Search Results (12,731)

Herpes simplex virus type 2 (HSV-2) is the primary pathogen responsible for genital herpes. Predominantly transmitted via sexual contact, HSV-2 not only poses significant physical and psychological burdens on infected individuals but also substantially elevates the risk of HIV acquisition and represents a potentially fatal threat to newborns. Following primary infection, HSV-2 establishes lifelong latent infection within the sacral ganglia. Currently, there are no vaccines or therapeutics capable of eradicating this latent virus reservoir or effectively preventing initial infection. The core impediment to developing such interventions lies in the incomplete elucidation of the protective immune mechanisms against HSV-2 and its precise molecular pathogenesis. The host immune response against HSV-2 hinges critically on the coordinated interplay between innate and adaptive immunity. The innate immune system, serving as the first line of defense, acts to curtail early viral replication and initiate adaptive responses. This is achieved through mechanisms, including the genital mucosal barrier, activation of Toll-like receptors (TLRs), the cGAS-STING signaling pathway, interferon (IFN)-mediated antiviral effector functions, and activation of innate immune cells such as natural killer (NK) cells and dendritic cells (DCs). Crucially, however, HSV-2 counteracts these host defenses by expressing immune modulatory proteins (e.g., ICP0, ICP27, ICP35) that target key host antiviral signaling pathways, thereby affecting immune evasion. Within the adaptive immune response, neutralizing antibodies generated by the humoral immunity can provide localized protection at mucosal sites, but their protective efficacy is limited due to sophisticated viral immune evasion mechanisms. Cellular immunity, particularly mediated by CD4+ T cells, constitutes the core mechanism for viral clearance and suppression of recurrent outbreaks. Notably, tissue-resident memory T cells (TRMs) play a pivotal role in controlling the reactivation of latent HSV-2 within the ganglia. This review integrates current research advances to delineate the innate and adaptive immune mechanisms engaged during HSV-2 infection from the perspective of the dynamic host–virus interplay, with an ultimate aim to provide a theoretical foundation informing the rational development of preventive vaccines and therapeutic agents against HSV-2. Full article

Human papillomavirus (HPV), especially high-risk HPV types, is a significant public health concern due to its association with various cancers and increased risk of acquiring other sexually transmitted infections (STIs). In most cases, host immunity rapidly responds to and clears HPV infections, but persistent or latent infections can increase susceptibility to cancer. A better understanding of how HPV interacts with and evades the immune response is vital to understanding disease progression and guiding the next generation of vaccines and immunotherapies. This review article provides a comprehensive overview of the immune mechanisms involved in HPV infection, highlighting the roles of T cells and other immune subsets. We discuss the immune evasion strategies employed by HPV and subsequent modulation of the immune microenvironment. Additionally, we explore the current therapeutic landscape and emerging immunotherapeutic approaches under investigation. By unveiling the intricacies of the immune response to HPV, we may inform improved strategies for the treatment of HPV-related diseases. Full article

Listeria monocytogenes (LM) is a major foodborne pathogen causing illnesses ranging from gastroenteritis to severe systemic infections. The key virulence factors include bacterial motility, hemolysin and lecithinase production, and invasion of host tissues. This study investigated the anti-virulence effects of cannabidiol (CBD), the main non-psychoactive compound in Cannabis sativa, against LM. The minimum inhibitory concentration (MIC, 2289 μM; 719.8 µg/mL) and sub-inhibitory concentration (SIC, 11.92 μM; 3.75 µg/mL) of CBD were determined for LM strains Scott A and ATCC 19115. Cultures were treated with SIC, 6× SIC, 1/4× MIC, and MIC to assess effects on motility, hemolysin and lecithinase production, and adhesion and invasion of human intestinal (Caco-2) and brain endothelial (HBMEC) cells, alongside virulence gene expression by RT-qPCR. Cannabidiol’s efficacy was also determined using a Galleria mellonella larval infection model at SIC and 6× SIC. Cannabidiol at 6× SIC significantly reduced motility, toxin production, and host cell adhesion and invasion (p < 0.05). RT-qPCR revealed downregulation of key virulence genes, including prfA, hly, plcA, plcB, iap, motA, motB, actA, inlA, and inlB. In vivo, CBD enhanced larval survival in a dose-dependent manner and cytotoxicity was observed at concentrations above 33.75 µg/mL. These results indicate that CBD, at non-bactericidal levels, effectively suppresses multiple virulence mechanisms in LM, highlighting its potential as a novel anti-virulence agent for food safety and therapeutic applications. Full article

