ACS Infectious Diseases最新文献_第8页

Anti-Intracellular MRSA Activity of Antibiotic-Loaded Lipid-Polymer Hybrid Nanoparticles and Their Effectiveness in Murine Skin Wound Infection Models. 抗生素负载脂质聚合物混合纳米粒子的抗细胞内 MRSA 活性及其在小鼠皮肤伤口感染模型中的有效性

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-03-14 Epub Date: 2025-02-13 DOI: 10.1021/acsinfecdis.4c01016

Wenrui Li, Chuan Hao Tan, Jong-Suep Baek, Lai Jiang, Noele Kai Jing Ng, Kelvin Kian Long Chong, Jun Jie Wong, Liheng Gao, Kimberly A Kline, Say Chye Joachim Loo

{"title":"Anti-Intracellular MRSA Activity of Antibiotic-Loaded Lipid-Polymer Hybrid Nanoparticles and Their Effectiveness in Murine Skin Wound Infection Models.","authors":"Wenrui Li, Chuan Hao Tan, Jong-Suep Baek, Lai Jiang, Noele Kai Jing Ng, Kelvin Kian Long Chong, Jun Jie Wong, Liheng Gao, Kimberly A Kline, Say Chye Joachim Loo","doi":"10.1021/acsinfecdis.4c01016","DOIUrl":"10.1021/acsinfecdis.4c01016","url":null,"abstract":"Methicillin-resistant Staphylococcus aureus (MRSA) is a significant concern for skin and soft tissue infections. Apart from biofilm formation, these bacteria can reside intracellularly in phagocytic and nonphagocytic mammalian cells, complicating treatment with conventional antibiotics. Lipid-polymer hybrid nanoparticle (LPN) systems, combining the advantages of polymeric nanoparticles and liposomes, represent a new generation of nanocarriers with the potential to address these therapeutic challenges. In this study, gentamicin (Gen) and vancomycin (Van) were encapsulated in LPNs and evaluated for their ability to eliminate intracellular MRSA in phagocytic macrophage RAW-Blue cells and nonphagocytic epithelial HaCaT cells. Compared to free antibiotics at 100 μg/mL, LPN formulations significantly reduced intracellular bacterial loads in both cell lines. Specifically, LPN-Van resulted in approximately 0.7 Log CFU/well reduction in RAW-Blue cells and 0.3 Log CFU/well reduction in HaCaT cells. LPN-Gen showed a more pronounced reduction, with approximately 1.26 Log CFU/well reduction in RAW-Blue cells and 0.45 Log CFU/well reduction in HaCaT cells. In vivo, LPN-Van at 500 μg/mL significantly reduced MRSA biofilm viability compared to untreated controls (p < 0.001), achieving 98% eradication based on median values. In comparison, free vancomycin achieved a nonstatistically significant 79.2% reduction in biofilm viability compared to control. Prophylactically, LPN-Van at 500 μg/mL decreased MRSA levels to the limit of detection, resulting in a ∼3.5 Log reduction in the median CFU/wound compared to free vancomycin. No acute dermal toxicity was observed for LPN-Van based on histological analysis. These data indicate that LPNs show promise as a drug delivery platform technology to address intracellular infections.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"750-761"},"PeriodicalIF":4.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412303","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}

引用次数: 0

Identification of Substituted 4-Aminocinnolines as Broad-Spectrum Antiparasitic Agents. 取代4-氨基皂苷类广谱抗寄生虫剂的鉴定。

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-03-14 Epub Date: 2025-02-12 DOI: 10.1021/acsinfecdis.4c00666

Andrew Spaulding, Amrita Sharma, Miriam A Giardini, Benjamin Hoffman, Jean A Bernatchez, Laura-Isobel McCall, Claudia M Calvet, Jasmin Ackermann, Julia M Souza, Diane Thomas, Caroline C Millard, William G Devine, Baljinder Singh, Everton M Silva, Susan E Leed, Norma E Roncal, Erica C Penn, Jessey Erath, Gaurav Kumar, Yadira Sepulveda, Arnold Garcia, Ana Rodriguez, Nelly El-Sakkary, Richard J Sciotti, Robert F Campbell, Jeremiah D Momper, James H McKerrow, Conor R Caffrey, Jair L Siqueira-Neto, Michael P Pollastri, Kojo Mensa-Wilmot, Lori Ferrins

