mBio最新文献

{"title":"Endoplasmic reticulum facilitates the coordinated division of <i>Salmonella</i>-containing vacuoles.","authors":"Umesh Chopra, Priyanka Bhansali, Subba Rao Gangi Setty, Dipshikha Chakravortty","doi":"10.1128/mbio.00114-25","DOIUrl":"10.1128/mbio.00114-25","url":null,"abstract":"<p><p><i>Salmonella</i> Typhimurium (STM) resides in a membrane-bound compartment called the <i>Salmonella</i>-containing vacuole (SCV) in several infected cell types where bacterial and SCV division occur synchronously to maintain a single bacterium per vacuole. However, the mechanism behind this synchronous fission is not well understood. Fission of intracellular organelles is known to be regulated by the dynamic tubular endoplasmic reticulum (ER). In this study, we evaluated the role of ER in controlling SCV division. Interestingly, <i>Salmonella</i>-infected cells show activation of the unfolded protein response (UPR) and expansion of ER tubules. Altering the expression of ER morphology regulators, such as reticulon-4a (Rtn4a) and CLIMP63, significantly impacted bacterial proliferation, suggesting a potential role of tubular ER in facilitating SCV division. Live-cell imaging revealed the marking of tubular ER at the center of 78% of SCV division sites. This study also explored the role of SteA (a known <i>Salmonella</i> effector in modulating membrane dynamics) in coordinating the SCV division. SteA resides on the SCV membranes and helps form membrane contact between SCV and ER. The colocalization of ER with SCV enclosing STMΔ<i>steA</i> was significantly reduced, compared with SCV of STM WT or STMΔ<i>steA:steA</i>. STMΔ<i>steA</i> shows profound defects in SCV division, resulting in multiple bacteria in a single vacuole with proliferation defects. <i>In vivo</i>, the STMΔ<i>steA</i> shows a defect in colonization in the spleen and liver and affects the initial survival rate of mice. Overall, this study suggests a coordinated role of bacterial effector SteA in promoting ER contact/association with SCVs and regulating SCV division.IMPORTANCEThis study highlights the essential role of the host endoplasmic reticulum in facilitating SCV division and maintaining a single bacterium per vacuole. The <i>Salmonella</i> effector SteA helps maintain the single bacterium per vacuole state. In the absence of SteA, <i>Salmonella</i> resides as multiple bacteria within a single large vacuole. The STMΔ<i>steA</i> shows reduced proliferation under <i>in vitro</i> conditions and exhibits colonization defects <i>in vivo</i>, highlighting the importance of this effector in <i>Salmonella</i> pathogenesis. These findings suggest that targeting SteA could provide a novel therapeutic approach to inhibit <i>Salmonella</i> pathogenicity.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":"16 5","pages":"e0011425"},"PeriodicalIF":5.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077215/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144017792","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}

{"title":"Fructose activates a stress response shared by methylglyoxal and hydrogen peroxide in <i>Streptococcus mutans</i>.","authors":"Alejandro R Walker, Danniel N Pham, Payam Noeparvar, Alexandra M Peterson, Marissa K Lipp, José A Lemos, Lin Zeng","doi":"10.1128/mbio.00485-25","DOIUrl":"10.1128/mbio.00485-25","url":null,"abstract":"<p><p>Fructose catabolism by <i>Streptococcus mutans</i> is initiated by three phosphotransferase (PTS) transporters yielding fructose-1-phosphate (F-1-P) or fructose-6-phosphate. Deletion of one such F-1-P-generating PTS, <i>fruI</i>, was shown to reduce the cariogenicity of <i>S. mutans</i> in rats fed a high-sucrose diet. Moreover, a recent study linked fructose metabolism in <i>S. mutans</i> to a reactive electrophile species methylglyoxal. Here, we conducted a comparative transcriptomic analysis of <i>S. mutans</i> treated briefly with 50 mM fructose, 50 mM glucose, 5 mM methylglyoxal, or 0.5 mM hydrogen peroxide (H₂O₂). The results revealed a striking overlap between the fructose and methylglyoxal transcriptomes, totaling 176 genes, 61 of which were also shared with the H₂O₂ transcriptome. This core of 61 genes encompassed many of the same pathways affected by exposure to low pH or zinc intoxication. Consistent with these findings, fructose negatively impacted the metal homeostasis of a mutant deficient in zinc expulsion and the growth of a mutant of the major oxidative stress regulator SpxA1. Importantly, fructose metabolism lowered culture pH at a faster pace, allowed better survival under acidic and nutrient-depleted conditions, and enhanced the competitiveness of <i>S. mutans</i> against <i>Streptococcus sanguinis</i>, although a moderated level of F-1-P might further boost some of these benefits. Conversely, several commensal streptococcal species displayed a greater sensitivity to fructose that may negatively affect their persistence and competitiveness