Epstein-Barr virus (EBV) infection has been related to multiple epithelial cancers and lymphomas. Current efforts in developing a prophylactic EBV vaccine have focused on inducing neutralizing antibodies. However, given the lifelong and persistent nature of EBV infection following primary infection, it is rationalized that an ideal vaccine should elicit both humoral and cellular immune responses targeting multiple stages of the EBV lifecycle. This study used a DNA vector and a TianTan vaccinia virus to express key EBV antigens, including BZLF1, EBNA1, EBNA3B, and gH/gL, to generate multi-antigen vaccines. The multi-antigen vaccine expressing all four antigens and the multi-antigen vaccine expressing BZLF1, EBNA1, and EBNA3B showed comparable protection effects and prevented 100% and 80% of humanized mice, respectively, from EBV-induced fatal B cell lymphoma by activating BZLF1, EBNA1, and EBNA3B specific T cell. The vaccine expressing lytic protein BZLF1 elicited stronger T cell responses and conferred superior protection compared to vaccines targeting single latent EBNA1 or EBNA3B. The vaccine solely expressing gH/gL exhibited no T cell protective effects in our humanized mice model. Our study implicates the potential of EBV vaccines that induce potent cellular responses targeting both latent and lytic phases of the EBV life cycle in the prevention of EBV-induced B cell lymphoma.
摘要天疱疮病毒(EBV)感染与多种上皮癌和淋巴瘤有关。目前,开发预防性 EBV 疫苗的工作主要集中在诱导中和抗体上。然而,鉴于 EBV 感染在原发感染后会终身持续存在,因此理想的疫苗应该针对 EBV 生命周期的多个阶段引起体液免疫和细胞免疫反应。本研究使用 DNA 载体和天坛疫苗病毒表达 EBV 的关键抗原,包括 BZLF1、EBNA1、EBNA3B 和 gH/gL,以产生多抗原疫苗。通过激活 BZLF1、EBNA1 和 EBNA3B 特异性 T 细胞,表达所有四种抗原的多抗原疫苗和表达 BZLF1、EBNA1 和 EBNA3B 的多抗原疫苗显示出了相当的保护效果,分别 100% 和 80% 的人源化小鼠免于 EBV 诱导的致命 B 细胞淋巴瘤。与针对单一潜伏 EBNA1 或 EBNA3B 的疫苗相比,表达溶菌蛋白 BZLF1 的疫苗能激发更强的 T 细胞反应,并提供更优越的保护。在我们的人源化小鼠模型中,仅表达 gH/gL 的疫苗没有表现出 T 细胞保护作用。我们的研究表明,针对 EBV 生命周期的潜伏期和溶解期诱导强效细胞应答的 EBV 疫苗具有预防 EBV 诱导的 B 细胞淋巴瘤的潜力。
{"title":"TianTan vaccinia virus-based EBV vaccines targeting both latent and lytic antigens elicits potent immunity against lethal EBV challenge in humanized mice.","authors":"Xinyu Zhang, Yanhong Chen, Shuhui Wang, Ling Zhong, Zheng Xiang, Xiao Zhang, Shanshan Zhang, Xiang Zhou, Wanlin Zhang, Yan Zhou, Qiuting Zhang, Jingtong Liang, Yanran Luo, Yufei Wang, Ling Chen, Xiaoping Ye, Qisheng Feng, Mu-Sheng Zeng, Ying Liu, Yi-Xin Zeng, Yiming Shao, Miao Xu","doi":"10.1080/22221751.2024.2412640","DOIUrl":"10.1080/22221751.2024.2412640","url":null,"abstract":"<p><p>Epstein-Barr virus (EBV) infection has been related to multiple epithelial cancers and lymphomas. Current efforts in developing a prophylactic EBV vaccine have focused on inducing neutralizing antibodies. However, given the lifelong and persistent nature of EBV infection following primary infection, it is rationalized that an ideal vaccine should elicit both humoral and cellular immune responses targeting multiple stages of the EBV lifecycle. This study used a DNA vector and a TianTan vaccinia virus to express key EBV antigens, including BZLF1, EBNA1, EBNA3B, and gH/gL, to generate multi-antigen vaccines. The