommendations for comprehensive management in tropical regions.","authors":"Man Sun, Huan Zhou","doi":"10.1016/j.lanmic.2024.07.013","DOIUrl":"https://doi.org/10.1016/j.lanmic.2024.07.013","url":null,"abstract":"","PeriodicalId":46633,"journal":{"name":"Lancet Microbe","volume":null,"pages":null},"PeriodicalIF":20.9,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141898624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-02DOI: 10.1016/j.lanmic.2024.100962
Timothy Jesudason
{"title":"Antibacterial agents in preclinical and clinical development.","authors":"Timothy Jesudason","doi":"10.1016/j.lanmic.2024.100962","DOIUrl":"https://doi.org/10.1016/j.lanmic.2024.100962","url":null,"abstract":"","PeriodicalId":46633,"journal":{"name":"Lancet Microbe","volume":null,"pages":null},"PeriodicalIF":20.9,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141894590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01DOI: 10.1016/S2666-5247(24)00052-1
Background
The intensive use of antibiotics has resulted in strong natural selection for the evolution of antimicrobial resistance (AMR), but whether, and under what circumstances, the removal of antibiotics would result in a rapid reduction in AMR has been insufficiently explored. We aimed to test the hypothesis that in the simple, yet common, case of AMR conferred by a single gene, removing antibiotics would quickly reduce the prevalence of resistance if the AMR gene imposes a high fitness cost and costless resistance is extremely rare among its proximal mutants.
Methods
In this genetic study, to test our hypothesis, we used the mcr-1 gene in Escherichia coli, which confers resistance to the last-resort antibiotic colistin, as a model. A high-throughput reverse genetics approach was used to evaluate mcr-1 variants for their fitness cost and resistance levels relative to a non-functional construct, by measuring relative growth rates in colistin-free media and at 2 μg/mL and 4 μg/mL colistin. We identified costless resistant mcr-1 mutants, and examined their properties within the context of the sequential organisation of mcr-1’s functional domains as well as the evolutionary accessibility of these mutations. Finally, a simple population genetic model incorporating the measured fitness cost was constructed and tested against previously published real-world data of mcr-1 prevalence in colonised inpatients in China since the 2017 colistin ban in fodder additives.
Findings
We estimated the relative growth rates of 14 742 mcr-1 E coli variants (including the wild type), 3449 of which were single-nucleotide mutants. E coli showed 73·8% less growth per 24 h when carrying wild-type mcr-1 compared with the non-functional construct. 6252 (42·4%) of 14 741 mcr-1 mutants showed colistin resistance accompanied by significant fitness costs, when grown under 4 μg/mL colistin selection. 43 (0·3%) mcr-1 mutants exhibited costless resistance, most of which contained multiple mutations. Among the 3449 single mutants of mcr-1, 3433 (99·5%) had a fitness cost when grown in colistin-free media, with a mean relative growth of 0·305 (SD 0·193) compared with the non-functional variant. 3059 (88·7%) and 1833 (53·1%) of 3449 single mutants outgrew the non-functional mcr-1 in the presence of 2 μg/mL and 4 μg/mL colistin, respectively. Single mutations that gave rise to costless mutants were rare in all three domains of mcr-1 (transmembrane domain, flexible linker, and catalytic domain), but the linker domain was enriched with cost-reducing and resistance-enhancing mutations and depleted with cost-increasing mutations. The population genetics model based on the experimental data accurately predicts the rapid decline in mcr-1 prevalence in real-world data.
