mBio最新文献

{"title":"Key fungal coinfections: epidemiology, mechanisms of pathogenesis, and beyond.","authors":"Danielle L Silva, Nalu T A Peres, Daniel A Santos","doi":"10.1128/mbio.00562-25","DOIUrl":"10.1128/mbio.00562-25","url":null,"abstract":"<p><p>Coinfection is defined as the occurrence of at least two genetically distinct infectious agents within the same host. Historically, fungal infections have been neglected, leading to an underestimation of their impact on public health systems. However, fungal coinfections have become increasingly prevalent, emerging as a significant global health concern. This review explores fungal coinfections commonly associated with HIV, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza, <i>Mycobacterium tuberculosis</i>, and <i>Pseudomonas</i> species. These include candidiasis, aspergillosis, paracoccidioidomycosis, cryptococcosis, histoplasmosis, pneumocystosis, sporotrichosis, and mucormycosis. We discuss the key local and systemic mechanisms that contribute to the occurrence of these coinfections. HIV infects CD4+ cells, causing systemic immunosuppression, particularly impairing the adaptive immune response. The inflammatory response to SARS-CoV-2 infection disrupts both pulmonary and systemic homeostasis, rendering individuals more vulnerable to local and disseminated fungal coinfections. Severe influenza promotes fungal coinfections by triggering the production of pro-inflammatory cytokines, which damage the epithelial-endothelial barrier and impair the recognition and phagocytosis of fungal cells. Tuberculosis can replace normal lung parenchyma with collagen tissue, leading to alterations in lung architecture, compromising its function. Interaction between <i>Pseudomonas</i> and <i>Aspergillus</i> during coinfection involves the competition for iron availability and an adaptive response to its deprivation. Therefore, the specific interactions between each underlying disease and fungal coinfections are detailed in this review. In addition, we highlight the risk factors associated with coinfections, pathophysiology, epidemiology, and the challenges of early diagnosis. Recognizing the substantial worldwide public health burden posed by fungal coinfections is crucial to improve survival rates.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0056225"},"PeriodicalIF":5.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764280","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":"Signaling pathways governing the pathobiological features and antifungal drug resistance of <i>Candida auris</i>.","authors":"Hyunjin Cha, Doyeon Won, Yong-Sun Bahn","doi":"10.1128/mbio.02475-23","DOIUrl":"10.1128/mbio.02475-23","url":null,"abstract":"<p><p><i>Candida auris</i> is an emerging multidrug-resistant fungal pathogen that poses a significant global health threat. Since its discovery in 2009, <i>C. auris</i> has rapidly spread worldwide, causing severe infections with high mortality rates, particularly in healthcare settings. Its ability to persist in the environment, form biofilms, and resist multiple antifungal drugs underscores the urgent need to understand its pathogenicity mechanisms and associated signaling pathways. Such insights are crucial for elucidating its unique virulence traits and developing targeted therapeutic strategies. Current studies have identified several key pathways involved in its pathogenicity and antifungal drug resistance. The Ras/cAMP/PKA pathway regulates critical virulence factors, including thermotolerance, morphological plasticity, and biofilm formation. The mitogen-activated protein kinase (MAPK) and calcineurin pathways contribute to stress responses and antifungal drug resistance. The regulation of Ace2 and morphogenesis (RAM) pathway influences cell aggregation, while the target of rapamycin (TOR) pathway affects filamentous growth and biofilm development. However, the distinct characteristics of <i>C. auris</i>, such as its rapid environmental spread and clade-specific traits, warrant further investigation into additional signaling pathways. This review provides a comprehensive analysis of known signaling pathways associated with <i>C. auris</i> pathogenicity and antifungal drug resistance, integrating insights from other fungal pathogens. By synthesizing current knowledge and identifying research gaps, this review offers new perspectives on future research directions and potential therapeutic targets against this formidable pathogen.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0247523"},"PeriodicalIF":5.