Search Results (248)

Prophages are bacteriophage genomes that are part of bacterial chromosomes. They are not just dormant passengers; they actively shape pathogen biology. For example, in skin-infecting pathogens such as Staphylococcus aureus, Streptococcus pyogenes, and Pseudomonas aeruginosa, prophages carry important virulence factors, cytotoxins, superantigens, immune evasion clusters, and epigenetic regulators that directly affect the course of skin and soft tissue infections. This same prophage biology provides a therapeutic strategy: prophage-derived molecules, including endolysins, holins, spanins, and polysaccharide depolymerases, demonstrate potent antimicrobial and antibiofilm activity against drug-resistant skin pathogens, with several candidates now in clinical development. Engineered chimeric lysins, CRISPR-encoded prophage delivery systems, and the systematic mining of the skin microbiome phageome collectively enhance the translational potential of this biology. This review integrates mechanistic insights into prophage-mediated virulence. It assesses the translational landscape of prophage-derived therapeutics, delineating the conceptual and clinical frontiers that characterize the forthcoming chapter in this domain. Full article

The body’s microbiota plays a fundamental role in maintaining homeostasis and influences immune function, metabolism, and tissue integrity. A growing body of research suggests that fluctuations in the composition and abundance of individual microbiota populations may influence cancer development and the effectiveness of therapy. The condition of microbiota dysbiosis has been demonstrated to induce chronic inflammation, immune system dysregulation, and, most significantly, modulation of molecular pathways that promote tumorigenesis. The efficacy and toxicity of cancer treatment can be influenced by the composition of the microbiota. Bacteria can modify the effectiveness and toxicity of chemotherapy and immunotherapy by affecting drug metabolism and the body’s immune response. In contrast, the development of anticancer therapies that utilize bacteria is gaining increasing interest. This alternative to conventional treatment utilizes the natural ability of certain bacterial species to selectively colonize hypoxic and necrotic environments. The exploration of natural and genetically modified bacteria as vectors for the delivery of cytotoxins, immunomodulators, or therapeutic genes in the combat of cancer is a current area of research. In addition, their capacity to stimulate an antitumor immune response is also exploited. Preclinical investigations in animals have demonstrated the efficacy of this therapeutic approach, underscoring the promise of bacterial therapies as either an adjunct to conventional treatment or as a standalone strategy for combating cancer. This article synthesizes the current knowledge regarding the role of microbiota in carcinogenesis in animals and discusses recent developments in the field of bacterial therapies. The text also addresses the challenges, safety considerations, and future perspectives associated with translating microbiota-targeted and bacterial therapies into veterinary and comparative oncology. Full article

Toxigenic Klebsiella oxytoca strains linked to antibiotic-associated hemorrhagic colitis produce the cytotoxins tilimycin and tilivalline, which contribute to intestinal epithelial damage during infection. Tilimycin and tilivalline are synthesized by enzymes encoded within the nonribosomal peptide synthetase (NRPS) operon, yet the regulatory mechanisms controlling operon expression remain poorly understood. SdiA, an orphan LuxR-type quorum-sensing regulator, detects exogenous N-acyl homoserine lactones (AHLs) produced by neighboring bacterial species and modulates gene expression in response to interspecies communication. Although SdiA has been implicated in virulence regulation in several enteric pathogens, its role in K. oxytoca remains unclear. This study demonstrates that SdiA positively regulates npsA, the first gene in the NRPS operon, and that this regulatory effect is enhanced in the presence of exogenous AHL. Electrophoretic mobility shift assays indicate that SdiA directly binds to the upstream regulatory region of npsA, supporting a direct interaction consistent with positive transcriptional regulation. Furthermore, deletion of sdiA significantly reduces cytotoxicity toward HeLa cells under the conditions tested. Collectively, these findings identify SdiA as a quorum-sensing-responsive activator of npsA expression and support its role in modulating cytotoxicity in toxigenic K. oxytoca strains. These results provide new insight into the influence of interspecies quorum-sensing signals on virulence-associated regulatory pathways in K. oxytoca. Full article

The Cape cobra (Naja nivea), one of Africa’s most lethal snakes, can cause rapid, life-threatening paralysis. However, the impact of this venom on platelet function and blood coagulation remains poorly understood. To address this gap, we investigated the enzymatic profiles and the impacts of N. nivea venom on multiple aspects of haemostasis using human whole blood. Our results illustrate that Cape cobra venom significantly increases clotting time in rotational thromboelastometry without affecting other coagulation parameters. This venom significantly inhibits platelet aggregation and activation yet does not exert cytotoxic effects on platelets. The venom was subsequently fractionated using reverse-phase high-performance liquid chromatography, and the most potent purified fraction was identified as a cytotoxin (three-finger toxin) through mass spectrometry. This purified fraction showed an inhibitory effect on platelet activity. These findings highlight that N. nivea venom can induce haemotoxicity in addition to neurotoxicity. Moreover, three-finger toxins may be promising candidates for bioprospecting to develop novel antithrombotic agents. Full article