{"title":"Identification of Substituted 4-Aminocinnolines as Broad-Spectrum Antiparasitic Agents.","authors":"Andrew Spaulding, Amrita Sharma, Miriam A Giardini, Benjamin Hoffman, Jean A Bernatchez, Laura-Isobel McCall, Claudia M Calvet, Jasmin Ackermann, Julia M Souza, Diane Thomas, Caroline C Millard, William G Devine, Baljinder Singh, Everton M Silva, Susan E Leed, Norma E Roncal, Erica C Penn, Jessey Erath, Gaurav Kumar, Yadira Sepulveda, Arnold Garcia, Ana Rodriguez, Nelly El-Sakkary, Richard J Sciotti, Robert F Campbell, Jeremiah D Momper, James H McKerrow, Conor R Caffrey, Jair L Siqueira-Neto, Michael P Pollastri, Kojo Mensa-Wilmot, Lori Ferrins","doi":"10.1021/acsinfecdis.4c00666","DOIUrl":"10.1021/acsinfecdis.4c00666","url":null,"abstract":"Neglected tropical diseases such as Chagas disease, human African trypanosomiasis, leishmaniasis, and schistosomiasis have a significant global health impact in predominantly developing countries, although these diseases are spreading due to increased international travel and population migration. Drug repurposing with a focus on increasing antiparasitic potency and drug-like properties is a cost-effective and efficient route to the development of new therapies. Here we identify compounds that have potent activity against Trypanosoma cruzi and Leishmania donovani, and the latter were progressed into the murine model of infection. Despite the potent in vitro activity, there was no effect on parasitemia, necessitating further work to improve the pharmacokinetic properties of this series. Nonetheless, valuable insights have been obtained into the structure-activity and structure-property relationships of this compound series.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"584-599"},"PeriodicalIF":4.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915375/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397487","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}

引用次数: 0

AHM-1: An Inclusion to the Arsenal of β-Lactam Resistance in Clostridioides difficile. 艰难梭菌β-内酰胺抗性库中的AHM-1。

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-03-14 Epub Date: 2025-02-07 DOI: 10.1021/acsinfecdis.4c00741

Abirlal Mukherjee, Jyoti Barman, Chandrachur Ghosh, Rajsekhar Adhikary, Kunal Dhankhar, Partha Roy, Sulagna Basu, Saugata Hazra

{"title":"AHM-1: An Inclusion to the Arsenal of β-Lactam Resistance in Clostridioides difficile.","authors":"Abirlal Mukherjee, Jyoti Barman, Chandrachur Ghosh, Rajsekhar Adhikary, Kunal Dhankhar, Partha Roy, Sulagna Basu, Saugata Hazra","doi":"10.1021/acsinfecdis.4c00741","DOIUrl":"10.1021/acsinfecdis.4c00741","url":null,"abstract":"This study delves into a newly discovered MBL (metallo-β-lactamase) in Clostridioides difficile, a formidable pathogen known for causing nosocomial infections and exhibiting resistance to antimicrobial agents. The primary objective was to unravel its structure-function relationship. This research establishes the enzyme AHM-1 as a subclass B3-like MBL. Experimental results reveal that the enzyme's active site consists of two Zn2+ atoms exhibiting tetrahedral and trigonal bipyramidal coordination, similar to B1 and B3 MBLs. Notably, within its active site, it exhibits a lower binding capacity for other transition metal ions such as Fe2+, Mn2+, and Ni2+ compared to Zn2+. The zinc-binding sites of B1 and B3 MBLs contain strictly conserved His116-His118-His196 and Asp120-Cys221/His121-His263. The absence of all the conserved residues except His116, Asp120, and His121 in the Zn-binding site distinctly separates this enzyme from these two MBL subclasses. Conserved zinc binding motifs present in B1 and B3 MBLs are H-X-H-X-D and H-X-H-X-D-H, respectively. The presence of the H-X-D-X-D-H motif in the enzyme, similar to that in B3 enzymes, along with sequence and structural analysis, places this new enzyme closer to the enzymes belonging to the B3 subclass. This study also identifies the likely catalytic residues responsible for its β-lactamase activity, similar to B3 MBLs. In contrast to MBLs, this enzyme displays hydrolytic activity toward aztreonam. It also shows higher catalytic efficiency toward higher generation cephalosporins. This study thus underscores the significance of a novel enzyme with β-lactamase activity in Clostridioides difficile, highlighting its potential implications for clinical treatment due to its disparities from conventional MBLs.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"653-664"},"PeriodicalIF":4.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363254","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}