multi-antigen vaccine expressing all four antigens and the multi-antigen vaccine expressing BZLF1, EBNA1, and EBNA3B showed comparable protection effects and prevented 100% and 80% of humanized mice, respectively, from EBV-induced fatal B cell lymphoma by activating BZLF1, EBNA1, and EBNA3B specific T cell. The vaccine expressing lytic protein BZLF1 elicited stronger T cell responses and conferred superior protection compared to vaccines targeting single latent EBNA1 or EBNA3B. The vaccine solely expressing gH/gL exhibited no T cell protective effects in our humanized mice model. Our study implicates the potential of EBV vaccines that induce potent cellular responses targeting both latent and lytic phases of the EBV life cycle in the prevention of EBV-induced B cell lymphoma.</p>","PeriodicalId":11602,"journal":{"name":"Emerging Microbes & Infections","volume":" ","pages":"2412640"},"PeriodicalIF":8.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11485817/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142388956","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}
Pub Date : 2024-12-01Epub Date: 2024-02-06DOI: 10.1080/22221751.2023.2292077
Moritz Staudacher, Julian Frederic Hotz, Richard Kriz, Katharina Schefberger, Lisa Schneider, Kathrin Spettel, Peter Starzengruber, Jürgen Benjamin Hagemann, Amelie Leutzendorff, Heinz Burgmann, Heimo Lagler
Invasive Staphylococcus aureus infections are associated with a high burden of disease, case fatality rate and healthcare costs. Oxazolidinones such as linezolid and tedizolid are considered potential treatment choices for conditions involving methicillin resistance or penicillin allergies. Additionally, they are being investigated as potential inhibitors of toxins in toxin-mediated diseases. In this study, linezolid and tedizolid were evaluated in an in vitro resistance development model for induction of resistance in S. aureus. Whole genome sequencing was conducted to elucidate resistance mechanisms through the identification of causal mutations. After inducing resistance to both linezolid and tedizolid, several partially novel single nucleotide variants (SNVs) were detected in the rplC gene, which encodes the 50S ribosome protein L3 in S. aureus. These SNVs were found to decrease the binding affinity, potentially serving as the underlying cause for oxazolidinone resistance. Furthermore, in opposite to linezolid we were able to induce phenotypically small colony variants of S. aureus after induction of resistance with tedizolid for the first time in literature. In summary, even if different antibiotic concentrations were required and SNVs were detected, the principal capacity of S. aureus to develop resistance to oxazolidinones seems to differ between linezolid and tedizolid in-vivo but not in vitro. Stepwise induction of resistance seems to be a time and cost-effective tool for assessing resistance evolution. Inducted-resistant strains should be examined and documented for epidemiological reasons, if MICs start to rise or oxazolidinone-resistant S. aureus outbreaks become more frequent.