{"title":"Assessment of the reversibility of resistance in the absence of antibiotics and its relationship with the resistance gene's fitness cost: a genetic study with mcr-1","authors":"","doi":"10.1016/S2666-5247(24)00052-1","DOIUrl":"10.1016/S2666-5247(24)00052-1","url":null,"abstract":"<div><h3>Background</h3><p>The intensive use of antibiotics has resulted in strong natural selection for the evolution of antimicrobial resistance (AMR), but whether, and under what circumstances, the removal of antibiotics would result in a rapid reduction in AMR has been insufficiently explored. We aimed to test the hypothesis that in the simple, yet common, case of AMR conferred by a single gene, removing antibiotics would quickly reduce the prevalence of resistance if the AMR gene imposes a high fitness cost and costless resistance is extremely rare among its proximal mutants.</p></div><div><h3>Methods</h3><p>In this genetic study, to test our hypothesis, we used the <em>mcr-1</em> gene in <em>Escherichia coli</em>, which confers resistance to the last-resort antibiotic colistin, as a model. A high-throughput reverse genetics approach was used to evaluate <em>mcr-1</em> variants for their fitness cost and resistance levels relative to a non-functional construct, by measuring relative growth rates in colistin-free media and at 2 μg/mL and 4 μg/mL colistin. We identified costless resistant <em>mcr-1</em> mutants, and examined their properties within the context of the sequential organisation of <em>mcr-1</em>’s functional domains as well as the evolutionary accessibility of these mutations. Finally, a simple population genetic model incorporating the measured fitness cost was constructed and tested against previously published real-world data of <em>mcr-1</em> prevalence in colonised inpatients in China since the 2017 colistin ban in fodder additives.</p></div><div><h3>Findings</h3><p>We estimated the relative growth rates of 14 742 <em>mcr-1 E coli</em> variants (including the wild type), 3449 of which were single-nucleotide mutants. <em>E coli</em> showed 73·8% less growth per 24 h when carrying wild-type <em>mcr-1</em> compared with the non-functional construct. 6252 (42·4%) of 14 741 <em>mcr-1</em> mutants showed colistin resistance accompanied by significant fitness costs, when grown under 4 μg/mL colistin selection. 43 (0·3%) <em>mcr-1</em> mutants exhibited costless resistance, most of which contained multiple mutations. Among the 3449 single mutants of <em>mcr-1</em>, 3433 (99·5%) had a fitness cost when grown in colistin-free media, with a mean relative growth of 0·305 (SD 0·193) compared with the non-functional variant. 3059 (88·7%) and 1833 (53·1%) of 3449 single mutants outgrew the non-functional <em>mcr-1</em> in the presence of 2 μg/mL and 4 μg/mL colistin, respectively. Single mutations that gave rise to costless mutants were rare in all three domains of <em>mcr-1</em> (transmembrane domain, flexible linker, and catalytic domain), but the linker domain was enriched with cost-reducing and resistance-enhancing mutations and depleted with cost-increasing mutations. The population genetics model based on the experimental data accurately predicts the rapid decline in <em>mcr-1</em> prevalence in real-world data.</p></div><div><h3>Inte","PeriodicalId":46633,"journal":{"name":"Lancet Microbe","volume":null,"pages":null},"PeriodicalIF":20.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666524724000521/pdfft?md5=1262172eff4a612dbc1b5de78e66ff6d&pid=1-s2.0-S2666524724000521-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141318596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01DOI: 10.1016/S2666-5247(24)00155-1
{"title":"ESCMID Global 2024","authors":"","doi":"10.1016/S2666-5247(24)00155-1","DOIUrl":"10.1016/S2666-5247(24)00155-1","url":null,"abstract":"","PeriodicalId":46633,"journal":{"name":"Lancet Microbe","volume":null,"pages":null},"PeriodicalIF":20.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666524724001551/pdfft?md5=0a10e5ee33c3934346fd9e9577437989&pid=1-s2.0-S2666524724001551-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141474688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01DOI: 10.1016/S2666-5247(24)00053-3
Background
The antibiotic bedaquiline is a key component of new WHO regimens for drug-resistant tuberculosis; however, predicting bedaquiline resistance from bacterial genotypes remains challenging. We aimed to understand the genetic mechanisms of bedaquiline resistance by analysing Mycobacterium tuberculosis isolates from South Africa.
Methods
For this genomic analysis, we conducted whole-genome sequencing of Mycobacterium tuberculosis samples collected at two referral laboratories in Cape Town and Johannesburg, covering regions of South Africa with a high prevalence of tuberculosis. We used the tool ARIBA to measure the status of predefined genes that are associated with bedaquiline resistance. To produce a broad genetic landscape of M tuberculosis in South Africa, we extended our analysis to include all publicly available isolates from the European Nucleotide Archive, including isolates obtained by the CRyPTIC consortium, for which minimum inhibitory concentrations of bedaquiline were available.
Findings
Between Jan 10, 2019, and July, 22, 2020, we sequenced 505 M tuberculosis isolates from 461 patients. Of the 64 isolates with mutations within the mmpR5 regulatory gene, we found 53 (83%) had independent acquisition of 31 different mutations, with a particular enrichment of truncated MmpR5 in bedaquiline-resistant isolates resulting from either frameshift mutations or the introduction of an insertion element. Truncation occurred across three M tuberculosis lineages, and were present in 66% of bedaquiline-resistant isolates. Although the distributions overlapped, the median minimum inhibitory concentration of bedaquiline was 0·25 mg/L (IQR 0·12–0·25) in mmpR5-disrupted isolates, compared with 0·06 mg/L (0·03–0·06) in wild-type M tuberculosis.