引用次数: 0

Fluorescence Lifetime Imaging Detects Long-Lifetime Signal Associated with Reduced Pyocyanin at the Surface of Pseudomonas aeruginosa Biofilms and in Cross-Feeding Conditions. 荧光寿命成像检测铜绿假单胞菌生物膜表面和交叉喂养条件下与减少的Pyocyanin相关的长寿命信号。

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-03-14 Epub Date: 2025-03-04 DOI: 10.1021/acsinfecdis.4c00489

Tara Gallagher, Simon Leemans, Alexander S Dvornikov, Kumar Perinbam, Joshua Fong, Christina Kim, Joseph Kapcia, Miki Kagawa, Adam Grosvirt-Dramen, Allon I Hochbaum, Michelle A Digman, Enrico Gratton, Albert Siryaporn, Katrine Whiteson

{"title":"Fluorescence Lifetime Imaging Detects Long-Lifetime Signal Associated with Reduced Pyocyanin at the Surface of Pseudomonas aeruginosa Biofilms and in Cross-Feeding Conditions.","authors":"Tara Gallagher, Simon Leemans, Alexander S Dvornikov, Kumar Perinbam, Joshua Fong, Christina Kim, Joseph Kapcia, Miki Kagawa, Adam Grosvirt-Dramen, Allon I Hochbaum, Michelle A Digman, Enrico Gratton, Albert Siryaporn, Katrine Whiteson","doi":"10.1021/acsinfecdis.4c00489","DOIUrl":"10.1021/acsinfecdis.4c00489","url":null,"abstract":"Understanding bacterial physiology in real-world environments requires noninvasive approaches and is a challenging yet necessary endeavor to effectively treat infectious disease. Bacteria evolve strategies to tolerate chemical gradients associated with infections. The DIVER (Deep Imaging Via Enhanced Recovery) microscope can image autofluorescence and fluorescence lifetime throughout samples with high optical scattering, enabling the study of naturally formed chemical gradients throughout intact biofilms. Using the DIVER, a long fluorescent lifetime signal associated with reduced pyocyanin, a molecule for electron cycling in low oxygen, was detected in low-oxygen conditions at the surface of Pseudomonas aeruginosa biofilms and in the presence of fermentation metabolites from Rothia mucilaginosa, which cocolonizes infected airways with P. aeruginosa. These findings underscore the utility of the DIVER microscope and fluorescent lifetime for noninvasive studies of bacterial physiology within complex environments, which could inform on more effective strategies for managing chronic infection.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"543-549"},"PeriodicalIF":4.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915379/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539444","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}

引用次数: 0

Thiazole Derivatives as Promising Candidates for Cryptococcosis Therapy. 噻唑衍生物作为隐球菌病治疗的有希望的候选者。

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-03-14 Epub Date: 2025-02-07 DOI: 10.1021/acsinfecdis.4c00732

Victor Augusto Teixeira Leocádio, Isabela L Miranda, Martha H C Magalhães, Valtair Severino Dos Santos Júnior, José Eduardo Goncalves, Renata Barbosa Oliveira, Vinicius Gonçalves Maltarollo, Rafael Wesley Bastos, Gustavo Goldman, Susana Johann, Nalu Teixeira de Aguiar Peres, Daniel de Assis Santos

{"title":"Thiazole Derivatives as Promising Candidates for Cryptococcosis Therapy.","authors":"Victor Augusto Teixeira Leocádio, Isabela L Miranda, Martha H C Magalhães, Valtair Severino Dos Santos Júnior, José Eduardo Goncalves, Renata Barbosa Oliveira, Vinicius Gonçalves Maltarollo, Rafael Wesley Bastos, Gustavo Goldman, Susana Johann, Nalu Teixeira de Aguiar Peres, Daniel de Assis Santos","doi":"10.1021/acsinfecdis.4c00732","DOIUrl":"10.1021/acsinfecdis.4c00732","url":null,"abstract":"Cryptococcosis is a severe fungal infection primarily caused by two encapsulated yeasts: Cryptococcus neoformans and C. gattii. The most significant complication is cryptococcal meningitis, where the fungus crosses the blood-brain barrier, leading to a severe brain infection. Current treatments, which include amphotericin B and flucytosine or fluconazole, are often toxic and not very effective. Therefore, there is a pressing need for new antifungal agents. This study screened 30 thiazole derivatives for their antifungal activity against Cryptococcus and their toxicity to brain cells. Four compounds (RN86, RN88, RJ37, and RVJ42) showed particularly strong effects. These compounds reduced ergosterol levels in the fungal membrane and inhibited its ability to cross the blood-brain barrier. Notably, RN86 and RVJ42 improved survival rates in a mouse model of cryptococcosis by lowering the fungal load in the lungs and brain. These findings suggest that these derivatives could be promising treatments for pulmonary and neurocryptococcosis.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"639-652"},"PeriodicalIF":4.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915371/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363255","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}