in dental biofilm. In conclusion, fructose metabolism is integrated into the stress core of <i>S. mutans</i> and regulates critical functions required for survival and its ability to induce dysbiosis in the oral cavity.IMPORTANCEFructose is a common monosaccharide in the biosphere, yet its overconsumption has been linked to various health problems in humans including insulin resistance, obesity, diabetes, non-alcoholic liver diseases, and even cancer. These effects are in large part attributable to the unique biochemical characteristics and metabolic responses associated with the degradation of fructose. Yet, an understanding of the effects of fructose on the physiology of bacteria and its implications for the human microbiome is severely lacking. Here, we performed a series of analyses on the gene regulation of a dental pathogen <i>Streptococcus mutans</i> by exposing it to fructose and other important stress agents. Further supported by growth, persistence, and competition assays, our findings revealed the ability of fructose to activate a set of stress-related functions that may prove critical to the ability of the bacterium to persist and cause diseases both within and without the oral cavity.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":"16 5","pages":"e0048525"},"PeriodicalIF":5.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077213/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144024873","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}

{"title":"Diversification of DIX domain-containing proteins in the SAR supergroup.","authors":"Maria-Myrto Kostareli, Timo Westerink, Gabriel Couillaud, Maaria Peippo, Francine Govers, Dolf Weijers, Edouard Evangelisti","doi":"10.1128/mbio.03966-24","DOIUrl":"10.1128/mbio.03966-24","url":null,"abstract":"<p><p>Polarity establishment is crucial for development, cellular organization, and signaling in living organisms. In animals and plants, this process involves DIX domain-containing proteins (DDPs) that assemble into oligomers via head-to-tail DIX polymerization, facilitating localized protein aggregation. This study uncovers the unexpected diversity of DDPs within the SAR supergroup, characterizing four DDPs with novel domain combinations conserved in Stramenopiles and Alveolates. These proteins are predominantly found in micro-swimmers and species with a motile stage in their life cycle. We hypothesize that DDPs from these eukaryotic lineages may be involved in cell polarity-related processes, including those associated with motility. Our work provides insights for further investigations of DDPs in protists and will enable the development of evolution-informed control strategies against pathogens and parasites within this clade.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":"16 5","pages":"e0396624"},"PeriodicalIF":5.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077222/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144031424","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}

{"title":"Biochemical mapping reveals a conserved heme transport mechanism via CcmCD in System I bacterial cytochrome <i>c</i> biogenesis.","authors":"Alicia N Kreiman, Sarah E Garner, Susan C Carroll, Molly C Sutherland","doi":"10.1128/mbio.03515-24","DOIUrl":"10.1128/mbio.03515-24","url":null,"abstract":"<p><p>Heme is a redox-active cofactor for essential processes across all domains of life. Heme's redox capabilities are responsible for its biological significance but also make it highly cytotoxic, requiring tight intracellular regulation. Thus, the mechanisms of heme trafficking are still not well understood. To address this, the bacterial cytochrome <i>c</i> biogenesis pathways are being developed into model systems to elucidate mechanisms of heme trafficking. These pathways function to attach heme to apocytochrome <i>c</i>, which requires the transport of heme from inside to outside of the cell. Here, we focus on the System I pathway (CcmABCDEFGH) which is proposed to function in two steps: CcmABCD transports heme across the membrane and attaches it to CcmE. HoloCcmE then transports heme to the holocytochrome <i>c</i> synthase, CcmFH, for attachment to apocytochrome <i>c</i>. To interrogate heme transport across the membrane, we focus on CcmCD, which can form holoCcmE independent of CcmAB, leading to the hypothesis that CcmCD is a heme transporter. A structure-function analysis via cysteine/heme crosslinking identified a heme acceptance domain and heme transport channel in CcmCD. Bioinformatic analysis and structural predictions across prokaryotic organisms determined that the heme acceptance domains are structurally variable, potentially to interact with diverse heme delivery proteins. In contrast, the CcmC transmembrane heme channel is structurally conserved, indicating a common mechanism for transmembrane heme transport. We provide direct biochemical evidence mapping the CcmCD heme channel and providing insights into general mechanisms of heme trafficking by other putative heme transporters.