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077148/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143772634","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":"Higher proportions of circulating CXCR3+ CCR6- Tfh cells as a hallmark of impaired CD4+ T-cell recovery in HIV-1-infected immunological non-responders.","authors":"Ruthu Nagaraju, Pruthvi S Gowda, Durai M Gunasekaran, Anita S Desai, Udaykumar Ranga, Ramesh N R Masthi, Manjunatha M Venkataswamy","doi":"10.1128/mbio.00575-25","DOIUrl":"10.1128/mbio.00575-25","url":null,"abstract":"<p><p>Despite long-term suppressive antiretroviral therapy (ART), immune dysregulation due to impaired reconstitution of CD4+ T cells is a major hurdle for reducing morbidity and mortality in HIV-1-infected immunological non-responders (INRs, CD4+ T cells ≤350 cells/µL). To evaluate potential immunological factors associated with impaired CD4+ T-cell reconstitution, we performed comprehensive immunophenotyping of multiple subsets of CD4+ T cells among HIV-1-infected individuals with high (>350 cells/µL) and low (≤350 cells/µL) CD4+ T cells, either ART-naïve or ART-exposed (median, 10 years). In comparison to other groups, INRs showed exclusively elevated proportions of CXCR3+ CCR6- Th1-like circulatory T follicular helper (cTfh1) CD4+ T cells, correlating negatively with CD4+ T cells (<i>r</i> = -0.6769, <i>P</i> < 0.0001), suggesting a strong association with incomplete CD4+ T-cell recovery. In contrast, compared to INRs, higher proportions of CXCR3- CCR6+ Th17-like cTfh cells (cTfh17) in immunological responders (IRs, CD4+ T cells >350 cells/µL) showed no correlation with CD4+ T-cell counts, suggesting a lack of association with CD4+ T-cell recovery. Additionally, proportions of activated (CD4+ CD38+ HLA-DR+) and regulatory (CD4+ CD25+/hi CD127-/lo) CD4+ T cells were increased in INRs compared to IRs, as previously known. A negative correlation was also observed between the CD4+ T-cell counts and activated (<i>r</i> = -0.6726, <i>P</i> < 0.0001) or regulatory (<i>r</i> = -0.5627, <i>P</i> < 0.0001) CD4+ T-cell proportions among IRs and INRs. Our study highlights that immune dysregulation associated with skewing of cTfh cells toward CXCR3+ CCR6- Th1-like phenotype may be the leading cause of inefficient CD4+ T-cell recovery in INRs and can serve as a hallmark of impaired CD4+ T-cell reconstitution.IMPORTANCEThe altered proportions of CD4+ T-cell subsets in immunological non-responders (INRs) indicate their involvement in poor CD4+ T-cell reconstitution. Reversing these alterations may help prevent the loss of CD4+ T cells. Particularly, blocking cTfh-cell polarization toward CXCR3+ CCR6- cTfh-cell subset may help restore CD4+ T-cell counts in INRs, thereby preventing increased risk of morbidity and mortality.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0057525"},"PeriodicalIF":5.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143700590","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":"Differential crosstalk between toxin-immunity protein homologs divides <i>Myxococcus</i> nonself siblings into close and distant social relatives.","authors":"Feng Wang, Jing Luo, Zheng Zhang, Ya Liu, Duo Hong Sheng, Li Zhuo, Yue-Zhong Li","doi":"10.1128/mbio.03902-24","DOIUrl":"10.1128/mbio.03902-24","url":null,"abstract":"<p><p>Many bacteria discriminate self and nonself using toxins and their corresponding immunity proteins. The toxin-immunity systems often include homologs, potentially creating crosstalk with unknown influences on kin discrimination. In this study, we investigated the kinship controlled by four homologous toxin-immunity systems in the social bacterium <i>Myxococcus xanthus</i>. We determined that the four homologous systems each play an independent role in the discrimination of self and nonself. However, the immunity proteins inactivate not only the corresponding nuclease toxin proteins but also some non-corresponding toxin proteins, depending on their sequence and structural similarities. The nonself relatives controlled by toxin-immunity proteins with or without crosstalk exhibit differential co-growth and collaborative behaviors. We concluded that differential crosstalk between toxin-immunity protein homologs can divide bacterial nonself lineages into close and distant relatives displaying differential collaboration and antagonistic behaviors.IMPORTANCEThis study significantly contributes to our knowledge of kin selection and social behavior in bacteria. The interactions between four homologous toxin-immunity protein systems of <i>Myxococcus xanthus</i> were investigated, and evidence was obtained that these systems can distinguish