引用次数: 0

Active- and Allosteric-Site Cyclic Peptide Inhibitors of Secreted M. tuberculosis Chorismate Mutase. 分泌结核分枝杆菌螯合酸突变酶的活性和变构位点环肽抑制剂。

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-03-14 Epub Date: 2025-02-04 DOI: 10.1021/acsinfecdis.4c00798

Renier H P van Neer, Patricia K Dranchak, Mahesh Aitha, Lijun Liu, Emma K Carlson, Isabella E Jacobsen, Kevin Battaile, Yuhong Fang, Dingyin Tao, Ganesha Rai, Janak Padia, Scott Lovell, Hiroaki Suga, James Inglese

{"title":"Active- and Allosteric-Site Cyclic Peptide Inhibitors of Secreted M. tuberculosis Chorismate Mutase.","authors":"Renier H P van Neer, Patricia K Dranchak, Mahesh Aitha, Lijun Liu, Emma K Carlson, Isabella E Jacobsen, Kevin Battaile, Yuhong Fang, Dingyin Tao, Ganesha Rai, Janak Padia, Scott Lovell, Hiroaki Suga, James Inglese","doi":"10.1021/acsinfecdis.4c00798","DOIUrl":"10.1021/acsinfecdis.4c00798","url":null,"abstract":"The secreted Chorismate mutase enzyme of Mycobacterium tuberculosis (*MtbCM) is an underexplored potential target for the development of new antitubercular agents that are increasingly needed as antibiotic resistance rises in prevalence. As an enzyme suspected to be involved in virulence and host-pathogen interactions, disruption of its function could circumvent the difficulty of treating tuberculosis-infected granulomas. Drug development, however, is limited by novel ligand discovery. Currently, *MtbCM activity is measured by using a low throughput acid/base-mediated product derivatization absorbance assay. Here, we utilized an RNA-display affinity selection approach enabled by the Random Peptides Integrated Discovery (RaPID) system to screen a vast library of macrocyclic peptides (MCP) for novel *MtbCM ligands. Peptides identified from the RaPID selection, and analogs thereof identified by analyzing the selection population dynamics, produced a new class of *MtbCM inhibiting MCPs. Among these were two noteworthy \"chorismides\", whose binding modes were elucidated by X-ray crystallography. Both were potent inhibitors of the CM enzyme activity. One was identified as an allosteric binding peptide revealing a novel inhibition approach, while the other is an active-site binding peptide that when conjugated to a fluorescent probe allowed for the development of a series of alternative fluorescence-based ligand-displacement assays that can be utilized for the assessment of potential *MtbCM inhibitors.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"703-714"},"PeriodicalIF":4.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187542","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}

引用次数: 0

Aptamer-Based Diagnosis for Plasmodium vivax Specific Malaria. 基于适配体的间日疟原虫特异性疟疾诊断。

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-03-14 Epub Date: 2025-03-05 DOI: 10.1021/acsinfecdis.4c01047

Mohd Shoeb Alam, Abhijeet Dhiman, Tanu Bhardwaj, Sudarshana Chatterjee, Vaishali Lakra, Manish Tripathi, Khusboo Lohani, Yagya Dutt Sharma, Bijay Ranjan Mirdha, Amit Kumar, Tarun Kumar Sharma, Sumit Rathore