{"title":"Differences in oxazolidinone resistance mechanisms and small colony variants emergence of <i>Staphylococcus aureus</i> induced in an <i>in vitro</i> resistance development model.","authors":"Moritz Staudacher, Julian Frederic Hotz, Richard Kriz, Katharina Schefberger, Lisa Schneider, Kathrin Spettel, Peter Starzengruber, Jürgen Benjamin Hagemann, Amelie Leutzendorff, Heinz Burgmann, Heimo Lagler","doi":"10.1080/22221751.2023.2292077","DOIUrl":"10.1080/22221751.2023.2292077","url":null,"abstract":"<p><p>Invasive <i>Staphylococcus aureus</i> infections are associated with a high burden of disease, case fatality rate and healthcare costs. Oxazolidinones such as linezolid and tedizolid are considered potential treatment choices for conditions involving methicillin resistance or penicillin allergies. Additionally, they are being investigated as potential inhibitors of toxins in toxin-mediated diseases. In this study, linezolid and tedizolid were evaluated in an <i>in vitro</i> resistance development model for induction of resistance in <i>S. aureus</i>. Whole genome sequencing was conducted to elucidate resistance mechanisms through the identification of causal mutations. After inducing resistance to both linezolid and tedizolid, several partially novel single nucleotide variants (SNVs) were detected in the <i>rplC</i> gene, which encodes the 50S ribosome protein L3 in <i>S. aureus</i>. These SNVs were found to decrease the binding affinity, potentially serving as the underlying cause for oxazolidinone resistance. Furthermore, in opposite to linezolid we were able to induce phenotypically small colony variants of <i>S. aureus</i> after induction of resistance with tedizolid for the first time in literature. In summary, even if different antibiotic concentrations were required and SNVs were detected, the principal capacity of <i>S. aureus</i> to develop resistance to oxazolidinones seems to differ between linezolid and tedizolid <i>in-vivo</i> but not <i>in vitro</i>. Stepwise induction of resistance seems to be a time and cost-effective tool for assessing resistance evolution. Inducted-resistant strains should be examined and documented for epidemiological reasons, if MICs start to rise or oxazolidinone-resistant <i>S. aureus</i> outbreaks become more frequent.</p>","PeriodicalId":11602,"journal":{"name":"Emerging Microbes & Infections","volume":" ","pages":"2292077"},"PeriodicalIF":13.2,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10849000/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138487004","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}
Pub Date : 2024-12-01Epub Date: 2024-01-07DOI: 10.1080/22221751.2023.2300452
V Douglas Landers, Milton Thomas, Cierra M Isom, Deepa Karki, Kevin J Sokoloski
ABSTRACTAlphaviruses are arthropod-borne, single-stranded positive-sense RNA viruses that are recognized as rapidly emerging pathogens. Despite being exquisitely sensitive to the effects of the innate immune response alphaviruses can readily replicate, disseminate, and induce pathogenesis in immunologically competent hosts. Nonetheless, how alphaviruses evade the induction of an innate immune response prior to viral gene expression, or in non-permissive infections, is unknown. Previously we reported the identification of a novel host/pathogen interaction between the viral Capsid (CP) protein and the host IRAK1 protein. The CP/IRAK1 interaction was determined to negatively impact IRAK1-dependent PAMP detection in vitro, however, the precise importance of the CP/IRAK1 interaction to alphaviral infection remained unknown. Here we detail the identification of the CP/IRAK1 interaction determinants of the Sindbis virus (SINV) CP protein and examine the importance of the interaction to alphaviral infection and pathogenesis in vivo using an interaction deficient mutant of the model neurotropic strain of SINV. Importantly, these interaction determinants are highly conserved across multiple Old-World alphaviruses, including Ross River virus (RRV), Mayaro virus (MAYV), Chikungunya virus (CHIKV), and Semliki Forest virus (SFV). In the absence of a functional CP/IRAK1 interaction, SINV replication is significantly restricted and fails to disseminate from the primary site of inoculation due to the induction of a robust type-I Interferon response. Altogether these data indicate that the evasion of IRAK1-dependent signalling is critical to overcoming the host innate immune response and the in vivo data presented here demonstrate the importance of the CP/IRAK1 interaction to neurovirulence and pathogenesis.