The interaction between Angiostrongylus vasorum and the vascular endothelium of the host plays a key role in the pathogenesis of canine angiostrongylosis. The adult stage of A. vasorum resides in right ventricles and pulmonary arteries of dogs and foxes and maintains close contact with the endothelium, whose activation may contribute to the hemostatic and hemorrhagic disorders observed in infected animals. However, the molecular mechanisms underlying this endothelial dysfunction remain poorly understood. To investigate this interaction, an in vitro model of vascular endothelial cells was stimulated with the adult A. vasorum homogenate. Quantitative proteomic analysis, combined with bioinformatic tools, identified 691 and 6011 protein groups in the cell supernatants and the cell lysates, respectively. Of these, 213 proteins in the cell supernatants (193 up-regulated and 20 down-regulated) and 564 in the cell lysates (358 up-regulated and 206 down-regulated) showed differential expression compared to control cells. Up-regulated proteins included TFPI, CD59, VWF, ANGPT2, MMRN1, and FLT1, which are involved in endothelial activation, angio-genesis, and coagulation regulation. Conversely, C3, SERPINE1, SERPINB2, PLAU, PLAUR, and ICAM1 were down-regulated, suggesting modulation of fibrinolysis, inflammation, and cell adhesion pathways. These findings indicate that adult A. vasorum homogenate induces a multifactorial endothelial activation characterized by dysregulation of coagulation, complement, and vascular remodelling pathways. Future studies focusing on the temporal and molecular characterization of endothelial responses to excretory/secretory antigens in both definitive and accidental hosts will further clarify the mechanisms of vascular pathology and parasite tolerance. Full article

Three new cyclic tetrapeptides (nectriatidels A-C, 1–3), two new curvularin analogs (6 and 7), and four known compounds (4 and 5, 8 and 9) were isolated from the marine-derived fungal-bacterial symbiont Aspergillus spelaeus GXIMD 04541/Sphingomonas echinoides GXIMD 04532, which was obtained from Mauritia arabica in shallow coastal waters. Their structures were elucidated through NMR spectroscopy and HRESIMS, and their absolute configurations were determined by Marfey’s method and quantum chemical calculations. Compounds 1–5 showed moderate amphotericin B (AmB)-potentiating activity against Candida albicans. Compounds 7 and 8 exhibited significant activities against Mycobacterium tuberculosis, with MIC values of 32 and 16 μg/mL, respectively. Additionally, compounds 7 and 8 exhibited moderate cytotoxicity against human colorectal cancer cell lines DLD-1 and SW480, with IC₅₀ values of 25~36 μM. Whole-genome sequencing of A. spelaeus revealed a 35.91 Mb assembly encoding 106 biosynthetic gene clusters (BGCs). antiSMASH analysis revealed that 79 of these BGCs (74.5%) displayed no significant similarity to known pathways in the MIBiG database, which is dominated by hybrid clusters, terpene, T1PKS, NRPS, and NRPS-like types. Genomic analysis identified the putative biosynthetic gene clusters for these metabolites and confirmed the fungal host as the predominant producer. Full article

Brucella is a neglected foodborne pathogen, which contaminates milk, dairy products, meat, and meat products of infected animals. However, the role of the Brucella putative effector (BPE) protein family, which relies on the type IV secretion system (T4SS) in Brucella abortus, remains unclear. We demonstrated that BPE159 mediates the regulation of host nuclei in autophagy. The host-interacting protein Eci1 was screened using yeast two-hybridization, molecular docking, and immunoprecipitation, and BPE159-deleted (ΔBPE159) and complementary (ΔBPE159-C) strains were constructed by homologous recombination. We evaluated their growth, survival, and replication and measured the expression of autophagy-related cytokine mRNAs in macrophages. BPE159 was localized in the nucleus of host cells and interacted with Eci1 to downregulate the expression of macrophage autophagy factors, thereby inhibiting host autophagy and enabling the persistence of Brucella. These findings highlight the critical role of BPE159 in mediating autophagy through Eci1 in host cells to promote Brucella survival in host cells. Full article