{"title":"Aptamer-Based Diagnosis for Plasmodium vivax Specific Malaria.","authors":"Mohd Shoeb Alam, Abhijeet Dhiman, Tanu Bhardwaj, Sudarshana Chatterjee, Vaishali Lakra, Manish Tripathi, Khusboo Lohani, Yagya Dutt Sharma, Bijay Ranjan Mirdha, Amit Kumar, Tarun Kumar Sharma, Sumit Rathore","doi":"10.1021/acsinfecdis.4c01047","DOIUrl":"10.1021/acsinfecdis.4c01047","url":null,"abstract":"Malaria, caused by a protozoan parasite of the genus Plasmodium, is a severe infectious disease with life-threatening consequences that has burdened mankind for centuries. Although Plasmodium falciparum (P. falciparum) malaria is more prevalent globally than Plasmodium vivax (P. vivax) malaria, India bears the largest burden of P. vivax malaria, with over 3.6 million cases accounting for ∼48% of global P. vivax malaria cases. Existing detection methods for P. vivax malaria are costly or tedious or have low accuracy. To address the need for a specific diagnostic assay for P. vivax, we generated aptamers specific to Plasmodium vivax tryptophan-rich antigen (PvTRAg). We employed them in an aptamer-linked immobilized sorbent assay (ALISA) to detect P. vivax malaria infections. The two most specific aptamers for PvTRAg, identified as Apt_14 and Apt_16, were obtained using the Systematic Evolution of Ligands by Exponential Enrichment. The dissociation constant (KD) values of Apt_14 and Apt_16 were 1.9 and 1.2 nM, respectively, indicating high affinity to PvTRAg. The limit of detection for both aptamers was found to be 2.5 nM. During clinical validation, the sensitivity of 96% and 84% was obtained with Apt_14- and Apt_16-based ALISA with 100% specificity. The aptamers demonstrated nonsignificant cross-reactivity with other nonmalarial antigens and PvTRAg homologues along with a high level of selectivity for PvTRAg over P. falciparum antigens and various other antigens. Altogether, our findings confirm the effectiveness of DNA aptamers for the accurate diagnosis of P. vivax malaria and lay the groundwork for developing an aptamer-based diagnostic assay for malaria.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"762-772"},"PeriodicalIF":4.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555303","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}

引用次数: 0

Plasmodium Infection Modulates Host Inflammatory Response through circRNAs during the Intracellular Stage in Red Blood Cells. 在红细胞胞内阶段，疟原虫感染通过环状rna调节宿主炎症反应。

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-03-14 DOI: 10.1021/acsinfecdis.5c00037

Wenxin Xu, Shuangchun Liu, Wanqian Li, Bin Xu, Ting Shan, Ronghai Lin, Yun-Ting Du, Guang Chen

{"title":"Plasmodium Infection Modulates Host Inflammatory Response through circRNAs during the Intracellular Stage in Red Blood Cells.","authors":"Wenxin Xu, Shuangchun Liu, Wanqian Li, Bin Xu, Ting Shan, Ronghai Lin, Yun-Ting Du, Guang Chen","doi":"10.1021/acsinfecdis.5c00037","DOIUrl":"https://doi.org/10.1021/acsinfecdis.5c00037","url":null,"abstract":"The integration of RNA- and DNA-based assays enables the investigation of disease dynamics, specifically assessing the role of asymptomatic or subclinical infections in malaria transmission. Circular RNAs (circRNAs), a distinct category of noncoding RNAs, are implicated in numerous pathogenic mechanisms. As of now, research has yet to explore circRNAs' function in malaria infection. The findings revealed that Plasmodium infection upregulated 60 circRNAs and downregulated 71 in BALB/c mice. We selected 11 differentially expressed (DE) circRNAs according to function prediction of target miRNA-mRNA and coding protein, and these were further confirmed by validation experiments. IRESfinder, GO, and KEGG evaluations indicated that 7 DE circRNAs possess protein-coding potential and are enriched in the MAPK signaling cascade. In P.y17XL-infected BALB/c mouse models, the findings substantiated that the dynamic characteristics of DE circRNAs correlated with inflammation, and the MAPK and NF-κB signaling cascades were activated, also contributing to the inflammatory reaction during malaria infection. This study establishes Plasmodium-induced circRNA expression as a novel mechanism by which the parasite modulates host immune signaling, advancing the understanding of Plasmodium-host cell interactions. In addition, 42 circRNAs were found in normal BALB/c mice, and 25 circRNAs were discovered in P.y17XL-infected BALB/c mice, excluding 1238 circRNAs shared by normal and P.y17XL-infected BALB/c mice. Plasmodium infection changes the expression profile of circRNAs in the host, and these altered circRNAs are involved in the inflammatory response during malaria infection. In addition, Plasmodium possibly regulates the reverse splicing of pre-mRNA or m6A modification of RNA, inducing the production of novel circRNAs in the host.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143622823","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}

引用次数: 0

Nonstructural Protein 1 of Influenza A (NS1A) Demonstrates Strain-Specific dsRNA Binding Capabilities. 甲型流感（NS1A）非结构蛋白1显示菌株特异性dsRNA结合能力。