{"title":"Capsid protein mediated evasion of IRAK1-dependent signalling is essential to Sindbis virus neuroinvasion and virulence in mice.","authors":"V Douglas Landers, Milton Thomas, Cierra M Isom, Deepa Karki, Kevin J Sokoloski","doi":"10.1080/22221751.2023.2300452","DOIUrl":"10.1080/22221751.2023.2300452","url":null,"abstract":"<p><p><b>ABSTRACT</b>Alphaviruses are arthropod-borne, single-stranded positive-sense RNA viruses that are recognized as rapidly emerging pathogens. Despite being exquisitely sensitive to the effects of the innate immune response alphaviruses can readily replicate, disseminate, and induce pathogenesis in immunologically competent hosts. Nonetheless, how alphaviruses evade the induction of an innate immune response prior to viral gene expression, or in non-permissive infections, is unknown. Previously we reported the identification of a novel host/pathogen interaction between the viral Capsid (CP) protein and the host IRAK1 protein. The CP/IRAK1 interaction was determined to negatively impact IRAK1-dependent PAMP detection <i>in vitro</i>, however, the precise importance of the CP/IRAK1 interaction to alphaviral infection remained unknown. Here we detail the identification of the CP/IRAK1 interaction determinants of the Sindbis virus (SINV) CP protein and examine the importance of the interaction to alphaviral infection and pathogenesis <i>in vivo</i> using an interaction deficient mutant of the model neurotropic strain of SINV. Importantly, these interaction determinants are highly conserved across multiple Old-World alphaviruses, including Ross River virus (RRV), Mayaro virus (MAYV), Chikungunya virus (CHIKV), and Semliki Forest virus (SFV). In the absence of a functional CP/IRAK1 interaction, SINV replication is significantly restricted and fails to disseminate from the primary site of inoculation due to the induction of a robust type-I Interferon response. Altogether these data indicate that the evasion of IRAK1-dependent signalling is critical to overcoming the host innate immune response and the <i>in vivo</i> data presented here demonstrate the importance of the CP/IRAK1 interaction to neurovirulence and pathogenesis.</p>","PeriodicalId":11602,"journal":{"name":"Emerging Microbes & Infections","volume":" ","pages":"2300452"},"PeriodicalIF":13.2,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10773654/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139073580","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}
Pub Date : 2024-12-01Epub Date: 2024-01-07DOI: 10.1080/22221751.2023.2300525
Yaqin Peng, Yue Liu, Xuegao Yu, Jingchun Fang, Zhaowang Guo, Kang Liao, Peisong Chen, Penghao Guo
Candida auris is an emerging multidrug-resistant fungal pathogen worldwide. To date, it has not been reported in Guangdong, China. For the first time, we reported 7 cases of C. auris candidemia from two hospitals in Guangdong. The clinical and microbiological characteristics of these cases were investigated carefully. Two geographic clades, i.e. III and I, were found popular in different hospitals by whole genome sequencing analyses. All C. auris isolates from bloodstream were resistant to fluconazole, 5 of which belonged to Clade III harbouring VF125AL mutation in the ERG11 gene. The isolates with Clade I presented Y132F mutation in the ERG11 gene as well as resistance to amphotericin B. All isolates exhibited strong biofilm-forming capacity and non-aggregative phenotype. The mean time from admission to onset of C. auris candidemia was 39.4 days (range: 12 - 80 days). Despite performing appropriate therapeutic regimen, 42.9% (3/7) of patients experienced occurrences of C. auris candidemia and colonization after the first positive bloodstream. C. auris colonization was still observed after the first C. auris candidemia for 81 days in some patient. Microbiologic eradication from bloodstream was achieved in 85.7% (6/7) of patients at discharge. In conclusion, this study offers a crucial insight into unravelling the multiple origins of C. auris in Guangdong, highlighting great challenges in clinical prevention and control.
