ACS Infectious Diseases最新文献

{"title":"Rv2741 Promotes Mycobacterium Survival by Modulating Macrophage Function via the IL-1α-MAPK Axis","authors":"Xintong He,&nbsp;Yonglin He,&nbsp;Xichuan Deng,&nbsp;Nan Lu,&nbsp;Anlong Li,&nbsp;Sijia Gao,&nbsp;Shiyan He,&nbsp;Yuran Wang,&nbsp;Nanzhe Fu,&nbsp;Zijie Wang,&nbsp;Yuxin Nie and Lei Xu*,&nbsp;","doi":"10.1021/acsinfecdis.4c0079010.1021/acsinfecdis.4c00790","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00790https://doi.org/10.1021/acsinfecdis.4c00790","url":null,"abstract":"<p >One of the primary healthcare problems in the world today is tuberculosis (TB), a chronic infectious illness brought on by <i>Mycobacterium tuberculosis</i> (<i>M. tuberculosis</i>). A distinct family of PE_PGRS proteins, encoded by the <i>M. tuberculosis</i> genome, has attracted more attention because of their involvement in immune evasion and bacterial pathogenicity. Nevertheless, the specific functions and mechanisms of action for the majority of PE_PGRS proteins remain largely unexplored. This study focuses on the Rv2741 (PE_PGRS47) gene, which is exclusively present in pathogenic mycobacteria. To examine the function of Rv2741 in host–pathogen interactions, we created recombinant strains of <i>Mycobacterium smegmatis</i> (<i>M. smegmatis</i>) that expressed the <i>M. tuberculosis</i> Rv2741 gene. IL-1α was found to be a key mediator of host response modulation by Rv2741. Rv2741 downregulates the secretion of IL-1α and inhibits the MAPK signaling pathway, particularly the p38 and ERK1/2 pathways, thereby cooperatively inhibiting macrophage autophagy and apoptosis. Meanwhile, the decrease in IL-1α secretion directly leads to changes in the cytokine secretion pattern and a reduction in nitric oxide (NO) production. This multifaceted regulatory mechanism ultimately favors the survival of <i>M. smegmatis</i> in macrophages. This research significantly expands our understanding of Rv2741 function, revealing its crucial role as a multifunctional virulence factor in the immune evasion of <i>M. tuberculosis</i>.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 3","pages":"676–688 676–688"},"PeriodicalIF":4.0,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143608967","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}

{"title":"Immunomodulatory Nanoparticles Induce Autophagy in Macrophages and Reduce Mycobacterium tuberculosis Burden in the Lungs of Mice","authors":"Raymonde B. Bekale,&nbsp;Retsepile E. Maphasa,&nbsp;Sarah D’Souza,&nbsp;Nai Jen Hsu,&nbsp;Avril Walters,&nbsp;Naomi Okugbeni,&nbsp;Craig Kinnear,&nbsp;Muazzam Jacobs,&nbsp;Samantha L. Sampson,&nbsp;Mervin Meyer,&nbsp;Gene D. Morse and Admire Dube*,&nbsp;","doi":"10.1021/acsinfecdis.4c0071310.1021/acsinfecdis.4c00713","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00713https://doi.org/10.1021/acsinfecdis.4c00713","url":null,"abstract":"<p >Tuberculosis (TB) is the leading cause of death from infectious disease. Macrophages are the primary immune responders and become the primary host cells for the causative agent <i>Mycobacterium tuberculosis</i>. Following the uptake of <i>M. tuberculosis</i>, the inherent antimicrobial action of macrophages is dampened, enabling the bacterium to reside within these cells and multiply. Rising resistance of <i>M. tuberculosis</i> to antibiotics has led to the investigation of novel approaches for the treatment of TB. Here, we report a host-directed approach, employing biomimetic Curdlan poly(lactic-<i>co</i>-glycolic acid) (C-PLGA) nanoparticles (NPs), and examine autophagy induction in infected macrophages, eradication of <i>M. tuberculosis</i> and immune modulation in a mouse model. We demonstrate that the NPs induce autophagy in <i>M. tuberculosis</i>-infected macrophages. Treatment of H37Rv infected C57BL/6 mice with these NPs reduced <i>M. tuberculosis</i> burden in the lungs of mice and modulated cytokines and chemokines and this work demonstrates that these immunomodulatory NPs are a potential treatment approach for TB.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 3","pages":"610–625 610–625"},"PeriodicalIF":4.0,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsinfecdis.4c00713","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143608934","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}

