Frontiers in Cellular and Infection Microbiology最新文献

Background: Vancomycin-resistant Enterococcus faecium and Enterococcus faecalis (VRE) are increasingly recognized as major opportunistic pathogens in immunocompromised patients, where they may cause bloodstream infections (BSIs). The present study aimed to characterize a cohort of immunocompromised patients colonized or infected with VRE, performing genomic analysis of these isolates. Additionally, we investigated the impact of bacterial culture supernatants on Caco-2 epithelial cells, focusing on adhesion and cytotoxicity to elucidate mechanisms related to epithelial dysfunction and bacterial translocation.

Methods: We conducted a retrospective study including 46 VRE from two Italian hospitals. Clinical and epidemiological data were collected, and isolates were characterized by antimicrobial susceptibility testing and whole-genome sequencing. Four representative isolates (E. faecium ST80, E. faecium ST117, E. faecalis ST28, and E. faecalis ST179) and two reference strains (ATCC 29212™ and ATCC 51299™) were selected for in vitro analyses. Adhesion to Caco-2 monolayers was quantified, while cytotoxicity was assessed using MTT assays with bacterial cell-free supernatants (CS). Hydrogen peroxide (H₂O₂) production was measured using the Amplex^® Red Hydrogen Peroxide/Peroxidase Assay Kit.

Results: The majority of isolates were E. faecium (78.3%), predominantly ST80 and ST117, possessed multiple resistance determinants. E. faecalis isolates displayed greater sequence type diversity with a ST28 predominance, carrying virulence genes as ebp, gelE, and elrA. In vitro, bloodstream-derived isolates (E. faecium 51, E. faecalis 52) and reference strain ATCC 29212™ adhered more strongly to Caco-2 cells than other isolates. CS from invasive isolates and ATCC 51299™ significantly reduced epithelial cell viability at 24 h (p < 0.01). In these isolates, H₂O₂ higher quantification was documented in a cellular model.

Discussion: Our findings highlighted the convergence of antimicrobial resistance and virulence traits in VRE, alongside functional evidence of strain-dependent adhesion and secretion of cytotoxic metabolites. Elevated H₂O₂ production provides a possible path between enterococcal secretomes and epithelial injury, suggesting oxidative stress as a contributor to epithelial dysfunction and potential translocation. These insights expand current understanding of VRE pathogenesis and point to novel therapeutic approaches aimed at preserving epithelial integrity and mitigating oxidative damage in high-risk patients.

Enterovirus A71 (EV-A71) is one of the main pathogens causing hand, foot, and mouth disease (HFMD), and this virus exhibits substantial genetic diversity. To clarify its genomic evolutionary features, this study conducted a phylodynamic analysis on EV-A71 viruses collected in Qingdao (a northern Chinese city) between 2023 and 2024. EV-A71 was identified using a commercial real-time quantitative PCR (qPCR) assay; EV-A71-positive samples were then inoculated into rhabdomyosarcoma (RD) cells for virus isolation. The complete genome sequences and VP1 gene sequences of EV-A71 strains were amplified and analyzed, with IQ-TREE, SimPlot, and RDP4 software used to evaluate their evolutionary characteristics. Among 2,083 clinical samples, 27 were EV-A71-positive, with 19 isolates successfully cultured. Whole-genome analysis confirmed the co-circulation of EV-A71 genotypes C4 (5 strains) and B5 (14 strains). The C4 strains showed high homology to a strain isolated in China in 2019 and carried six lineage-specific mutations. In contrast, the B5 strains clustered into two distinct lineages, including recombinants that had undergone genetic recombination with coxsackievirus A4 (CV-A4) and coxsackievirus A2 (CV-A2). Notably, all EV-A71 strains collected from Qingdao maintained a serine (S) at the 17th amino acid residue of the VP1 region. This work enhances our understanding of the geographical distribution of EV-A71 by confirming the sustained circulation of genotype B5 in northern China and identifying a novel C4/B5 co-circulation pattern in Qingdao-a pattern reflecting complex local evolutionary dynamics. It emphasizes expanding genomic sequencing coverage to monitor B5 and recombinant strains, refining surveillance, and guiding HFMD prevention and control.