</p><p><strong>Importance: </strong>Heme is a biologically important cofactor for proteins involved with essential cellular functions, such as oxygen transport and energy production. Heme can also be toxic to cells and thus requires tight regulation and specific trafficking pathways. As a result, much effort has been devoted to understanding how this important, yet cytotoxic, molecule is transported. While several heme transporters/importers/exporters have been identified, the biochemical mechanisms of transport are not well understood, representing a major knowledge gap. Here, the bacterial cytochrome <i>c</i> biogenesis pathway, System I (CcmABCDEFGH), is used to elucidate the transmembrane transport of heme via CcmCD. We utilize a cysteine/heme crosslinking approach, which can trap endogenous heme in specific domains, to biochemically map the heme transport channel in CcmCD, demonstrating that CcmCD is a heme transporter. These results suggest a model for heme trafficking by other heme transporters in both prokaryotes and eukaryotes.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0351524"},"PeriodicalIF":5.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077264/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143752767","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}

{"title":"Cellular SLC35B4 promotes internalization during influenza A virus entry.","authors":"Guangwen Wang, Li Jiang, Ya Yan, Fandi Kong, Qibing Li, Jie Zhang, Shuangshuang Hou, Bo Wang, Xiurong Wang, Huihui Kong, Guohua Deng, Jianzhong Shi, Guobin Tian, Xianying Zeng, Hualan Chen, Chengjun Li","doi":"10.1128/mbio.00194-25","DOIUrl":"10.1128/mbio.00194-25","url":null,"abstract":"<p><p>SLC35B4, a nucleotide sugar transporter that mediates the transport of UDP-GlcNAc and UDP-xylose, was found to be required for the replication of influenza A virus (IAV) of the H5N1 subtype in our genome-wide siRNA library screen. We found that defective IAV replication in SLC35B4-deficient A549 cells was independent of virus strain specificity, and the virulence of IAV in Slc35b4 knockdown mice was also decreased. By examining the individual stages of the IAV replication cycle, we discovered that the amount of internalized IAV was significantly reduced in SLC35B4-knockout A549 cells. Mechanistically, SLC35B4 facilitated IAV replication by transporting UDP-xylose, which attaches to the serine residue of heparan sulfate proteoglycans (HSPGs) in the heparan sulfate (HS) biosynthesis pathway. Knockdown of associated host factors (i.e., XYLT2, B4GALT7, EXT1, and EXT2) in the HS biosynthesis pathway also impaired IAV replication. Furthermore, we revealed that AGRN, a unique HSPG family member, was important for the endocytosis of IAV in A549 cells. Moreover, we found that the homeostasis of the AGRN protein was regulated by HS modification mediated by the initial UDP-xylose transporter SLC35B4, thereby affecting the expression level of endocytic adapter AP2B1 to influence IAV internalization. Collectively, these findings establish that SLC35B4 is an important regulator of IAV replication and uncover the underlying mechanisms by which SLC35B4 employs UDP-xylose transport activity to promote IAV internalization.IMPORTANCEThe entry process of IAV represents a favorable target for drug development. In this study, we identified SLC35B4 as an important host factor for the efficient replication of different subtypes of IAV <i>in vitro</i> and for the virulence of IAV in mice. We revealed that SLC35B4 employed its UDP-xylose transport activity to promote the HS biosynthesis pathway, thereby assisting IAV internalization into target cells in the early stage of viral infection. Consistently, several downstream factors in the HS biosynthesis pathway, i.e., XYLT2, B4GALT7, EXT1, and EXT2, as well as a specific HSPG member AGRN were also important for the replication of IAV. Furthermore, the UDP-xylose-transporting activity of SLC35B4 was involved in the regulation of the homeostasis of the AGRN protein by HS modification, which influenced virus internalization by affecting the expression levels of AP2B1. Together, the identification of the SLC35B4-XYLT2-B4GALT7-EXT1-EXT2-AGRN-AP2B1 axis may shed light on the development of potential anti-IAV therapeutics.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0019425"},"PeriodicalIF":5.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077083/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143700965","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}