{"title":"Acinetobacter baumannii Employs a Rare Fatty Acid Desaturase for Niche-Specific Host Adaptation","authors":"Felise G. Adams,&nbsp;Saleh Alquethamy,&nbsp;Jack K. Waters,&nbsp;Brynley J. Davies,&nbsp;Ella Haracic,&nbsp;Jeffrey D. Nanson,&nbsp;James C. Paton,&nbsp;Jade K. Forwood,&nbsp;Karl A. Hassan,&nbsp;Erin B. Brazel,&nbsp;Claudia Trappetti and Bart A. Eijkelkamp*,&nbsp;","doi":"10.1021/acsinfecdis.4c0076510.1021/acsinfecdis.4c00765","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00765https://doi.org/10.1021/acsinfecdis.4c00765","url":null,"abstract":"<p ><i>Acinetobacter baumannii</i> is a hospital-associated pathogen with unique fatty acid homeostasis features. This includes a reliance on desaturases for proliferation, due to an inability to generate unsaturated fatty acids during the synthesis cycles. However, there are various unexplained gaps in <i>A. baumannii</i> fatty acid homeostasis, such as the desaturation of <i>de novo</i> synthesized fatty acids. We identified a conserved desaturase (DesC) with a rare structural feature that may have roles in coordinating fatty acids with acyl carrier protein conjugants. We showed that DesC can generate fatty acids with <i>cis</i> double bonds in the delta-9 position. Profiling of <i>A. baumannii</i> fatty acids and mRNA transcripts emphasized its significance during fatty acid synthesis. DesC was found to be most critical in mouse niches where <i>A. baumannii</i> relies on fatty acid synthesis. This work has contributed to our understanding of core metabolic features that are key to the disease potential of <i>A. baumannii</i>.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 3","pages":"550–557 550–557"},"PeriodicalIF":4.0,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143609043","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}

{"title":"Neutrophil-<i>Leishmania infantum</i> Interaction Induces Neutrophil Extracellular Traps, DAMPs, and Inflammatory Molecule Release.","authors":"Paulo Ricardo Porfírio do Nascimento, Carolina Oliveira Mendes-Aguiar, Ingryd Câmara Morais, João Firmino Rodrigues Neto, Mary E Wilson, Selma Maria Bezerra Jerônimo","doi":"10.1021/acsinfecdis.4c00820","DOIUrl":"10.1021/acsinfecdis.4c00820","url":null,"abstract":"<p><p>Neutrophils, the first cells to arrive at infection sites, release neutrophil extracellular traps (NETs) comprising nuclear and/or mitochondrial DNA webs decorated with proteins. Similar to other parasites, <i>Leishmania infantum</i> induces NET extrusion. However, our understanding of NET formation and neutrophil fate after NET release in a Leishmania infection context is limited. Our study aimed to determine the DNA origin of the NET scaffolds released by human neutrophils in response to chemical or <i>L. infantum</i> stimulation. Neutrophils were incubated with PMA, PHA, LPS, or <i>L. infantum</i>, followed by DNA and elastase activity quantification; additionally, we evaluated the source of DNA that composes NETs. Neutrophil viability was evaluated by annexin-V/7AAd labeling. Expression of IL6, TNFA, IL10, CXCL1, CXCL8, and FPR1 in response to the <i>L. infantum</i> interaction was assessed. Neutrophils incubated with chemicals or <i>L. infantum</i> released NETs. However, neutrophils stimulated by the chemicals showed lower viability after 1 h in comparison to neutrophils incubated with parasites. NETs from chemically stimulated neutrophils were mainly composed of nuclear DNA. Conversely, the NET induced by the parasites was of mitochondrial DNA origin and had no leishmanicidal activity. After 4 h of parasite stimulation, neutrophils peak the expression of genes such as IL6, TNFA, CXCL1, CXCL8, and FPR1. Our study demonstrates that neutrophils produce NETs after chemical or <i>L. infantum</i> exposure. Although they are not toxic to the parasite, NETs are released as danger signals. These findings support the role of neutrophils in releasing signaling molecules, which influence the inflammatory environment in which the infectious process occurs.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"483-492"},"PeriodicalIF":4.0,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11833875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062126","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}