Drug-induced liver injury (DILI) remains a major obstacle in clinical pharmacotherapy and a leading cause of acute liver failure and drug withdrawal worldwide. Conventional mechanistic models centered on hepatic xenobiotic metabolism, oxidative stress, and immune injury cannot fully account for the substantial interindividual variability and the unpredictable nature of idiosyncratic DILI. Increasing evidence shows that the gut microbiota and its metabolites critically shape hepatic susceptibility through modulation of drug metabolism, inflammatory signaling, and intestinal barrier integrity. This review summarizes current understanding of the gut-liver axis in DILI pathogenesis, with a focus on microbial enzymes such as β-glucuronidase that reactivate detoxified drug conjugates, microbial dysbiosis that disrupts bile acid homeostasis, and depletion of short chain fatty acids and indole derivatives that normally support epithelial defenses and immunologic tolerance. Drug-specific microbial patterns are discussed, including acetaminophen, amoxicillin-clavulanate, anti-tuberculosis regimens, and immune checkpoint inhibitors. We introduce the concept of metabotype-dependent hepatotoxicity, which emphasizes that individual microbial metabolic profiles influence DILI risk. Advances in metagenomics, metabolomics, and integrative multi-omics enable the identification of microbial biomarkers and functional pathways associated with DILI susceptibility. Emerging therapeutic strategies include restoration of microbial homeostasis, selective inhibition of microbial enzymes, and supplementation of hepatoprotective metabolites. Finally, we outline key challenges and future directions toward translating microbiome-based insights into clinical prediction and precision prevention of DILI. Importantly, this review integrates microbial metabolic functions with precision hepatology concepts, highlighting how metabotype-driven variability can be leveraged for individualized DILI risk assessment.

Periodontal disease (PD) is one of the most prevalent chronic oral diseases globally, characterized by chronic inflammatory responses in the gingiva and supporting periodontal tissues. Recent epidemiological and mechanistic studies have indicated that PD not only adversely affects oral health but is also significantly associated with gastric and colorectal cancers. This article reviews the potential link between PD and these gastrointestinal malignancies, exploring the underlying pathogenic mechanisms and potential strategies for preventing and treating gastric and colorectal cancers through the management of PD. Periodontal health management may represent an adjunct avenue for the prevention and control of gastrointestinal cancers; however, high-quality longitudinal and interventional studies are needed to clarify causality.

Objectives: Leishmaniasis is a vector-borne neglected tropical infectious disease hat can be fatal if visceral leishmaniasis is left untreated. At present, many drugs have been used to treat leishmaniasis. This study aims to compare the efficacy and safety of different drugs to treat leishmaniasis through a network meta-analysis.

Methods: All studies were retrieved from PubMed, Embase, and Cochrane databases, and the search time was from the date of database establishment to February 21, 2024. We assessed rates of clinical cure, mortality, and adverse effects (diarrhea, vomiting, injection site pain, and liver-enzyme abnormalities). We performed subgroup analyses of rates of clinical cure according to geographic region. All statistical analyses were performed using R and STATA 14.0 software for network meta-analysis. PROSPERO registration number: CRD42023478585.

Results: 12 articles with 2483 patients were included in this study, and the therapeutic effects of 5 drugs were evaluated. The results of the network Meta-analysis showed that the clinical cure rate of miltefosine, pentavalent antimony, and paromomycin was inferior to amphotericin B (RR 0.31; 95%CI 0.07-11.4, RR 0.23; 95%CI 0.04-1.39, RR 0.12; 95% CI 0.01-1.55), and amphotericin B may have the highest clinical cure rate. The mortality of pentavalent antimony was higher than that of amphotericin B and miltefosine (RR 4.81; 95%CI 0.42-41.45, RR 3.75; 95% CI 0.57-24.74), pentavalent antimony may be the drug with the highest mortality during treatment. About adverse effects, vomiting, and diarrhea were most common with miltefosine, and pain at the injection site and abnormalities in aspartate aminotransferase and alanine aminotransferase were most common with paromomycin. Subgroup analysis showed that clinical cure rates using Pentavalent antimony treatment were better in Brazil than in Ethiopia and India.

Conclusions: This systematic review and network meta-analysis provide a new comparative framework for the clinical management of leishmaniasis. The results of network meta-analysis suggest that amphotericin B may be the first choice for the treatment of leishmaniasis, pentavalent antimony may be the drug with the highest mortality during treatment, miltefosine causes the highest incidence of gastrointestinal reactions, and paromomycin causes the highest incidence of injection site pain, aspartate aminotransferase, and alanine aminotransferase abnormalities. More high-quality studies are still needed to further determine the optimal drug for the clinical treatment of leishmaniasis in the future.

Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023478585.

Understanding the immunoregulatory mechanism during cytomegalovirus (CMV) infection may help to combat CMV reactivation in immunocompromised or immunosuppressed individuals. Here we developed a CMV infection model in immunocompetent Sprague Dawley (SD) rats with Priscott strain and explored the cross-talk between autophagic dynamics and metabolism alterations in CD8⁺ T cells post infection. We previously found that primary CMV infection induced a remarkable increase of CD8⁺ T cells which reached the peak around week 3 and returned to pre-inoculation status since week 6 post viral infection. In this study, our results demonstrated that the autophagic activity of CD8⁺ T cells was augmented at week 3 while decreased at week 6, which was closely associated with the up- (week 3 and 4) or down-regulation (since week 6) of metabolic markers ENTPD1 and SLC27A2. Furthermore, the in vitro study showed that the levels of these metabolic markers in rat splenocytes were modulated by autophagy inhibitors and enhancers. Our study indicated that the dynamic alterations of autophagy exerted a critical role in regulating the metabolic adaptation of CD8⁺ T cells during CMV infection process, and provides an ideal animal model for further research on the pathological mechanisms based on CMV latency.