between self and nonself cells within a species. Importantly, this study revealed that nonself lineages, which display varying degrees of genetic relatedness, can co-grow and collaborate in distinct patterns. This discovery implies that the differential crosstalk between homologous toxin-immunity proteins can mimic the degree of kinship; through this activity, bacteria can differentiate close and distant relatives. This novel insight into bacterial social dynamics and kin discrimination supports kin selection theory and enriches our knowledge on microbial interactions and evolutionary strategies. These findings have broad implications for microbial ecology, evolution, and the development of cooperation strategies.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0390224"},"PeriodicalIF":5.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077131/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730618","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":"New dimensions in acidocalcisome research: the potential of cryo-EM to uncover novel aspects of protozoan parasite physiology.","authors":"Ingrid Augusto, Moara Lemos, Wendell Girard-Dias, José de Anchieta Oliveira Filho, Pedro G Pascutti, Wanderley de Souza, Kildare Miranda","doi":"10.1128/mbio.01662-24","DOIUrl":"10.1128/mbio.01662-24","url":null,"abstract":"<p><p>Cryo-electron microscopy (cryo-EM) has revolutionized structural biology by enabling high-resolution, near-native visualization of macromolecular structures and entire cells. Its application to etiologic agents of diseases is an expanding field, particularly for those caused by viruses or unicellular eukaryotes, such as protozoan parasites and fungi. This review focuses on acidocalcisomes-ion-rich, multifunctional organelles essential for cell physiology and survival in several pathogens. The structure and function of these organelles are examined through a range of electron microscopy techniques, using <i>Trypanosoma cruzi</i> as a model. The advantages and limitations of the methods employed to study acidocalcisome morphofunctional organization-such as chemical fixation, plunge and high-pressure freezing, cryo-electron microscopy of vitrified sections (CEMOVIS), freeze-drying, freeze substitution, tomography, and microanalysis using X rays and inelastic scattered electrons-are discussed, alongside their contributions to our current understanding of acidocalcisome structure and function. Recent advances in cryo-EM and its potential to address longstanding questions and fill existing gaps in our understanding of parasite ion mobilization mechanisms and physiology are also discussed.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0166224"},"PeriodicalIF":5.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077218/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803511","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":"Distinct strategies of diguanylate cyclase domain proteins on inhibition of virulence and interbacterial competition by agrobacteria.","authors":"Xuan Lai, Manda Yu, Chiu-Ping Cheng, Erh-Min Lai","doi":"10.1128/mbio.00039-25","DOIUrl":"10.1128/mbio.00039-25","url":null,"abstract":"<p><p>Diguanylate cyclases (DGCs) synthesize bis-(3',5')-cyclic diguanylic acid (c-di-GMP), a critical bacterial second messenger that coordinates diverse biological processes. <i>Agrobacterium tumefaciens</i>, a plant pathogen causing crown gall disease, relies on type IV secretion system for pathogenesis and type VI secretion system (T6SS) for interbacterial competition. Our study identified two putative DGCs, named <u>d</u>iguanylate <u>c</u>yclase domain proteins regulating <u>v</u>irulences A and B (DcvA and DcvB), that negatively regulate virulence through distinct mechanisms. DcvA suppresses virulence by targeting the VirA/VirG two-component system downstream of VirA. This inhibition is independent of c-di-GMP levels. DcvB positively regulates biofilm formation, inhibits T6SS-mediated interbacterial competition, and suppresses virulence via the ChvG/ChvI two-component system downstream of ChvG. These effects are dependent on its cyclase activity and the associated increase in intracellular c-di-GMP levels. These findings suggest that DcvA and DcvB control virulence and interbacterial competition using different mechanisms in <i>Agrobacterium</i>. DcvA suppresses virulence, independent of c-di-GMP, and DcvB enhances global c-di-GMP concentration to promote biofilm formation and inhibits virulence and T6SS antibacterial activity. The findings provide understanding of how DGC domain proteins orchestrate complex