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-03-13 DOI: 10.1021/acsinfecdis.4c00882

Veronica A Smith, Aubrey R Schall, John W Tomsho

{"title":"Nonstructural Protein 1 of Influenza A (NS1A) Demonstrates Strain-Specific dsRNA Binding Capabilities.","authors":"Veronica A Smith, Aubrey R Schall, John W Tomsho","doi":"10.1021/acsinfecdis.4c00882","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00882","url":null,"abstract":"Nonstructural protein 1 of influenza A (NS1A) is a key virulence factor produced inside host cells infected with Influenza A Virus (IAV) and consists of an N-terminal dsRNA binding domain (RBD) and a C-terminal effector domain (ED), joined by a flexible linker. While NS1A is a highly promiscuous protein with a number of intracellular functions, its primary function is nonspecific dsRNA binding that enables influenza to evade our innate immune system. For this reason, NS1A has long been proposed as a potential drug target. Previous research in the field has demonstrated the necessity of dimer formation through the RBD to enable dsRNA binding, which is further enhanced by oligomerization through ED interactions. However, there has been minimal exploration of potential strain-specific effects on dsRNA binding. Most existing studies are limited to the A/Udorn/307/1972 strain, often with a C-terminal tail deletion. Here we utilize fluorescence polarization (FP) paired with fluorescence-based electrophoretic mobility shift assays (fEMSA) to characterize the dsRNA binding properties of NS1A from the H1N1 strain responsible for the 1918 \"Spanish Flu\" with an intact C-terminal tail. We show that A/Brevig Mission/1/1918 NS1A contains specific residues in the RBD that enhance dsRNA binding. We further demonstrate that both Brevig Mission and Udorn NS1A bind directly to dsRNA through the highly basic C-terminal tail of the ED. These novel binding interactions may have contributed to the increased pathogenicity of the 1918 flu pandemic and may have implications for NS1A-targeted antivirals.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143622837","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}

引用次数: 0

Nonstructural Protein 1 of Influenza A (NS1A) Demonstrates Strain-Specific dsRNA Binding Capabilities 甲型流感（NS1A）非结构蛋白1显示菌株特异性dsRNA结合能力

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-03-13 DOI: 10.1021/acsinfecdis.4c0088210.1021/acsinfecdis.4c00882

Veronica A. Smith, Aubrey R. Schall and John W. Tomsho*,

{"title":"Nonstructural Protein 1 of Influenza A (NS1A) Demonstrates Strain-Specific dsRNA Binding Capabilities","authors":"Veronica A. Smith, Aubrey R. Schall and John W. Tomsho*, ","doi":"10.1021/acsinfecdis.4c0088210.1021/acsinfecdis.4c00882","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00882https://doi.org/10.1021/acsinfecdis.4c00882","url":null,"abstract":"Nonstructural protein 1 of influenza A (NS1A) is a key virulence factor produced inside host cells infected with Influenza A Virus (IAV) and consists of an N-terminal dsRNA binding domain (RBD) and a C-terminal effector domain (ED), joined by a flexible linker. While NS1A is a highly promiscuous protein with a number of intracellular functions, its primary function is nonspecific dsRNA binding that enables influenza to evade our innate immune system. For this reason, NS1A has long been proposed as a potential drug target. Previous research in the field has demonstrated the necessity of dimer formation through the RBD to enable dsRNA binding, which is further enhanced by oligomerization through ED interactions. However, there has been minimal exploration of potential strain-specific effects on dsRNA binding. Most existing studies are limited to the A/Udorn/307/1972 strain, often with a C-terminal tail deletion. Here we utilize fluorescence polarization (FP) paired with fluorescence-based electrophoretic mobility shift assays (fEMSA) to characterize the dsRNA binding properties of NS1A from the H1N1 strain responsible for the 1918 “Spanish Flu” with an intact C-terminal tail. We show that A/Brevig Mission/1/1918 NS1A contains specific residues in the RBD that enhance dsRNA binding. We further demonstrate that both Brevig Mission and Udorn NS1A bind directly to dsRNA through the highly basic C-terminal tail of the ED. These novel binding interactions may have contributed to the increased pathogenicity of the 1918 flu pandemic and may have implications for NS1A-targeted antivirals.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 4","pages":"859–868 859–868"},"PeriodicalIF":4.0,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsinfecdis.4c00882","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143814670","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}

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