{"title":"Infectious Diseases Chemical \"Cookbooks\": Celebrating Women's Authorship in <i>ACS Infectious Diseases</i>.","authors":"Helen I Zgurskaya","doi":"10.1021/acsinfecdis.4c00916","DOIUrl":"10.1021/acsinfecdis.4c00916","url":null,"abstract":"","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"264-270"},"PeriodicalIF":4.0,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143057508","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}

{"title":"Mechanistic Insights into the Divergent Membrane Activities of a Viroporin from Chikungunya Virus and Its Transframe Variant.","authors":"Kirti Suhag, Subhomoi Borkotoky, Shumaila Iqbal Siddiqui, Jitender Kumar, Chandra Shekhar Kumar, Pushkar Tatiya, Subhendu Ghosh, Manidipa Banerjee","doi":"10.1021/acsinfecdis.4c00562","DOIUrl":"10.1021/acsinfecdis.4c00562","url":null,"abstract":"<p><p>Alphaviruses, a genus of vector-borne viruses in the <i>Togaviridae</i> family, encode a small ion-channel-forming protein, 6K, and its transframe variant (TF) during infections. Although 6K/TF have vital roles in glycoprotein transport, virus assembly, and budding, there is no mechanistic explanation for these functions. We investigated the distinct biochemical functionalities of 6K and TF from the mosquito-borne alphavirus, Chikungunya Virus. We show that like 6K, TF is also capable of forming ion channels in bilayer membranes. The assemblies formed by 6K in membranes are structurally more complex and potentially more ion-restrictive than those formed by TF. Both 6K and TF show strong affinity toward the ER membranes, indicating that the localization of these components at the plasma membrane, as previously reported, is either linked to post-translational modification or mediated through interaction with binding partners. These structural and functional insights may elucidate the distinct roles of 6K and TF in the alphavirus life cycle.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"430-441"},"PeriodicalIF":4.0,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913174","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}

{"title":"Potential of <i>Mycobacterium tuberculosis</i> Type II NADH-Dehydrogenase in Antitubercular Drug Discovery.","authors":"Pallavi Saha, Mohit Kumar, Deepak K Sharma","doi":"10.1021/acsinfecdis.4c01005","DOIUrl":"10.1021/acsinfecdis.4c01005","url":null,"abstract":"<p><p>The type II NADH-dehydrogenase enzyme in <i>Mycobacterium tuberculosis</i> plays a critical role in the efficient functioning of the oxidative phosphorylation pathway. It acts as the entry point for electrons in the electron transport chain, which is essential for fulfilling the energy requirements of both replicating and nonreplicating mycobacterial species. Due to the absence of the type II NADH-dehydrogenase enzyme in mammalian mitochondria, targeting the type II NADH-dehydrogenase enzyme for antitubercular drug discovery could be a vigilant approach. Utilizing type II NADH-dehydrogenase inhibitors in antitubercular therapy led to bactericidal response, even in monotherapy. However, the absence of the cryo-EM structure of <i>Mycobacterium tuberculosis</i> type II NADH-dehydrogenase has constrained drug discovery efforts to rely on high-throughput screening methods, limiting the use of structure-based drug discovery. Here, we have delineated the literature-reported <i>Mycobacterium tuberculosis</i> type II NADH-dehydrogenase inhibitors and the rationale behind selecting this specific enzyme for antitubercular drug discovery, along with shedding light on the architecture of the enzyme structure and functionality. The gap in the current research and future research direction for TB treatment have been addressed.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"398-412"},"PeriodicalIF":4.0,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981973","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}

{"title":"Mechanisms of Azole Potentiation: Insights from Drug Repurposing Approaches.","authors":"Juan Xiong, Hui Lu, Yuanying Jiang","doi":"10.1021/acsinfecdis.4c00657","DOIUrl":"10.1021/acsinfecdis.4c00657","url":null,"abstract":"<p><p>The emergence of azole resistance and tolerance in pathogenic fungi has emerged as a significant public health concern, emphasizing the urgency for innovative strategies to bolster the efficacy of azole-based treatments. Drug repurposing stands as a promising and practical avenue for advancing antifungal therapy, with the potential for swift clinical translation. This review offers a comprehensive overview of azole synergistic agents uncovered through drug repurposing strategies, alongside an in-depth exploration of the mechanisms by which these agents augment azole potency. Drawing from these mechanisms, we delineate strategies aimed at enhancing azole effectiveness, such as inhibiting efflux pumps to elevate azole concentrations within fungal cells, intensifying ergosterol synthesis inhibition, mitigating fungal cell resistance to azoles, and disrupting biological processes extending beyond ergosterol synthesis. This review is beneficial for the development of these potentiators, as it meticulously examines instances and provides nuanced discussions on the mechanisms underlying the progression of azole potentiators through drug repurposing strategies.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"305-322"},"PeriodicalIF":4.0,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142918808","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}