{"title":"First report of <i>Candida auris</i> in Guangdong, China: clinical and microbiological characteristics of 7 episodes of candidemia.","authors":"Yaqin Peng, Yue Liu, Xuegao Yu, Jingchun Fang, Zhaowang Guo, Kang Liao, Peisong Chen, Penghao Guo","doi":"10.1080/22221751.2023.2300525","DOIUrl":"10.1080/22221751.2023.2300525","url":null,"abstract":"<p><p><i>Candida auris</i> is an emerging multidrug-resistant fungal pathogen worldwide. To date, it has not been reported in Guangdong, China. For the first time, we reported 7 cases of <i>C. auris</i> candidemia from two hospitals in Guangdong. The clinical and microbiological characteristics of these cases were investigated carefully. Two geographic clades, i.e. III and I, were found popular in different hospitals by whole genome sequencing analyses. All <i>C. auris</i> isolates from bloodstream were resistant to fluconazole, 5 of which belonged to Clade III harbouring VF125AL mutation in the <i>ERG11</i> gene. The isolates with Clade I presented Y132F mutation in the <i>ERG11</i> gene as well as resistance to amphotericin B. All isolates exhibited strong biofilm-forming capacity and non-aggregative phenotype. The mean time from admission to onset of <i>C. auris</i> candidemia was 39.4 days (range: 12 - 80 days). Despite performing appropriate therapeutic regimen, 42.9% (3/7) of patients experienced occurrences of <i>C. auris</i> candidemia and colonization after the first positive bloodstream. <i>C. auris</i> colonization was still observed after the first <i>C. auris</i> candidemia for 81 days in some patient. Microbiologic eradication from bloodstream was achieved in 85.7% (6/7) of patients at discharge. In conclusion, this study offers a crucial insight into unravelling the multiple origins of <i>C. auris</i> in Guangdong, highlighting great challenges in clinical prevention and control.</p>","PeriodicalId":11602,"journal":{"name":"Emerging Microbes & Infections","volume":" ","pages":"2300525"},"PeriodicalIF":13.2,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10773663/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139073582","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}
Pub Date : 2024-12-01Epub Date: 2024-01-07DOI: 10.1080/22221751.2023.2300466
Wei Yang, Chen Zhang, Li-Bo Liu, Zhan-Zhan Bian, Jia-Tong Chang, Dong-Ying Fan, Na Gao, Pei-Gang Wang, Jing An
During its global epidemic, Zika virus (ZIKV) attracted widespread attention due to its link with various severe neurological symptoms and potential harm to male fertility. However, the understanding of how ZIKV invades and persists in the male reproductive system is limited due to the lack of immunocompetent small animal models. In this study, immunocompetent murine models were generated by using anti-IFNAR antibody blocked C57BL/6 male mice and human STAT2 (hSTAT2) knock in (KI) male mice. After infection, viral RNA could persist in the testes even after the disappearance of viremia. We also found a population of ZIKV-susceptible S100A4+ monocytes/macrophages that were recruited into testes from peripheral blood and played a crucial role for ZIKV infection in the testis. By using single-cell RNA sequencing, we also proved that S100A4+ monocytes/macrophages had a great impact on the microenvironment of ZIKV-infected testes, thus promoting ZIKV-induced testicular lesions. In conclusion, this study proposed a novel mechanism of long-term ZIKV infection in the male reproductive system.
{"title":"Immunocompetent mouse models revealed that S100A4<sup>+</sup> monocytes/macrophages facilitate long-term Zika virus infection in the testes.","authors":"Wei Yang, Chen Zhang, Li-Bo Liu, Zhan-Zhan Bian, Jia-Tong Chang, Dong-Ying Fan, Na Gao, Pei-Gang Wang, Jing An","doi":"10.1080/22221751.2023.2300466","DOIUrl":"10.1080/22221751.2023.2300466","url":null,"abstract":"<p><p>During its global epidemic, Zika virus (ZIKV) attracted widespread attention due to its link with various severe neurological symptoms and potential harm to male fertility. However, the understanding of how ZIKV invades and persists in the male reproductive system is limited due to the lack of immunocompetent small animal models. In this study, immunocompetent murine models were generated by using anti-IFNAR antibody blocked C57BL/6 male mice and human STAT2 (hSTAT2) knock in (KI) male mice. After infection, viral RNA could persist in the testes even after the disappearance of viremia. We also found a population of ZIKV-susceptible S100A4<sup>+</sup> monocytes/macrophages that were recruited into testes from peripheral blood and played a crucial role for ZIKV infection in the testis. By using single-cell RNA sequencing, we also proved that S100A4<sup>+</sup> monocytes/macrophages had a great impact on the microenvironment of ZIKV-infected testes, thus promoting ZIKV-induced testicular lesions. In conclusion, this study proposed a novel mechanism of long-term ZIKV infection in the male reproductive system.</p>","PeriodicalId":11602,"journal":{"name":"Emerging Microbes & Infections","volume":" ","pages":"2300466"},"PeriodicalIF":13.2,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10773650/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139073583","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}
Pub Date : 2024-12-01Epub Date: 2024-01-11DOI: 10.1080/22221751.2023.2287118
Yuanting Yang, Heather Miller, Maria G Byazrova, Fabio Cndotti, Kamel Benlagha, Niels Olsen Saraiva Camara, Junming Shi, Huamei Forsman, Pamela Lee, Lu Yang, Alexander Filatov, Zhimin Zhai, Chaohong Liu
This review gives an overview of the protective role of CD8+ T cells in SARS-CoV-2 infection. The cross-reactive responses intermediated by CD8+ T cells in unexposed cohorts are described. Additionally, the relevance of resident CD8+ T cells in the upper and lower airway during infection and CD8+ T-cell responses following vaccination are discussed, including recent worrisome breakthrough infections and variants of concerns (VOCs). Lastly, we explain the correlation between CD8+ T cells and COVID-19 severity. This review aids in a deeper comprehension of the association between CD8+ T cells and SARS-CoV-2 and broadens a vision for future exploration.