{"title":"Functional characterization of a novel protein-coding circular RNA, circRNA_1193, from the <i>mAAP</i> gene in silkworm and its role in antiviral defense against BmCPV.","authors":"Song Li, Zeen Shen, Hongchuan Zhao, Xialing Chen, Qunnan Qiu, Xinyu Tong, Min Zhu, Xing Zhang, Chengliang Gong, Xiaolong Hu","doi":"10.1128/mbio.00125-25","DOIUrl":"10.1128/mbio.00125-25","url":null,"abstract":"<p><p>A novel circular RNA, circRNA_1193, which originates from the <i>membrane alanyl aminopeptidase-like</i> gene in silkworms, was explored for its potential function and regulatory mechanism. We validated the presence of circRNA_1193 in <i>Bombyx mori</i> cytoplasmic polyhedrosis virus (BmCPV)-infected silkworm ovary cell line (BmN) cells through a combination of reverse transcription polymerase chain reaction, Northern blotting, and <i>in situ</i> hybridization. CircRNA_1193 exhibited tissue-specific expression, being highly enriched in the midgut and Malpighian tubules, and displayed a specific response to BmCPV infection, but not to <i>Bombyx mori</i> nucleopolyhedrovirus or lipopolysaccharide. Functional analyses revealed that the overexpression of circRNA_1193 suppressed BmCPV replication, whereas its knockdown increased viral replication. Bioinformatic analyses revealed potential internal ribosome entry sites, m6A methylation sites, and open reading frames (ORFs) within circRNA_1193, suggesting its potential coding capacity. We confirmed the translation of the ORF by constructing a DsRed reporter vector and demonstrating DsRed expression in transfected cells. Furthermore, a mutation of the start codon within circRNA_1193 abolished its antiviral activity, highlighting the crucial role of the translated protein, which is 35 kDa and is designated as VSP35. Furthermore, our data suggest that the formation of circRNA_1193 relies on reverse complementary flanking sequences. These findings unveil a novel protein-coding circular RNA in silkworms that plays a critical role in antiviral defense.</p><p><strong>Importance: </strong>This study identified a novel circular RNA, circRNA_1193, in the silkworm <i>Bombyx mori</i>, and revealed its critical role in antiviral defense against <i>Bombyx mori</i> cytoplasmic polyhedrosis virus (BmCPV). We demonstrated that circRNA_1193 exhibits tissue-specific expression, is upregulated in response to BmCPV infection, and possesses antiviral activity. Importantly, we show that circRNA_1193 encodes the viral protein VSP35, which is essential for its antiviral function. These findings provide new insights into the complex regulatory mechanisms of circular RNAs in antiviral immunity and underscore the potential of circular RNAs as therapeutic targets in viral diseases. The identification of a protein-coding circular RNA with antiviral activity in <i>B. mori</i> has broader implications for understanding the evolution and diversity of host defense mechanisms against viruses.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0012525"},"PeriodicalIF":5.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077084/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730733","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}

{"title":"Molecular mechanisms of drug resistance and compensation in SARS-CoV-2 main protease: the interplay between E166 and L50.","authors":"Sarah N Zvornicanin, Ala M Shaqra, Julia Flynn, Heidi Carias Martinez, Weiping Jia, Stephanie Moquin, Dustin Dovala, Daniel N Bolon, Nese Kurt Yilmaz, Celia A Schiffer","doi":"10.1128/mbio.04068-24","DOIUrl":"10.1128/mbio.04068-24","url":null,"abstract":"<p><p>The SARS-CoV-2 main protease (M^pro) is essential for viral replication and is a primary target for COVID-19 antivirals. Direct-acting antivirals such as nirmatrelvir, the active component of Paxlovid, target the M^pro active site to block viral polyprotein cleavage and thus replication. However, drug resistance mutations at the active site residue Glu166 (E166) have emerged during <i>in vitro</i> selection studies, raising concerns about the durability of current antiviral strategies. Here, we investigate the molecular basis of drug resistance conferred by E166A and E166V mutations against nirmatrelvir and the related PF-00835231, individually and in combination with the distal mutation L50F. We found that E166 mutations reduce nirmatrelvir potency by up to 3,000-fold while preserving substrate cleavage, with catalytic efficiency reduced by only up to twofold. This loss of catalytic efficiency was compensated for by the addition of L50F in the double-mutant variants. We have determined three cocrystal structures of the E166 variants (E166A, E166V, and E166V/L50F) bound to PF-00835231. Comparison of these structures with wild-type enzyme demonstrated that E166 is crucial for dimerization and for shaping the substrate-binding S1 pocket. Our findings highlight the mutability of E166, a prime site for resistance for inhibitors that leverage direct interactions with this position, and the potential emergence of highly resistant and active variants in combination with the compensatory mutation L50F. These insights support the design of inhibitors that target conserved protease features and avoid E166 side-chain interactions to minimize susceptibility to resistance.