{"title":"Evaluation of Synthetic Peptides from <i>Schistosoma mansoni</i> ATP Diphosphohydrolase 1: In Silico Approaches for Characterization and Prospective Application in Diagnosis of Schistosomiasis.","authors":"Danielle Gomes Marconato, Beatriz Paiva Nogueira, Vinícius Carius de Souza, Rafaella Fortini Grenfell E Queiroz, Clovis R Nakaie, Eveline Gomes Vasconcelos, Priscila de Faria Pinto","doi":"10.1021/acsinfecdis.4c00697","DOIUrl":"10.1021/acsinfecdis.4c00697","url":null,"abstract":"<p><p>Schistosomiasis is the infection caused by <i>Schistosoma mansoni</i> and constitutes a worldwide public health problem. The parasitological recommended method and serological methods can be used for the detection of eggs and antibodies, respectively. However, both have limitations, especially in low endemicity areas. Thus, new approaches for the diagnosis of schistosomiasis are essential. In this study, a six-amino acid peptide and derived sequences from SmATPDase1 were synthesized for the evaluation of immunogenicity. SmATPDase1 is included in a protein group in <i>S. mansoni</i> tegument; therefore, its peptides could be potential candidates for diagnostic antigens. In the hypothetical SmATPDase1 three-dimensional structure, peptides are located in a region exposed and accessible to antibody binding. In addition, peptide amino acid sequences are conserved in the most relevant <i>Schistosoma</i> species and have low identity with human NTPDases isoforms. Swiss mice immunization resulted in significant anti-peptide polyclonal antibodies production, which recognized a 63 kDa protein in tegument and adult worm preparations. By immunofluorescence microscopy, polyclonal antibodies also identified this enzyme in cercariae. Sera of infected animals presented high seropositivity in ELISA-peptides, with an area under curve (AUC) greater than 0.96 for all peptides. In mice with low parasite burden, we observed a seropositivity AUC > 0.9. Reactivity in the prepatent period exhibited AUC values greater than 0.94 for all peptides. Anti-P1425 monoclonal antibodies were successfully produced, and mAbs recognized the integral protein in ELISA and Western blots. The data indicate that peptides from SmATPDase1 are potential biomarkers for schistosomiasis, and anti-peptide antibodies are interesting tools for the detection of the infection.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"463-473"},"PeriodicalIF":4.0,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11833870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142976763","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}

{"title":"Small and Versatile Cyclotides as Anti-infective Agents.","authors":"Elizabete de Souza Cândido, Liryel Silva Gasparetto, Livia Veiga Luchi, João Pedro Farias Pimentel, Marlon Henrique Cardoso, Maria Lígia Rodrigues Macedo, Cesar de la Fuente-Nunez, Octávio Luiz Franco","doi":"10.1021/acsinfecdis.4c00957","DOIUrl":"10.1021/acsinfecdis.4c00957","url":null,"abstract":"<p><p>Plants provide an abundant source of potential therapeutic agents, including a diverse array of compounds, such as cyclotides, which are peptides known for their antimicrobial activity. Cyclotides are multifaceted molecules with a wide range of biological activities. Their unique topology forms a head-to-tail cyclic structure reinforced by a cysteine knot, which confers chemical and thermal stability. These molecules can directly target membranes of infectious agents by binding to phosphatidylethanolamine in lipid membranes, leading to membrane permeabilization. Additionally, they function as carriers and cell-penetrating molecules, demonstrating antiviral, antibacterial, antifungal, and nematicidal properties. The structure of cyclotides is also amenable to chemical synthesis, facilitating drug design through residue substitutions or grafting of bioactive epitopes within the cyclotide scaffold to enhance peptide stability. In this review, we explore the multifunctionality of these biomolecules as anti-infective agents, emphasizing their potential as a novel class of antimicrobial drugs.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"386-397"},"PeriodicalIF":4.0,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11833872/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021289","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}