regulatory networks to balance virulence, biofilm formation, and interbacterial competition, enabling them to adapt to changing environments.IMPORTANCEBacteria produce second messengers, such as c-di-GMP, to regulate various cellular processes, including biofilm formation, virulence, and bacterial antagonism. Diguanylate cyclases (DGCs) catalyze the biosynthesis of c-di-GMP and function to cope with changing environments through targeting specific effector proteins. In this study, we uncover that phytopathogenic agrobacteria deploy two DGC domain proteins to suppress virulence and interbacterial competition through two different regulatory pathways. One exhibits the DGC activity, enhancing global c-di-GMP concentration to elevate biofilm formation and inhibit virulence and antibacterial activity, while the other specifically suppresses virulence, independent of c-di-GMP biosynthesis. Our findings provide new insight into the distinct regulatory mechanisms of DGC domain proteins on regulating virulence and interbacterial competition, highlighting potential new strategies for controlling <i>Agrobacterium</i> pathogenicity.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":"16 5","pages":"e0003925"},"PeriodicalIF":5.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077199/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144001235","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":"Di-HAMP domains of a cytoplasmic chemoreceptor modulate nucleoid array formation and downstream signaling.","authors":"P J Jazleena, Apurba Das, Annick Guiseppi, Fabian Debard, Jaya Sharma, Mutum Yaikhomba, Tâm Mignot, Emilia M F Mauriello, Pananghat Gayathri","doi":"10.1128/mbio.00057-25","DOIUrl":"10.1128/mbio.00057-25","url":null,"abstract":"<p><p>In bacterial chemosensing, environmental cues are typically sensed by bacterial transmembrane receptors known as methyl-accepting chemotaxis proteins (MCPs). MCPs form highly organized arrays using the bacterial membrane as a scaffold. These arrays amplify the signals and transduce them into a cellular response. The FrzCD cytoplasmic receptor from <i>Myxococcus xanthus</i> is unique due to its ability to bind DNA and use the nucleoid as a scaffold to form arrays. In this study, we identified two HAMP (<u>h</u>istidine kinase, <u>a</u>denylyl cyclase, <u>M</u>CP, and <u>p</u>hosphatase) domains located between the DNA binding and signaling domains of FrzCD. <i>In vitro</i> experiments demonstrate that the di-HAMP domain restricts FrzCD to a dimeric form in solution and modulate FrzCD affinity for DNA, whereas the signaling domain stabilizes higher-order oligomeric assemblies upon DNA binding. Through fluorescence microscopy and analyses of <i>M. xanthus</i> social behavior, we demonstrate that the impact of the FrzCD HAMP domains on DNA binding and oligomerization significantly influences the formation of Frz clusters on the nucleoid as well as group motility and development. Our results suggest that the di-HAMP domain might have roles not only in signal transduction but also in the plasticity of chemosensory arrays. These observations illustrate mechanisms of regulation of a DNA-bound cytoplasmic array formed by a diffusible MCP.IMPORTANCEOur study identifies the presence of a di-HAMP domain in a cytoplasmic chemoreceptor, FrzCD, from <i>Myxococcus xanthus</i>, and highlights its role in dynamic receptor oligomerization on a DNA scaffold. By controlling receptor oligomerization and subsequently the array formation on the nucleoid, the di-HAMP domain imparts plasticity to receptor arrays. Such plasticity governs cellular responses to external signals and dictates bacterial social behaviors such as group motility and multicellular structure formation.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":"16 5","pages":"e0005725"},"PeriodicalIF":5.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077210/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144016191","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":"Infectivity and structure of SARS-CoV-2 after hydrogen peroxide treatment.","authors":"Saba R Aliyari, Guodong Xie, Xian Xia, Lulan Wang, Z Hong Zhou, Genhong Cheng","doi":"10.1128/mbio.03994-24","DOIUrl":"10.1128/mbio.03994-24","url":null,"abstract":"<p><p>Hydrogen peroxide (H₂O₂) exhibits broad-spectrum antiviral activity and is commonly used as an over-the-counter disinfecting agent. However, its potential activities against SARS-CoV-2 have not been systematically evaluated, and mechanisms of action are not well understood. In this study, we investigate H₂O₂'s antiviral activity against