{"title":"The characterization of CD8<sup>+</sup> T-cell responses in COVID-19.","authors":"Yuanting Yang, Heather Miller, Maria G Byazrova, Fabio Cndotti, Kamel Benlagha, Niels Olsen Saraiva Camara, Junming Shi, Huamei Forsman, Pamela Lee, Lu Yang, Alexander Filatov, Zhimin Zhai, Chaohong Liu","doi":"10.1080/22221751.2023.2287118","DOIUrl":"10.1080/22221751.2023.2287118","url":null,"abstract":"<p><p>This review gives an overview of the protective role of CD8<sup>+</sup> T cells in SARS-CoV-2 infection. The cross-reactive responses intermediated by CD8<sup>+</sup> T cells in unexposed cohorts are described. Additionally, the relevance of resident CD8<sup>+</sup> T cells in the upper and lower airway during infection and CD8<sup>+</sup> T-cell responses following vaccination are discussed, including recent worrisome breakthrough infections and variants of concerns (VOCs). Lastly, we explain the correlation between CD8<sup>+</sup> T cells and COVID-19 severity. This review aids in a deeper comprehension of the association between CD8<sup>+</sup> T cells and SARS-CoV-2 and broadens a vision for future exploration.</p>","PeriodicalId":11602,"journal":{"name":"Emerging Microbes & Infections","volume":" ","pages":"2287118"},"PeriodicalIF":13.2,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10786432/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138290668","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}
Ceftazidime-avibactam (CZA) resistance is a huge threat in the clinic; however, the underlying mechanism responsible for high-level CZA resistance in Pseudomonas aeruginosa (PA) isolates remains unknown. In this study, a total of 5,763 P. aeruginosa isolates were collected from 2010 to 2022 to investigate the ceftazidime-avibactam (CZA) high-level resistance mechanisms of Pseudomonas aeruginosa (PA) isolates in China. Fifty-six PER-producing isolates were identified, including 50 isolates carrying blaPER-1 in PA, and 6 isolates carrying blaPER-4. Of these, 82.1% (46/56) were classified as DTR-PA isolates, and 76.79% (43/56) were resistant to CZA. Importantly, blaPER-1 and blaPER-4 overexpression led to 16-fold and >1024-fold increases in the MICs of CZA, respectively. WGS revealed that the blaPER-1 gene was located in two different transferable IncP-2-type plasmids and chromosomes, whereas blaPER-4 was found only on chromosomes and was carried by a class 1 integron embedded in a Tn6485-like transposon. Overexpression of efflux pumps may be associated with high-level CZA resistance in blaPER-1-positive strains. Kinetic parameter analysis revealed that PER-4 exhibited a similar kcat/Km with ceftazidime and a high (∼3359-fold) IC50 value with avibactam compared to PER-1. Our study found that overexpression of PER-1 combined with enhanced efflux pump expression and the low affinity of PER-4 for avibactam contributes to high-level resistance to CZA. Additionally, the Tn6485-like transposon plays a significant role in disseminating blaPER. Urgent active surveillance is required to prevent the further spread of high-level CZA resistance in DTR-PA isolates.