Interpretation
Reduction in the susceptibility of M tuberculosis to bedaquiline has evolved repeatedly across the phylogeny. In our data, we see no evidence that this reduction has led to the spread of a successful strain in South Africa. Binary phenotyping based on the bedaquiline breakpoint might be inappropriate to monitor resistance to this drug. We recommend the use of minimum inhibitory concentrations in addition to MmpR5 truncation screening to identify moderate increases in resistance to bedaquiline.
{"title":"MmpR5 protein truncation and bedaquiline resistance in Mycobacterium tuberculosis isolates from South Africa: a genomic analysis","authors":"","doi":"10.1016/S2666-5247(24)00053-3","DOIUrl":"10.1016/S2666-5247(24)00053-3","url":null,"abstract":"<div><h3>Background</h3><p>The antibiotic bedaquiline is a key component of new WHO regimens for drug-resistant tuberculosis; however, predicting bedaquiline resistance from bacterial genotypes remains challenging. We aimed to understand the genetic mechanisms of bedaquiline resistance by analysing <em>Mycobacterium tuberculosis</em> isolates from South Africa.</p></div><div><h3>Methods</h3><p>For this genomic analysis, we conducted whole-genome sequencing of <em>Mycobacterium tuberculosis</em> samples collected at two referral laboratories in Cape Town and Johannesburg, covering regions of South Africa with a high prevalence of tuberculosis. We used the tool ARIBA to measure the status of predefined genes that are associated with bedaquiline resistance. To produce a broad genetic landscape of <em>M tuberculosis</em> in South Africa, we extended our analysis to include all publicly available isolates from the European Nucleotide Archive, including isolates obtained by the CRyPTIC consortium, for which minimum inhibitory concentrations of bedaquiline were available.</p></div><div><h3>Findings</h3><p>Between Jan 10, 2019, and July, 22, 2020, we sequenced 505 <em>M tuberculosis</em> isolates from 461 patients. Of the 64 isolates with mutations within the <em>mmpR5</em> regulatory gene, we found 53 (83%) had independent acquisition of 31 different mutations, with a particular enrichment of truncated MmpR5 in bedaquiline-resistant isolates resulting from either frameshift mutations or the introduction of an insertion element. Truncation occurred across three <em>M tuberculosis</em> lineages, and were present in 66% of bedaquiline-resistant isolates. Although the distributions overlapped, the median minimum inhibitory concentration of bedaquiline was 0·25 mg/L (IQR 0·12–0·25) in <em>mmpR5</em>-disrupted isolates, compared with 0·06 mg/L (0·03–0·06) in wild-type <em>M tuberculosis</em>.</p></div><div><h3>Interpretation</h3><p>Reduction in the susceptibility of <em>M tuberculosis</em> to bedaquiline has evolved repeatedly across the phylogeny. In our data, we see no evidence that this reduction has led to the spread of a successful strain in South Africa. Binary phenotyping based on the bedaquiline breakpoint might be inappropriate to monitor resistance to this drug. We recommend the use of minimum inhibitory concentrations in addition to MmpR5 truncation screening to identify moderate increases in resistance to bedaquiline.</p></div><div><h3>Funding</h3><p>US Centers for Disease Control and Prevention.</p></div>","PeriodicalId":46633,"journal":{"name":"Lancet Microbe","volume":null,"pages":null},"PeriodicalIF":20.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666524724000533/pdfft?md5=ca88fce82bbe84a6d15c002b1b3a5e28&pid=1-s2.0-S2666524724000533-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141293817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01DOI: 10.1016/S2666-5247(24)00074-0
Background
Since the emergence of the global mpox outbreak in May, 2022, more than 90 000 cases have been diagnosed across 110 countries, disproportionately affecting people with HIV. The durability of mpox-specific immunity is unclear and reinfections have been reported. We aimed to compare mpox immune responses up to 6 months after diagnosis in participants with and without HIV and assess their effect on disease severity and viral clearance dynamics.
Methods
This study was embedded within a prospective, observational, multicentre cohort study of viral clearance dynamics among people with mpox in Spain (MoViE). We included women and men aged 18 years or older, who had signs of mpox, and reported having symptom onset within the previous 10 days at the moment of mpox diagnosis from three sex clinics of the Barcelona metropolitan area. Samples from skin ulcers were collected weekly to estimate the time to clear monkeypox virus (MPXV) from skin lesions. Blood samples were taken at diagnosis, 29, 91, and 182 days later for immune analysis. This included quantifying IgG and IgA against three mpox antigens by ELISA, evaluating in-vitro neutralisation, and characterising mpox-specific T-cell responses using interferon γ detecting enzyme-linked immunospot (ELISpot) assay and multiparametric flow cytometry.