To date, the problem of mastitis in cattle remains relevant for both the industrial sector and scientific research. Despite numerous active investigations, the causes of this disease have not been fully established. It is postulated that several factors may be involved, such as bacterial pathogens, animal husbandry practices, and weather and climatic conditions. In this study, we selected cows from farms in Yakutia to investigate microbial isolates present in the milk of cows affected by mastitis and treated with antibiotics. Five identified Staphylococcus aureus isolates were investigated using whole-genome sequencing (Illumina sequencing and nanopore sequencing), followed by analysis of virulence factors in the genomes and cultural properties of the isolates. The profile of S. aureus virulence genes (exotoxins, cytotoxins, superantigen-like proteins, adhesins) was identified via WGS. Hemolysin gene (hla) was detected in all isolates. An investigation of the cultural properties of the isolates, specifically through hemolysis of rabbit erythrocytes and Western blot analysis of the culture liquid of S. aureus, revealed different expression levels of alpha-hemolysin among the strains. One isolate (17-21) exhibited the highest secretion level of about 320 ± 37 ng, both in the hemolysis test and immunoblotting assay. An investigation of the isolates’ antibiotic resistance showed that all isolates exhibited multidrug resistance, as confirmed by the presence of antibiotic resistance genes in these isolates. One isolate (7-7) exhibited the broadest range of phenotypic resistance and was resistant to all tested antibiotics (except clindamycin). Phylogenetic analysis suggested that the evolution of these isolates occurred independently in their respective ecological niches, although their transfer from cattle to humans, and vice versa, is possible. Isolates 7-7, 18-22, 33-40, and 35-42 are most typical to Yakutian cattle, while isolate 17-21 might have been introduced from a different region. To the best of our knowledge, this is the first in-depth study into a range of S. aureus isolates associated with mastitis infection in Yakutian cattle. Full article

Background/Objectives: Mycobacterial infections and autoimmune diseases affect many worldwide, and growing evidence suggests that there is a bidirectional relationship. This review examines mechanisms by which various autoimmune diseases predispose patients to mycobacterial infections, and vice versa. Methods: We conducted a PubMed/MEDLINE search using the keywords “mycobacterium” and the names of the autoimmune conditions to identify relevant papers. Results: Rheumatoid arthritis therapies, especially TNF-α inhibitors, raise tuberculosis (TB) and non-tuberculous mycobacteria (NTM) risk. Type 1 diabetes features impaired cell-mediated immunity and macrophage dysfunction, with evidence for Mycobacterium avium subspecies paratuberculosis (MAP) mimicry involving HSP65–GAD65. In systemic lupus erythematosus, immune dysregulation plus corticosteroids and cytotoxins elevates TB and NTM risk, amplified in endemic settings. In multiple sclerosis, heightened TLR2/4/9 signaling agents that inhibit pyrimidine synthesis may increase IL-10 and reduce antimycobacterial immunity. Crohn’s disease shows genetic susceptibility (e.g., NOD2 variants) and MAP detection, supporting impaired clearance of intracellular mycobacteria. Conclusions: Overall, evidence supports a bidirectional relationship: mycobacterial antigens can initiate or amplify autoimmunity via molecular mimicry and chronic stimulation, while autoimmune biology and iatrogenic immunosuppression increase susceptibility to infection. Implications include latent TB screening before immunosuppression, attention to local epidemiology, and vigilance for NTM. Research priorities include prospective cohorts, mechanistic studies of mimicry and NOD2–TLR pathways, safety registries, and trials of screening and prophylaxis. Full article