{"title":"Genomic epidemiology and ceftazidime-avibactam high-level resistance mechanisms of <i>Pseudomonas aeruginosa</i> in China from 2010 to 2022.","authors":"Xi Li, Longjie Zhou, Tailong Lei, Xiaofan Zhang, Jiayao Yao, Jintao He, Haiyang Liu, Heng Cai, Jingshu Ji, Yiwei Zhu, Yuexing Tu, Yunsong Yu, Hua Zhou","doi":"10.1080/22221751.2024.2324068","DOIUrl":"10.1080/22221751.2024.2324068","url":null,"abstract":"<p><p>Ceftazidime-avibactam (CZA) resistance is a huge threat in the clinic; however, the underlying mechanism responsible for high-level CZA resistance in <i>Pseudomonas aeruginosa</i> (PA) isolates remains unknown. In this study, a total of 5,763 <i>P. aeruginosa</i> isolates were collected from 2010 to 2022 to investigate the ceftazidime-avibactam (CZA) high-level resistance mechanisms of <i>Pseudomonas aeruginosa</i> (PA) isolates in China. Fifty-six PER-producing isolates were identified, including 50 isolates carrying <i>bla</i><sub>PER-1</sub> in PA, and 6 isolates carrying <i>bla</i><sub>PER-4</sub>. Of these, 82.1% (46/56) were classified as DTR-PA isolates, and 76.79% (43/56) were resistant to CZA. Importantly, <i>bla</i><sub>PER-1</sub> and <i>bla</i><sub>PER-4</sub> overexpression led to 16-fold and >1024-fold increases in the MICs of CZA, respectively. WGS revealed that the <i>bla</i><sub>PER-1</sub> gene was located in two different transferable IncP-2-type plasmids and chromosomes, whereas <i>bla</i><sub>PER-4</sub> was found only on chromosomes and was carried by a class 1 integron embedded in a Tn<i>6485</i>-like transposon. Overexpression of efflux pumps may be associated with high-level CZA resistance in <i>bla</i><sub>PER-1</sub>-positive strains. Kinetic parameter analysis revealed that PER-4 exhibited a similar <i>kcat</i>/<i>Km</i> with ceftazidime and a high (∼3359-fold) IC50 value with avibactam compared to PER-1. Our study found that overexpression of PER-1 combined with enhanced efflux pump expression and the low affinity of PER-4 for avibactam contributes to high-level resistance to CZA. Additionally, the Tn<i>6485</i>-like transposon plays a significant role in disseminating <i>bla</i><sub>PER</sub>. Urgent active surveillance is required to prevent the further spread of high-level CZA resistance in DTR-PA isolates.</p>","PeriodicalId":11602,"journal":{"name":"Emerging Microbes & Infections","volume":" ","pages":"2324068"},"PeriodicalIF":13.2,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10939098/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139971432","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}
Pub Date : 2024-12-01Epub Date: 2024-03-03DOI: 10.1080/22221751.2024.2322649
Ehab A Salama, Yehia Elgammal, Aruna Wijeratne, Nadia A Lanman, Sagar M Utturkar, Atena Farhangian, Jianing Li, Brigitte Meunier, Tony R Hazbun, Mohamed N Seleem
Candida auris has emerged as a problematic fungal pathogen associated with high morbidity and mortality. Amphotericin B (AmB) is the most effective antifungal used to treat invasive fungal candidiasis, with resistance rarely observed among clinical isolates. However, C. auris possesses extraordinary resistant profiles against all available antifungal drugs, including AmB. In our pursuit of potential solutions, we screened a panel of 727 FDA-approved drugs. We identified the proton pump inhibitor lansoprazole (LNP) as a potent enhancer of AmB's activity against C. auris. LNP also potentiates the antifungal activity of AmB against other medically important species of Candida and Cryptococcus. Our investigations into the mechanism of action unveiled that LNP metabolite(s) interact with a crucial target in the mitochondrial respiratory chain (complex III, known as cytochrome bc1). This interaction increases oxidative stress within fungal cells. Our results demonstrated the critical role of an active respiratory function in the antifungal activity of LNP. Most importantly, LNP restored the efficacy of AmB in an immunocompromised mouse model, resulting in a 1.7-log (∼98%) CFU reduction in the burden of C. auris in the kidneys. Our findings strongly advocate for a comprehensive evaluation of LNP as a cytochrome bc1 inhibitor for combating drug-resistant C. auris infections.