Sepsis is a life-threatening syndrome characterized by dysregulated host responses to infection. In addition to early hyperinflammation, many patients develop profound immune suppression, and multiple targeted immunotherapies have failed to improve outcomes, highlighting the need for actionable biomarkers and new therapeutic strategies. Here, we integrated metabolomic and transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) and splenocytes in rat models of polymicrobial sepsis to identify metabolites associated with immune dysfunction. Candidate findings were validated using in vivo supplementation studies and in vitro functional assays, and clinical relevance was assessed in PBMCs from patients with sepsis and healthy volunteers. Across omics datasets, intracellular aspartate (ASP) was consistently reduced in immune cells during sepsis and was associated with features of immune paralysis. Supplementation with L-ornithine L-aspartate (LOLA), an ASP source, improved survival in septic rats, enhanced bacterial clearance, and mitigated acute kidney injury. In vitro, pharmacologic or genetic disruption of ASP production impaired phagocytosis and cytokine responses, which were partially rescued by ASP supplementation. Consistently, patients with sepsis exhibited lower intracellular ASP levels in PBMCs than healthy volunteers. Together, these results support a critical role for ASP in maintaining immune competence during sepsis and suggest that intracellular ASP may serve as a biomarker of immune suppression and a potential therapeutic target. Full article

This study demonstrates that the ericoid mycorrhizal (ERM) fungus RM2 can colonize the non-ericaceous host Malus robusta as a functional endophyte, enhancing drought resilience through an active avoidance strategy. Under drought, inoculation was associated with qualitative changes in root growth patterns, and inoculated seedlings showed a more extensive and branched root appearance compared with non-inoculated controls. This morphological tendency was accompanied by a distinctive physiological state of oxidative priming, characterized by elevated H₂O₂ as a signaling molecule, reduced antioxidant enzyme activity, and a marked shift toward proline-mediated osmotic adjustment. Transcriptomic analysis suggested a molecular basis for these responses: endophytic colonization reprogrammed auxin and brassinosteroid signaling, including the repression of auxin inactivation (GH3) and activation of genes involved in auxin transport (AUX1) and cell wall loosening (TCH4), which is consistent with sustained root growth under drought. Our findings indicate that ERM fungi can transcend traditional host barriers and improve drought performance via integrated oxidative signaling and hormonal regulation, highlighting their potential as cultivable biostimulants for sustainable horticulture. Full article

Rapid responses to environmental changes are essential for maintaining fitness. In pathogenic fungi such as the dermatophyte Trichophyton interdigitale, appropriate responses to environmental shifts determine successful infection. Transcriptional regulation and alternative splicing (AS) are key modulators of fungal adaptation and pathogenesis. Here, we validated the role of the transcription factor PacC in coordinating AS in T. interdigitale grown in infection-mimicking medium. RNA-seq analysis of a ΔpacC mutant revealed a predominance of intron retention events, mainly involving introns 1 and 2, indicating defective splicing and potential nonsense-mediated decay of genes related to ion transport, metabolism, and genome maintenance. These alterations compromised energy balance, ergosterol biosynthesis, and cellular homeostasis. PacC-dependent AS generated alternative isoforms of cytoskeletal and metabolic proteins, including myosin-1 and a GH3 β-glucosidase, potentially modulating enzymatic activity, metabolic burden, and cell wall remodeling during infection. Exon-skipping in the chromatin remodeler RSC1 suggests PacC involvement in epigenetic regulation under host-mimicking conditions. Transmission electron microscopy revealed possible Woronin bodies, cytoplasmic disruption, and cell wall thinning in the mutant. Overall, PacC integrates transcriptional and post-transcriptional regulation to promote adaptation, survival, and virulence, highlighting AS as a regulatory layer linking environmental sensing to metabolic and epigenetic plasticity in pathogenic fungi. Full article