</p><p><strong>Importance: </strong>Drug resistance remains a great challenge to modern medicine. This study investigates SARS-CoV-2 main protease variants E166A and E166V which confer nirmatrelvir resistance. These variants can retain considerable enzymatic activity through combination with the compensatory mutation L50F. For single- and double-mutant variant enzymes, we assessed catalytic efficiency, measured loss in potency for nirmatrelvir and its analog PF-00835231, and cocrystallized with inhibitors to investigate drug resistance caused by these mutations. Our results contribute toward understanding of molecular mechanisms of resistance and combinations of mutations, which pushes toward resistance-thwarting inhibitor design. These principles also apply broadly to many quickly evolving drug targets in infectious diseases.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0406824"},"PeriodicalIF":5.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077200/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780139","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}

{"title":"Tumor-colonizing <i>Pseudoalteromonas elyakovii</i> metabolically reprograms the tumor microenvironment and promotes breast ductal carcinoma.","authors":"Shuyan Liu, Youpeng Pan, Chaopeng Zheng, Qinghui Zheng, Yaoqiang Du, Yajuan Zheng, Hongchao Tang, Xiaozhen Liu, Jiancheng Mou, Xin Zeng, Zhuotao Yang, Wenjuan Gui, Yuning Tang, Mingxing Xu, Zhihao Ye, Haotian Su, Qiuran Xu, Xuli Meng","doi":"10.1128/mbio.03873-24","DOIUrl":"10.1128/mbio.03873-24","url":null,"abstract":"<p><p>The correlation between the microbiota found in tumors and tumor development is being progressively understood, specifically regarding its involvement in the initiation and advancement of tumors. We examined a total of 102 samples, examining the microbial composition at the species level in each person unveiled significant variations in both the microbial makeup and tumor proportions among individuals, examining the fluctuating alterations in the microbial profile during breast cancer advancement and progression. The levels of expression for <i>Pseudoalteromonas elyakovii</i> were notably elevated in the tumor groups when compared to the para-cancer normal group, aligning with the results obtained from qRT-PCR analysis. The relationship between tumor immunity and microorganisms within the tumor was investigated using double immunofluorescence staining combined with SweAMI probe <i>in situ</i> hybridization and scRNA-seq, allowing for an in-depth analysis of intratumoral microorganisms. Experiments have demonstrated that the supernatant derived from <i>P. elyakovii</i> displayed a significant ability to promote tumor growth and stimulation. In summary, we describe the characteristics of the intratumoral microbiota and the tumor-promoting effects of <i>P. elyakovii</i> supernatant within a small dose range in ductal carcinoma of the breast and characterize the potential clinical application value of intratumoural microorganisms in the progression of cancer and immunotherapy.</p><p><strong>Importance: </strong>Despite the existing studies, the specific microbial factors that influence the occurrence and progression of breast cancer still remain unclear. Researchers have clarified the distinctive microbial profile related to ductal carcinoma, a common histological type of breast cancer, in order to identify tumor-specific microbes and their roles in tumorigenesis. With the tumor microbiome as the focus, the enrichment of <i>Pseudoalteromonas elyakovii</i> features accelerates the disease progression in patients with ductal carcinoma of the breast. This study reveals the initial role relationship and innovative findings between <i>Pseudoalteromonas elyakovii</i> and ductal carcinoma in the breast.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0387324"},"PeriodicalIF":5.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077203/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795750","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}

{"title":"Transcriptional control of <i>C. albicans</i> white-opaque switching and modulation by environmental cues and strain background.","authors":"Anupam Sharma, Ameen Homayoon, Michael Weyler, Corey Frazer, Bernardo Ramírez-Zavala, Joachim Morschhäuser, Richard J Bennett","doi":"10.1128/mbio.00581-25","DOIUrl":"10.1128/mbio.00581-25","url":null,"abstract":"<p><p>The opportunistic fungal pathogen <i>Candida albicans</i> can undergo cellular transitions in response to environmental cues that impact its lifestyle and its interactions with the human host. This is exemplified by the white-opaque switch, which is a heritable transition between two phenotypic states that is regulated by a highly interconnected network of transcription factors (TFs). To obtain greater understanding of the transcriptional regulation of the switch, we generated a