白色念珠菌已成为一种棘手的真菌病原体,发病率和死亡率都很高。两性霉素 B(AmB)是治疗侵袭性真菌念珠菌病最有效的抗真菌药物,临床分离株很少出现耐药性。然而,念珠菌对包括两性霉素 B 在内的所有现有抗真菌药物都具有极强的耐药性。为了寻求潜在的解决方案,我们筛选了 727 种美国食品及药物管理局批准的药物。我们发现质子泵抑制剂兰索拉唑(LNP)能有效增强 AmB 对阿氏杆菌的活性。LNP 还能增强 AmB 对其他重要医学念珠菌和隐球菌的抗真菌活性。我们对其作用机制的研究发现,LNP 代谢物与线粒体呼吸链(复合体 III,即细胞色素 bc1)中的一个关键靶点相互作用。这种相互作用增加了真菌细胞内的氧化应激。我们的研究结果表明,活跃的呼吸功能在 LNP 的抗真菌活性中起着关键作用。最重要的是,LNP 恢复了 AmB 在免疫功能低下小鼠模型中的疗效,使肾脏中的阴沟肠杆菌负担减少了 1.7 个菌落(∼98%)。我们的研究结果强烈建议将 LNP 作为细胞色素 bc1 抑制剂进行全面评估,以抗击耐药性蛔虫感染。
{"title":"Lansoprazole interferes with fungal respiration and acts synergistically with amphotericin B against multidrug-resistant <i>Candida auris</i>.","authors":"Ehab A Salama, Yehia Elgammal, Aruna Wijeratne, Nadia A Lanman, Sagar M Utturkar, Atena Farhangian, Jianing Li, Brigitte Meunier, Tony R Hazbun, Mohamed N Seleem","doi":"10.1080/22221751.2024.2322649","DOIUrl":"10.1080/22221751.2024.2322649","url":null,"abstract":"<p><p><i>Candida auris</i> has emerged as a problematic fungal pathogen associated with high morbidity and mortality. Amphotericin B (AmB) is the most effective antifungal used to treat invasive fungal candidiasis, with resistance rarely observed among clinical isolates. However, <i>C. auris</i> possesses extraordinary resistant profiles against all available antifungal drugs, including AmB. In our pursuit of potential solutions, we screened a panel of 727 FDA-approved drugs. We identified the proton pump inhibitor lansoprazole (LNP) as a potent enhancer of AmB's activity against <i>C. auris.</i> LNP also potentiates the antifungal activity of AmB against other medically important species of <i>Candida</i> and <i>Cryptococcus.</i> Our investigations into the mechanism of action unveiled that LNP metabolite(s) interact with a crucial target in the mitochondrial respiratory chain (complex III, known as cytochrome <i>bc<sub>1</sub></i>). This interaction increases oxidative stress within fungal cells. Our results demonstrated the critical role of an active respiratory function in the antifungal activity of LNP. Most importantly, LNP restored the efficacy of AmB in an immunocompromised mouse model, resulting in a 1.7-log (∼98%) CFU reduction in the burden of <i>C. auris</i> in the kidneys. Our findings strongly advocate for a comprehensive evaluation of LNP as a cytochrome <i>bc<sub>1</sub></i> inhibitor for combating drug-resistant <i>C. auris</i> infections.</p>","PeriodicalId":11602,"journal":{"name":"Emerging Microbes & Infections","volume":"13 1","pages":"2322649"},"PeriodicalIF":13.2,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10911247/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140021221","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}