Background/Objectives: The large size of commonly used regulatory elements such as the cytomegalovirus (CMV) immediate-early promoter imposes a significant burden on the already restricted payload capacity of first-generation adenoviral vectors, potentially hindering the development of multi-antigen vaccine candidates. To address this limitation, we have engineered a panel of novel, small, semi-synthetic promoters designed to leverage the changes in transcriptomic milieu following adenoviral vector entry. Methods: Eight synthetic enhancer modules (SE1–SE8) were designed in silico, each composed of transcription factor binding sites (TFBSs) previously found in host genes that are upregulated during early adenoviral infection. These synthetic enhancers were coupled with a minimal CMV core promoter to generate a panel of compact semi-synthetic promoters (cSE1–cSE8), and their activity was evaluated in the context of ChAdOx1 viral vectors expressing GFP or a modified Plasmodium falciparum circumsporozoite (CSN) antigen. Promoter performance was characterised in vitro via flow cytometry, RT-qPCR, and Western blotting, and in vivo by quantifying antigen-specific T-cell (IFN-γ ELISpot) and IgG antibody (ELISA) responses in BALB/c mice. Results: In vitro characterisation revealed a wide range of promoter activity across the panel, with cSE3 and cSE5 driving transgene expression levels comparable to the benchmark CMV promoters despite their markedly reduced genomic footprint. In vivo, ChAdOx1 vectors incorporating cSE3 and cSE5 elicited potent antigen-specific T-cell and IgG responses that were comparable to those induced by the larger CMV control promoters. Conclusions: We have successfully developed semi-synthetic promoters that match the potency of the much larger, frequently used CMV promoters whilst simultaneously reducing genomic footprint. These novel regulatory elements will facilitate the design of next-generation vaccines, particularly those requiring large antigens or multi-antigen cassettes. Full article

The field of immunometabolism highlights the intricate interplay between immunity and metabolism. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a central component of innate immunity that detects double-stranded DNA (dsDNA) from a range of sources, including pathogenic and host-derived DNA. It is now recognized that the cGAS-STING pathway has broad implications in a variety of human conditions including cancer, age-related diseases, and autoimmune disorders. Given the abundance and diversity of lipids across cellular compartments serving as structural components and signaling molecules, it is unsurprising that lipid metabolism influences the regulation of cGAS-STING signaling. Lipids can directly alter signaling protein dynamics through interactions within membrane compartments, while alterations in lipid metabolism can remodel multiple cell-intrinsic signaling cascades. Here, we summarize emerging concepts and recent discoveries that have advanced our understanding of how lipid metabolism and lipids regulate the cGAS-STING pathway. Full article

Background/Objectives: The mycobacterial complex cell envelope serves as a formidable barrier against host immunity and antibiotics. Lipomannan (LM) and lipoarabinomannan (LAM) are key structural components of the mycobacterial envelope and potent immunomodulators. The mycobacterial lipoarabinomannan biosynthesis mannosyltransferase MptC modifies the multiple α-(1→2)-linked branched mannan residues of LAM in the mycobacteria. However, the role of MptC in mycobacterial infectivity, antibiotic susceptibility and host immune regulation remains poorly understood. Methods: An mptC (also named MSMEG_4247) knockout Mycobacterium smegmatis mc²-155 (M. smeg) strain (designated as M. smegΔmptC) was generated using CRISPR–Cas12a technology. The effects of MptC on bacterial physiology, cell wall permeability, drug sensitivity, immune cell function, and survival during infection are analyzed through glycogen staining, drug sensitivity tests, and cellular and mouse infection models. Results: MptC deficiency results in a loss of LM and increase in LAM synthesis. The M. smegΔmptC mutant strain exhibits enhanced cell wall permeability and reduces hydrophobicity. Functionally, the mptC knockout strain increases the intracellular cytokines (IFN-γ, TNF-a and IL-17) production of T cells in mice. Consequently, results based on both macrophage and mouse infection models demonstrate that the M. smegΔmptC strain has less bacterial loads and higher susceptibility to antibiotic rifampicin. Conclusions: Mannosyltransferase MptC plays an important role in maintaining cell wall integrity (via LM/LAM synthesis), regulating T cell responses, and influencing antibiotic susceptibility in mycobacteria. Full article