genome-wide, tetracycline-inducible TF library in the WO-1 strain background and identified those TFs whose forced expression induces white cells to switch to the opaque state. This set of opaque-inducing TFs was also evaluated for their ability to induce switching in a second strain background, that of the standard reference strain SC5314, as well as during growth on different laboratory media. These experiments identify 14 TFs that can drive white-to-opaque switching when overexpressed but that do so in a highly strain- and media-specific manner. In particular, changes in pH, amino acids, and zinc concentrations had marked effects on the ability of TFs to drive phenotypic switching. These results provide insights into the complex transcriptional regulation of switching in <i>C. albicans</i> and reveal that an interplay between genetic and environmental factors determines TF function and cell fate.IMPORTANCEThe white-opaque switch in <i>Candida albicans</i> represents a model system for understanding an epigenetic switch in a eukaryotic pathogen. Here, we generated an inducible library of the set of transcription factors (TFs) present in <i>C. albicans</i> and identify 14 TFs that can drive the white-to-opaque transition when ectopically expressed. We demonstrate that several of these TFs induce the switch in a highly strain- and media-specific manner. This highlights that both strain background and changes in experimental conditions (including different water sources) can profoundly impact the phenotypic consequences of TF overexpression. Moreover, the inducible TF library provides an invaluable tool for the further analysis of TF function in this important human pathogen.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0058125"},"PeriodicalIF":5.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077150/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811747","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}

{"title":"<i>Ex vivo</i> and <i>in vivo</i> HIV-1 latency reversal by \"Mukungulu,\" a protein kinase C-activating African medicinal plant extract.","authors":"Khumoekae Richard, Zhe Yuan, Hsin-Yao Tang, Aaron R Goldman, Riza Kuthu, Boingotlo Raphane, Emery T Register, Paridhima Sharma, Brian N Ross, Jessicamarie Morris, David E Williams, Carol Cheney, Guoxin Wu, Karam Mounzer, Gregory M Laird, Paul Zuck, Raymond J Andersen, Sundana Simonambango, Kerstin Andrae-Marobela, Ian Tietjen, Luis J Montaner","doi":"10.1128/mbio.03816-24","DOIUrl":"10.1128/mbio.03816-24","url":null,"abstract":"<p><p>New HIV latency-reversing agents (LRAs) are needed that can reactivate and/or eliminate HIV reservoirs. \"Mukungulu,\" prepared from the plant <i>Croton megalobotrys</i> Müll Arg., is traditionally used for HIV/AIDS management in northern Botswana despite an abundance of protein kinase C-activating phorbol esters (\"namushens\"). Here, we show that Mukungulu is tolerated in mice at up to 12.5 mg/kg while robustly reversing latency in antiretroviral therapy (ART)-suppressed HIV-infected humanized mice at 5 mg/kg. In primary cells from ART-suppressed people living with HIV-1, 1 µg/mL Mukungulu reverses latency at levels similar to or superior to anti-CD3/CD28 positive control, based on HIV gag-p24 protein expression, while the magnitude of HIV reactivation in peripheral blood mononuclear cells corresponds to intact proviral burden in CD4+ T-cells. Bioassay-guided fractionation identifies five namushen phorbol esters that can reactivate HIV, but when combined, they do not match Mukungulu's activity, suggesting the presence of additional enhancing factors. Together, these results identify Mukungulu as a robust natural LRA that is already in use by humans and which may warrant inclusion in future HIV cure and ART-free remission efforts.IMPORTANCECurrent HIV therapies do not act on the latent viral reservoir, which is the major obstacle toward achieving a drug-free HIV remission and/or an HIV cure. \"Mukungulu,\" a bark preparation from <i>Croton megalobotrys</i> Müll Arg., has been documented for its traditional use for HIV/AIDS management in northern Botswana. Here, we show that Mukungulu activates viral reservoirs, a key step toward identifying and potentially eliminating these reservoirs, in both cells from people living with HIV as well as in HIV-infected humanized mice. The majority of this activity is due to the abundance of five phorbol esters (\"namushens\"). This reverse pharmacology-based approach has therefore identified a potent activator of viral reservoirs that is already traditionally used by humans, which in turn can inform and advance western HIV cure and drug-free remission efforts.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":"16 5","pages":"e0381624"},"PeriodicalIF":5.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077168/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144008384","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}