Background/Objectives: Cervical cancer remains a leading cause of cancer morbidity and mortality worldwide. Although chemoradiation followed by brachytherapy is the curative-intent standard for locally advanced disease, outcomes remain heterogeneous and recurrence and distant metastasis persist. In parallel, immune checkpoint inhibitors (ICIs) and antibody–drug conjugates (ADCs) have expanded systemic options in recurrent or metastatic settings and created new opportunities for multimodality. This review aims to integrate treatment-relevant cervical cancer biology and biomarkers to clarify how chemoradiation, immunotherapy, and ADCs can be optimally selected, sequenced, and combined across disease states. Methods: We conducted a structured narrative, evidence-based literature synthesis focusing on cervical cancer management. The review encompassed: (i) the molecular and immune mechanisms underlying human papillomavirus (HPV)-driven carcinogenesis; (ii) contemporary diagnostic and staging approaches, including advanced imaging modalities and histopathological evaluation; and (iii) clinical and translational evidence supporting the optimization of chemoradiation, immune checkpoint inhibition, and antibody–drug conjugates, with emphasis on clinically validated or emerging biomarkers that are relevant to patient stratification and mechanistically rational combination or sequencing strategies. A systematic search of PubMed/MEDLINE, Embase, and major oncology conference proceedings was performed. Priority was given to peer-reviewed original research articles, high-impact clinical trials (Phase II–III), meta-analyses, and consensus guidelines published within the past 10 years to ensure contemporary relevance. Articles published prior to this period were generally excluded to maintain clinical currency; however, seminal studies that established foundational therapeutic standards, mechanistic paradigms, or landmark treatment milestones were intentionally retained due to their enduring influence on current practice. Exclusion criteria included non-peer-reviewed sources, case reports with limited generalizability, non-English publications, and studies lacking methodological rigor or clinical relevance to cervical cancer management. Preclinical studies were included selectively when directly informing therapeutic mechanisms, biomarker development, or translational rationale. This approach was designed to balance historical context with up-to-date clinical applicability, ensuring both scientific rigor and contemporary relevance. Results: Chemoradiation and brachytherapy remain essential for local control, while ICIs can restore antitumor T-cell activity in biomarker-enriched contexts. ADCs enable target-directed delivery of potent cytotoxins and may promote immunogenic cell death, supporting immunotherapy and radiation. However, key challenges include resistance mechanisms, toxicity management, and patient identification for the most beneficial combined multimodality. Conclusions: A biology- and biomarker-informed framework can guide more rational integration of multimodality therapy in cervical cancer. Future progress will depend on validated predictive biomarkers, optimized sequencing/combination strategies, and trials that balance efficacy with short- and long-term toxicity. Full article

The multiple-transferable resistance protein (MtrR) is a transcriptional repressor of the mtrCDE-encoded drug efflux pump and Type IV pilus biosynthesis (pilM), and an activator of penicillin-binding protein 1 (ponA) expression in Neisseria gonorrhoeae. Previously published microarray data suggested that MtrR is also an activator of ltgA expression in the gonococcus. LtgA is a lytic transglycosylase responsible for approximately half of recycled peptidoglycan fragments and released peptidoglycan-derived cytotoxins, which cause ciliary damage and induce specific inflammatory responses. The fragments generated by LtgA during peptidoglycan remodeling can either be recognized by the permease AmpG for uptake into the bacterial cytoplasm and recycled for new cell wall growth and general metabolism or released into the external milieu. Therefore, we sought to define the capacity of MtrR to regulate LtgA expression in gonococci. We show that MtrR binds to the ltgA promoter region in a concentration-dependent manner, and that this binding results both in increased ltgA mRNA transcription and LtgA protein levels during exponential growth. Deletion of mtrR in N. gonorrhoeae decreased peptidoglycan monomer release from growing cells and increased autolysis. These results suggest that MtrR regulation of ltgA impacts peptidoglycan-derived cytotoxin release and autolysis in the gonococcus. This study suggests a central role of MtrR in coordinating aspects of the cellular envelope that may contribute to gonococcal pathogenesis. Full article

Singlet oxygen (¹O₂), the excitation stage of the ground-state molecular oxygen, is a fundamental reactive oxygen species (ROS) with important functions in plant growth, development, and stress responses. In plant cells, ¹O₂ is mainly generated in the chloroplast due to photosensitizing activity of tetrapyrroles. Moreover, ¹O₂ can be generated in non-photosynthetic tissues when plants suffer environmental stresses. Although ¹O₂ was initially considered as a cytotoxin—causing merely photooxidative damages, more recent work suggests that ¹O₂ also acts as a signal that either triggers a programmed cell death response or promotes acclimation. The ¹O₂ signaling pathway is distinct and operates independently of other ROS signaling cascades. In Arabidopsis, EXECUTER1 (EX1) protein has been identified as a crucial signaling component that perceives and relays ¹O₂ signals to the nucleus, thereby initiating extensive transcriptional reprogramming. Additionally, oxidative products of carotenoids, such as β-cyclocitral, are also recognized as ¹O₂-derived signaling molecules. Through specific chloroplast-to-nucleus signaling and cross talk with hormone signaling networks—including jasmonic acid (JA) and salicylic acid (SA)—¹O₂ helps finely coordinate plant growth, defense responses, and cell fate decisions under fluctuating environmental conditions. This review aims to summarize current knowledge on ¹O₂ generation and signaling, ¹O₂-induced chloroplast changes under diverse stress conditions, and cross talk between ¹O₂ and phytohormone signaling. Full article