Findings
Of the 77 originally enrolled participants, we included 33 participants recruited between July 19, and Oct 6, 2022. Participants without HIV (19 [58%] participants) and participants with HIV (14 [42%] participants) had similar clinical severity and time to MPXV clearance in skin lesions. Participants with HIV had a CD4+ T-cell count median of 777 cells per μL (IQR 484–1533), and 11 (78%) of 14 were virally suppressed on antiretroviral therapy. Nine (27%) of 33 participants were age 49 years or older. 15 (45%) of 33 participants were originally from Spain, and all participants were men. Early humoral responses, particularly concentrations and breadth of IgG and IgA, were associated with milder disease and faster viral clearance. Orthopoxvirus-specific T cells count was also positively correlated with MPXV clearance. Antibody titres declined more rapidly in participants with HIV, but T-cell responses against MPXV were sustained up to day 182 after diagnosis, regardless of HIV status.
Interpretation
Higher breadth and magnitude of B-cell and T-cell responses are important in facilitating local viral clearance, limiting mpox dissemination, and reducing disease severity in individuals with preserved immune system. Antibodies appear to contribute to early viral control and T-cell responses are sustained over time, which might contribute to milder presentations during reinfection.
Funding
Fundació Lluita contra les Infeccions, IrsiCaixa, and Consorcio Centro de Investigación Biomédica en Red, Instituto de Salud Carlos III, Mi
背景：自 2022 年 5 月全球爆发麻风腮疫情以来，已有 110 个国家确诊了 90 000 多例病例，艾滋病毒感染者受到的影响尤为严重。水痘特异性免疫力的持久性尚不明确，且有再次感染的报道。我们旨在比较感染艾滋病毒和未感染艾滋病毒的参与者在确诊后 6 个月内的麻疹免疫反应，并评估其对疾病严重程度和病毒清除动态的影响：本研究是一项前瞻性、观察性、多中心队列研究（MoViE）的一部分，该研究针对的是西班牙水痘患者的病毒清除动态。我们纳入了巴塞罗那大都会地区三家性诊所中年龄在 18 岁或以上、有水痘症状并在水痘确诊时报告在过去 10 天内发病的女性和男性患者。每周采集一次皮肤溃疡样本，以估算清除皮损中猴痘病毒（MPXV）的时间。在确诊、29 天、91 天和 182 天后采集血液样本进行免疫分析。这包括通过酶联免疫吸附试验（ELISA）量化针对三种猴痘抗原的IgG和IgA，评估体外中和作用，以及使用干扰素γ检测酶联免疫吸附试验（ELISpot）和多参数流式细胞术鉴定猴痘特异性T细胞反应：在最初招募的 77 名参与者中，我们纳入了在 2022 年 7 月 19 日至 10 月 6 日期间招募的 33 名参与者。未感染艾滋病毒的参与者（19 人 [58%] ）和感染艾滋病毒的参与者（14 人 [42%] ）的临床严重程度和皮损中 MPXV 清除时间相似。感染艾滋病毒的参与者的 CD4+ T 细胞计数中位数为 777 cells per μL（IQR 484-1533），14 人中有 11 人（78%）在接受抗逆转录病毒治疗后病毒得到抑制。33 名参与者中有 9 人（27%）年龄在 49 岁或以上。33 名参与者中有 15 人（45%）来自西班牙，所有参与者均为男性。早期体液反应，尤其是 IgG 和 IgA 的浓度和广度，与病情较轻和病毒清除较快有关联。矫形病毒特异性 T 细胞数量也与 MPXV 清除率呈正相关。艾滋病毒感染者的抗体滴度下降更快，但无论艾滋病毒感染状况如何，针对 MPXV 的 T 细胞反应在确诊后第 182 天仍能持续：较高的 B 细胞和 T 细胞反应的广度和强度对于促进局部病毒清除、限制 mpox 传播以及降低免疫系统保留者的疾病严重程度非常重要。抗体似乎有助于早期病毒控制，而T细胞反应则会长期持续，这可能有助于再感染时病情的缓解：Fundació Lluita contra les Infeccions、IrsiCaixa 和 Consorcio Centro de Investigación Biomédica en Red、Instituto de Salud Carlos III、Ministerio de Ciencia、Innovación e Universidades。
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Pub Date : 2024-08-01DOI: 10.1016/S2666-5247(24)00111-3
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