Background: Lymphatic filariasis, caused by Wuchereria bancrofti, Brugia malayi, and Brugia timori, is transmitted by mosquitoes and persists as a major neglected tropical disease. Despite extensive elimination campaigns, information on vector infection prevalence remains fragmented, hindering evidence-based vector control strategies under the World Health Organization's Global Programme to Eliminate lymphatic filariasis.

Methods: A systematic review and meta-analysis was performed in accordance with PRISMA guidelines. Six databases (PubMed, Web of Science, ScienceDirect, CNKI, VIP, Wanfang) were searched up to April 2025. Eligible studies reported mosquito infection rates with defined sample size, location, and diagnostic method. Study quality was appraised using the Joanna Briggs Institute checklist for prevalence studies. Statistical synthesis was conducted in R (v4.1.2) using random-effects models. Subgroup analyses and meta-regression explored heterogeneity by region, mosquito genus, and detection method.

Results: Eighteen studies covering 160,423 mosquitoes from 10 countries were included. The pooled infection prevalence was 0.7% (95% CI [0.3-1.7]). Rates were highest in Asia (3.0%, 95% CI [0.0-10.7]), in Mansonia spp. (2.5%, 95% CI [0.8-4.9]), and when RT-PCR was applied (2.5%, 95% CI [0.0-11.0]). Higher prevalence was associated with post-2016 studies (1.9%), areas without mass drug administration programmes (1.7%), and regions with annual mean temperatures of 23-27 °C (5.2%). Considerable heterogeneity (I² = 100%) and publication bias (Egger's test, p = 0.006) were evident.

Conclusions: Filarial infections in mosquitoes remain widespread, with clear regional and methodological variability. Strengthened mosquito-based xenomonitoring, particularly using molecular diagnostic approaches, will be essential to accelerate progress toward global lymphatic filariasis elimination by 2030.

Background: Hypoxia is a hallmark of many diseases, including periodontitis, where it influences the immune cell behavior. In low-oxygen conditions, macrophages shift toward glycolytic metabolism, altering their phenotype and function, However, it remains unclear how these functional changes affect the interaction between macrophages and oral bacteria in the hypoxic environment of infectious tissue.

Methods: In this study, which focused on periodontitis, we addressed this gap by investigating how a physiologically relevant low oxygen tension (2% O₂) compared with normoxia (20% O₂) modulates the metabolism, morphology, migration, and interaction of macrophages with both commensal and pathogenic oral bacteria.

Results: Hypoxia activated the hypoxia-inducible factor-1 alpha (HIF-1α) signaling pathway, induced glycolytic metabolism, reduced proliferation, and led to a rounded morphology with amoeboid migration characteristics. Despite reduced mobility, hypoxic macrophages maintained their phagocytic capacity and effectively limited the intracellular proliferation of Streptococcus oralis and Porphyromonas gingivalis. Hypoxia also altered the cytokine profiles, with increased interleukin-1 beta (IL-1β) and IL-10, reduced tumor necrosis factor alpha (TNF-α), and enhanced reactive oxygen species production.

Conclusion: These findings highlight the plasticity of macrophages in adapting to low-oxygen environments and underscore their potential role in host defense and inflammation resolution in periodontal disease. The modulation of these responses may inform novel therapeutic approaches targeting hypoxia-associated immune dysfunction.

Neutrophils, as the predominant effector cells of innate immunity and the first line of defense at the oral mucosal barrier, play pivotal yet complex roles in both immune defense and pathological damage within the unique oral environment. The oral mucosa, continuously exposed to physical, chemical, and dense microbial challenges, necessitates a dynamic and robust immune response. Recent evidence highlights that neutrophils are not merely transient defenders but key regulators whose functions are profoundly shaped by the specific milieu of the oral cavity, differing significantly from other mucosal sites. However, the precise mechanisms by which neutrophils contribute to the pathogenesis of various oral mucosal diseases (OMDs), beyond their established role in barrier defense, remain inadequately synthesized and understood. This article systematically reviews the mechanisms underpinning neutrophil-mediated immune defense in the oral mucosa and critically summarizes their documented involvement in major OMDs, including oral candidiasis, recurrent aphthous ulcer, Behçet's disease, and oral potentially malignant disorders/cancer. By elucidating the unique interplay between oral environmental cues (microbiota, function, systemic factors) and neutrophil behavior, this review aims to provide novel insights into the immunopathogenesis of OMDs and inform future translational research targeting neutrophil function.