Pseudomonas aeruginosa is an opportunistic pathogen commonly associated with nosocomial infections and environmental dissemination. Among its high-risk clones, ST244 is notable for its global distribution and distinctive genomic traits. This study reports whole-genome sequencing of ten ST244 isolates from hospitalized patients and wastewater in a healthcare complex in Southeastern Brazil. Genomic comparisons revealed a highly conserved clonal group, with nine isolates forming a tight monophyletic cluster based on rMLST, SNP phylogeny, and average nucleotide identity (>99.5%). One isolate showed close phylogenetic proximity to strains from Asia and North America, suggesting international dissemination. Serotype analysis revealed both O5 and O12 variants, indicating intra-lineage antigenic diversity. Resistance profiling identified multidrug-resistant phenotypes carrying carbapenemase genes (bla_OXA-494, bla_OXA-396) and diverse insertion sequences (ISPa1, ISPa6, ISPa22, ISPa32, and ISPa37), facilitating horizontal gene transfer. Virulence gene analysis showed conserved elements related to adhesion, iron uptake, secretion systems, and quorum sensing, while the cytotoxin gene exoU was absent. These results highlight clonal persistence, possible intra-hospital transmission, and links to globally circulating ST244 sublineages. Our findings underscore the importance of genomic surveillance to track high-risk P. aeruginosa clones at the clinical–environmental interface. Full article

Extraintestinal pathogenic Escherichia coli (ExPEC) is a major cause of infections of the urinary tract, the bloodstream, and other non-intestinal sites in humans. ExPEC often resists the bactericidal action of human immune defenses including complement, antimicrobial peptides, antibodies, and cell-mediated killing. This review provides an overview of the main host defense strategies, and the mechanisms and molecules ExPEC engages to resist these human immune responses. Surface-exposed polysaccharides, outer membrane proteins, cytotoxins, and proteases are all part of the bacterial arsenal of defenses that can neutralize many of the host’s immune defenses. These factors work in concert to enable ExPEC to survive and thrive in extraintestinal environments of the human body. Full article

Staphylococcus aureus (S. aureus) is a major cause of human morbidity and mortality worldwide. Hemolysis caused by S. aureus cytotoxins is important for the acquisition of iron and subsequent bacterial survival during infection. S. aureus can express numerous hemolysins that have been shown to target human erythrocytes. However, the relative importance of each of these for causing hemolysis during pathogenesis in humans is not clear. In this study, we have examined the hemolytic capacity of different methicillin-resistant S. aureus (MRSA) deletion mutants against human erythrocytes in suspension using two separate assays. The first assay measured hemolysis caused by extracellular factors produced by MRSA, while the second measured hemolysis following co-culture of MRSA with human erythrocytes. Results from both assays demonstrated that phenol-soluble modulin-α peptides (PSMα) play a dominant role in causing hemolysis of human erythrocytes, highlighting a prominent target for novel therapeutic strategies designed to limit S. aureus iron acquisition and survival during human disease. Full article

Helicobacter pylori (H. pylori) is a Gram-negative, spiral-shaped bacterium that colonizes the human stomach and is linked to various gastroduodenal diseases. The severity of different clinical outcomes may be determined by the combination of virulence genes. The aim of this study was to assess the combinations of the cytotoxin-associated gene A (cagA), the vacuolating cytotoxin A gene (vacA), the outer inflammatory protein A gene (oipA), and the blood group antigen-binding adhesin gene (babA2) genotypes in H. pylori and their associations with the clinical outcomes of infection in patients from Central Brazil. This cross-sectional study included 106 patients who underwent endoscopy or gastrectomy. The presence and genotypes of H. pylori were confirmed using Polymerase Chain Reaction (PCR). Gastropathies were classified according to established severity criteria. Multivariate logistic regression and Venn diagrams were used to evaluate gene combinations. In this study, the infection prevalence was 65.1%. The cagA/vacA/oipA/babA2 combination showed a protective effect against erosive esophagitis (p = 0.002), erosive duodenitis (p = 0.003), and general duodenitis (p < 0.001). No significant association was observed between this gene combination and severe gastric diseases, although a trend toward protection against gastric atrophy was noted (p = 0.049). These findings suggest that the coexistence of cagA/vacA/oipA/babA2 may play a protective role against inflammatory lesions. Further studies should explore the functional role of these gene combinations, also considering the immunogenetic profile of the host. Full article