Epstein–Barr virus (EBV) is a human pathogenic and oncogenic herpesvirus, with worldwide importance, at times associated with serious to life-threatening symptoms, especially in immunocompromised hosts. The available preventive options against EBV disease are limited to medically elaborate and cost-intensive measures of cell-based immunotherapy. The development of novel options of anti-EBV drug targeting is currently a matter of intense international efforts. A putative target of the antiviral therapy approach is the EBV-encoded protein kinase BGLF4, which fulfills a multifaceted role in productive viral replication. So far, viral BGLF4 interactor proteins and phosphorylated substrates have occasionally been reported, but in particular cellular interactors await further characterization concerning both, their relevance for BGLF4 functionality and their accessibility to antiviral drugs. In this study, we have analyzed host cell–BGLF4 interaction, BGLF4 kinase properties, and BGLF4-directed small molecules. The main results are as follows: (i) a mass spectrometry-based interactomic study was performed with EBV-producing Akata-BX1 cells, thereby identifying the human pyruvate dehydrogenase (PDH) as a relevant BGLF4 interactor; (ii) BGLF4–PDH interaction was confirmed by protein coimmunoprecipitation, subcellular cofractionation, and confocal imaging; (iii) the BGLF4-mediated phosphorylation of PDH was demonstrated by an in vitro kinase assay (IVKA); (iv) a reduction in PDH phosphorylation was shown for selected kinase inhibitors, which also exerted BGLF4-directed inhibitory potential in a quantitative qSox-IVKA, and (v) these hit compounds showed anti-EBV activity in lytically induced P3HR-1 cells using qPCR measurement, as well as PDH-inhibitory activity using standardized PDH assays. These data lead to an improved understanding of EBV–host interaction that may open novel anti-EBV preventive opportunities. Combined, the findings point to PDH as a new cellular interactor of the EBV kinase BGLF4. Also, notably, the data on pharmacological intervention with kinase activity or substrate phosphorylation may possibly provide as yet untapped options of antiviral drug targeting. Full article

Background/Objectives: Extracellular vesicles (EVs) derived from probiotics represent a new and exciting frontier in host-microbe therapeutics. These nanoscale carriers are not merely cellular byproducts but are sophisticated mediators of intercellular communication, capable of modulating immune responses, reducing inflammation, and inhibiting pathogens through a rich cargo of bioactive molecules. Methods: The EVs isolated from the culture supernatants of the yeast probiotic candidate Pichia kudriavzevii were characterized for their dimensions, protein composition, and targeting both the gut pathogen virulence and the host inflammatory response. Results: The vesicles had a size distribution from 100 to 150 nm, which is consistent with previous reports on fungal EVs. Proteomic analysis of the purified EVs identified a complex array of 189 proteins, hypothesized to be responsible for some of the antimicrobial and immunomodulatory properties observed. Safety was a key consideration, and the isolated EVs demonstrated no cytotoxicity in human Caco-2 cells and no in vivo toxicity in the Galleria mellonella larval model, confirming their potential for safe use. Conclusions: The field is moving towards a new era of “postbiotics,” where cell-free therapies offer a safer, more stable alternative to live probiotics. Full article

Human immunodeficiency virus type 1 (HIV-1) is a retrovirus that integrates into the host cell’s DNA as a provirus. Transcription from the provirus is regulated in large part by cellular proteins and epigenetic factors. These may be repressive or permissive to productive infection. The host factors that regulate this balance are therefore attractive targets for HIV-1 therapeutics. Indeed, proviral chromatin is the focus of two of the current HIV-1 cure strategies. “Shock and Kill” uses latency reversal agents to open the provirus’s chromatin, promoting high levels of gene expression that induce the killing of infected cells. “Block and Lock” uses latency promoting agents to induce heterochromatin, blocking transcription and forcing HIV-1 into a state of deep latency. Here, the compounds investigated in both strategies are reviewed, including their chemical structures, mechanisms of action, and clinical results. Finally, the use of CRISPR-Cas therapeutics and the impact of chromatin architecture on its efficacy are discussed. Full article