SARS-CoV-2 infection and its impact on the virion's structural integrity as compared to the commonly used fixative agent paraformaldehyde (PFA). We show that H₂O₂ rapidly and directly inactivates SARS-CoV-2 with a half-maximal inhibitory concentration (IC50) of 0.0015%. Cryogenic electron tomography (cryo-ET) with subtomogram averaging reveals that treatment with PFA induced the viral trimeric spike protein (S) to adopt a post-fusion conformation, and treatment of viral particles with H₂O₂ locked S in its pre-fusion conformation. Therefore, H₂O₂ treatment likely has induced modifications, such as oxidation of cysteine residues within the S subunits of the spike trimer that locked them in their pre-fusion conformation. Locking of the meta-stable pre-fusion trimer prevents its transition to the post-fusion conformation, a process essential for viral fusion with host cells and entry into host cells. Together, our cellular, biochemical, and structural studies established that hydrogen peroxide can inactivate SARS-CoV-2 in tissue culture and uncovered its underlying molecular mechanism.IMPORTANCEHydrogen peroxide (H₂O₂) is the commonly used, over-the-counter antiseptic solution available in pharmacies, but its effect against the SARS-CoV-2 virus has not been evaluated systematically. In this study, we show that H₂O₂ inactivates the SARS-CoV-2 infectivity and establish the effective concentration of this activity. Cryogenic electron tomography and sub-tomogram averaging reveal a detailed structural understanding of how H₂O₂ affects the SARS-CoV-2 spike in comparison with that of the commonly used fixative PFA under identical conditions. We found that PFA promoted a post-fusion conformation of the viral spike protein, while H₂O₂ could potentially lock the spike in its pre-fusion state. Our findings not only substantiate the disinfectant efficacy of H₂O₂ as a potent agent against SARS-CoV-2 but also lay the groundwork for future investigations into targeted antiviral therapies that may leverage the virus' structural susceptibilities. In addition, this study may have significant implications for developing new antiviral strategies and improving existing disinfection protocols.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":"16 5","pages":"e0399424"},"PeriodicalIF":5.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077155/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144044002","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":"Synergistic induction of PGE2 by oral pathogens and TNF promotes gingival fibroblast-driven stromal-immune cross-talk in periodontitis.","authors":"Elwira Nieboga, Aureliusz Schuster, Dominika M Drapala, Mariia Melnykova, Aleksander Gut, Weronika Lipska, Mateusz Kwitniewski, Marcin Migaczewski, Marta Czesnikiewicz-Guzik, Tomasz Kaczmarzyk, Jan Potempa, Aleksander M Grabiec","doi":"10.1128/mbio.00046-25","DOIUrl":"10.1128/mbio.00046-25","url":null,"abstract":"<p><p>The interaction between pathogenic microorganisms and stromal cells, in particular fibroblasts, significantly contributes to the pathogenesis of many bacterially driven diseases. In periodontitis, oral pathogens penetrate the epithelial barrier and aggravate ongoing gingival inflammation by promoting the production of inflammatory mediators, such as prostaglandin E2 (PGE2). This study aimed to investigate the functional consequences of the interplay between oral pathogens and a pro-inflammatory environment in the activation of the PGE2 pathway in primary human gingival fibroblasts (GFs). GF infection with <i>Fusobacterium nucleatum</i>, <i>Porphyromonas gingivalis,</i> or <i>Filifactor alocis</i> in the presence of tumor necrosis factor (TNF) led to synergistic induction of cyclooxygenase-2 (COX-2), a key enzyme in the PGE2 synthesis pathway, as well as secretion of PGE2. A similar synergy in COX-2 upregulation was observed upon GF infection with oral pathogens in the presence of IL-1α, IL-1β, and interferon-α (IFN-α). This effect required toll-like receptor-2 (TLR2) and the p38 MAP kinase activation and was specific for fibroblasts as infection of macrophages or keratinocytes with oral pathogens in the proinflammatory environment did not cause synergistic COX-2 induction. Finally, we demonstrated that conditioned media from GFs infected with <i>F. nucleatum</i> under inflammatory conditions amplified the expression of the neutrophil chemokine <i>IL8</i> in macrophages and confirmed that this effect was mediated by synergistic induction of PGE2 in GFs. Collectively, we identify a new mechanism of stromal-immune cross-talk that is driven by synergistic