Differences in venom within snake species can affect the efficacy of antivenom, but how this variation manifests across broad geographical scales remains poorly understood. Naja atra envenoming causes severe morbidity in China, yet whether intraspecific venom variation exists across mainland regions is unknown. We collected venom samples from seven biogeographical regions (spanning > 2000 km latitude). Venom lethality, systemic toxicity (organ damage biomarkers and coagulopathy), and histopathology of major organs were assessed. Neutralization by antivenom and label-free quantitative proteomics (LC-MS/MS) were also performed. The results revealed a non-uniform LD₅₀, with venom from Yunnan exhibiting the highest lethality (2.1-fold higher than venom from Zhejiang, p < 0.001). Commercial antivenom showed lower neutralization efficacy against the venom from the Yunnan, Guangxi, and Guangdong regions. Regarding organ damage and coagulopathy, venom from Yunnan caused severe liver damage, while venom from the Zhejiang region induced significant coagulopathy. Finally, proteomic profiles identified 175 proteins: venom from Yunnan was dominated by phospholipases, contrasting with eastern regions (Anhui/Zhejiang: cytotoxins CTXs > 30%). Venom from Guangdong contained higher levels of the weak neurotoxin NNAM2 (5.2%). Collectively, significant geographical divergence exists in Chinese Cobra venom composition, systemic toxicity, and antivenom susceptibility, driven by differential expression of key toxins. Our study provides a molecular basis for precision management of snakebites, and we call for optimized antivenom production tailored to regional variations. Full article

Helicobacter pylori is a well-established causative agent of gastritis, peptic ulcers, gastric adenocarcinoma, and primary gastric lymphoma. It colonizes the human stomach and expresses numerous virulent factors that influence disease progression. Among these factors is the cytotoxin vacA gene, which encodes the vacuolating capacity of the cytotoxin and plays a key role in the bacterium’s pathogenic potential. This study investigated the allelic diversity of the vacA among H. pylori strains infecting patients in Jordan with various gastric conditions and examined potential associations between vacA s-and m- genotypes, histopathological and endoscopic findings, and the development of gastric diseases. Gastric biopsies were collected from 106 patients at two hospitals in Jordan who underwent endoscopic examination. The collected biopsies for each patient were subjected to histopathological assessment, urease detection using the Rapid Urease Test (RUT), a diagnostic test for H. pylori, and molecular detection of the vacA gene and its s and m alleles. The histopathology reports indicated that 83 of 106 patients exhibited gastric disorders, of which 81 samples showed features associated with H. pylori infection. The RUT was positive in 76 of 106 with an accuracy of 93.8%. Real-time polymerase chain reaction (RT-PCR) targeting the 16S rRNA gene confirmed the presence of H. pylori in 79 of 81 histologically diagnosed cases as infected (97.5%), while the vacA gene was detected only in 75 samples (~95%). To explore genetic diversity, PCR-amplified fragments underwent sequence analysis of the vacA gene. The m-allele was detected in 58 samples (73%), the s-allele was detected in 45 (57%), while both alleles were not detected in 13% of samples. The predominant genotype combination among Jordanians was vacA s2/m2 (50%), significantly linked to mild chronic gastritis, followed by s1/m2 (35%) and s1/m1 (11.8%) which are linked to severe gastric conditions including malignancies. Age-and gender-related differences in vacA genotype were observed with less virulent s2m2 and s1m2 genotypes predominating in younger adults specially males, while the more virulent m1 genotypes were found exclusively in females and middle-aged patients. Genomic sequencing revealed extensive diversity within H. pylori, likely reflecting its long-standing co-evolution with human hosts in Jordan. This genetic variability plays a key role in modulating virulence and influencing clinical outcomes. Comprehensive characterization of vacA genotypic variations through whole-genome sequencing is essential to enhance diagnostic precision, strengthen epidemiological surveillance, and inform targeted therapeutic strategies. While this study highlights the significance of the vacA m and s alleles, future research is recommended in order to investigate the other vacA allelic variations, such as the i, d, and c alleles, to achieve a more comprehensive understanding of H. pylori pathogenicity and associated disease severity across different strains. These investigations will be crucial for improving diagnostic accuracy and guiding the development of targeted therapeutic strategies. Full article