PGE2 induction by oral pathogens and inflammatory cytokines in GFs and may contribute to excessive macrophage activation and neutrophil infiltration in periodontitis.IMPORTANCEPeriodontitis is a highly prevalent, dysbiosis-driven chronic inflammatory disease that not only leads to tooth loss but also is associated with severe systemic diseases. In this work, we describe a novel mechanism responsible for excessive production of PGE2, which is a potent inflammatory mediator that significantly contributes to the pathogenesis of periodontitis. We found that infection of GFs with many species of oral pathogens in the presence of inflammatory cytokines produced by the host leads to synergistic induction of COX-2 expression and PGE2 production. We found that this fibroblast-specific amplification of the COX-2-PGE2 axis by oral pathogens and cytokines is driven by the p38 MAP kinase and promotes enhanced expression of a key neutrophil chemokine by macrophages. These studies have thus enabled the identification of a new mechanism of host-pathogen interactions in periodontitis, improving our understanding of the roles of GFs and their cross-talk with immune cells in disease pathogenesis.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0004625"},"PeriodicalIF":5.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077116/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143772643","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":"RIG-I and cGAS mediate antimicrobial and inflammatory responses of primary osteoblasts and osteoclasts to <i>Staphylococcus aureus</i>.","authors":"Erin L Mills, Samantha R Suptela, Mary-Kate Key, Ian Marriott, M Brittany Johnson","doi":"10.1128/mbio.03971-24","DOIUrl":"10.1128/mbio.03971-24","url":null,"abstract":"<p><p><i>Staphylococcus aureus</i> is the primary causative agent of osteomyelitis, and it is now apparent that osteoblasts and osteoclasts play a significant role in the pathogenesis of such infections. Their responses can either be protective or exacerbate inflammatory bone loss and are mediated by the recognition of microbial motifs by various pattern recognition receptors. We have recently reported that osteoblasts can respond to <i>S. aureus</i> challenge with the production of the type I interferon, interferon-beta, which can reduce the number of viable bacteria harbored within infected cells. In the present study, we demonstrate that <i>S. aureus</i> viability and internalization are necessary for maximal inflammatory cytokine and type I interferon responses of primary bone cells to this pathogen. Importantly, we show that primary murine and human bone cells constitutively express the cytosolic nucleic acid sensors, retinoic acid inducible gene I (RIG-I) and cyclic GMP-AMP synthase (cGAS), and demonstrate that such expression is markedly upregulated following <i>S. aureus</i> infection. The functional status of RIG-I and cGAS in osteoblasts and osteoclasts was confirmed by showing that specific ligands for each can also elevate their expression and induce cytokine responses. We have verified the specificity of such responses using siRNA knockdown or pharmacological inhibition and used these approaches to demonstrate that both sensors play a pivotal role in bone cell responses to infection with clinically relevant strains of <i>S. aureus</i>. Finally, we have begun to establish the biological significance of RIG-I- and cGAS-mediated bone cell responses with the demonstration that their attenuation increases <i>S. aureus</i> burden in infected cells, suggesting a potentially protective role for these sensors in osteomyelitis.IMPORTANCEStaphylococcal osteomyelitis is a severe infection that is often recalcitrant to current treatment strategies. We and others have demonstrated that resident bone cells are not merely passive victims but can respond to bacteria with the production of an array of immune mediators, including type I interferons, that could serve to limit such infections. Here, we demonstrate the functional expression of two cytosolic nucleic acid sensors, retinoic acid inducible gene I and cyclic GMP-AMP synthase, in primary murine and human osteoblasts and murine osteoclasts. We show that these pattern recognition receptors mediate potentially protective bone cell type I interferon responses to <i>Staphylococcus aureus</i> infection.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0397124"},"PeriodicalIF":5.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077190/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143710608","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}