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The rise of antibiotic resistance and the dwindling antimicrobial pipeline have emerged as significant threats to public health. The emergence of carbapenem-resistant Klebsiella pneumoniae (CRKP) poses a global threat, with limited options available for targeted therapy. The CRKP has experienced various changes and discoveries in recent years regarding its frequency, transmission traits, and mechanisms of resistance. In this comprehensive review, we present an in-depth analysis of the global epidemiology of K. pneumoniae, elucidate resistance mechanisms underlying its spread, explore evolutionary dynamics concerning carbapenem-resistant hypervirulent strains as well as KL64 strains of K. pneumoniae, and discuss recent therapeutic advancements and effective control strategies while providing insights into future directions. By going through up-to-date reports, we found that the ST11 KL64 CRKP subclone with high risk demonstrated significant potential for expansion and survival benefits, likely due to genetic influences. In addition, it should be noted that phage and nanoparticle treatments still pose significant risks for resistance development; hence, innovative infection prevention and control initiatives rooted in One Health principles are advocated as effective measures against K. pneumoniae transmission. In the future, further imperative research is warranted to comprehend bacterial resistance mechanisms by focusing particularly on microbiome studies’ application and implementation of the One Health strategy.

Extra-intestinal Pathogenic Escherichia coli (ExPEC) is defined as an extra-intestinal foodborne pathogen, and several dominant sequence types (STs) ExPEC isolates are highly virulent, with zoonotic potential. Bacteria extracellular vesicles (EVs) carry specific subsets of molecular cargo, which affect various biological processes in bacteria and host. The mechanisms of EVs formation in ExPEC remains to be elucidated. Here, the purified EVs of ExPEC strains of different STs were isolated with ultracentrifugation processes. A comparative analysis of the strain proteomes showed that cytoplasmic proteins accounted for a relatively high proportion of the proteins among ExPEC EVs. The proportion of cytoplasm-carrying vesicles in ExPEC EVs was calculated with a simple green fluorescent protein (GFP) expression method. The RecA/LexA-dependent SOS response is a critical mediator of generation of cytoplasm-carrying EVs. The SOS response activates the expression of prophage-associated endolysins, Epel1, Epel2.1, and Epel2.2, which triggered cell lysis, increasing the production of ExPEC cytoplasm-carrying EVs. The repressor LexA controlled directly the expression of these endolysins by binding to the SOS boxes in the endolysin promoter regions. Reducing bacterial viability stimulated the production of ExPEC EVs, especially cytoplasm-carrying EVs. The imbalance in cell division caused by exposure to H 2 O 2 , the deletion of ftsK genes, or t 6 A synthesis defects activated the RecA/LexA-dependent SOS response, inducing the expression of endolysins, and thus increasing the proportion of cytoplasm-carrying EVs in the total ExPEC EVs. Antibiotics, which decreased bacterial viability, also increase the production of ExPEC cytoplasm-carrying EVs through the SOS response. Changes in the proportion of cytoplasm-carrying EVs affected the total DNA content of ExPEC EVs. When macrophages are exposed to a higher proportion of cytoplasm-carrying vesicles, ExPEC EVs were more cytotoxic to macrophages, accompanied with more-severe mitochondrial disruption and a higher level of induced intrinsic apoptosis. In summary, we offered comprehensive insight into the proteome analysis of ExPEC EVs. This study demonstrated the novel formation mechanisms of E . coli cytoplasm-carrying EVs.

Background Avian pathogenic Escherichia coli (APEC) is the major pathogen causing important avian diseases in poultry. As an important subtype of extraintestinal pathogenic E. coli , APEC has zoonotic potential and is considered a foodborne pathogen. APEC extracellular vesicles (EVs) may play vital roles in the interaction of the pathogen with its host cells. However, the precise roles played by APEC EVs are still not completely clear, especially in immune cells. Results In this study, we investigated the relationships between APEC EVs and immune cells. The production and characteristics of the EVs of APEC isolate CT265 were identified. Toll like receptor 4 (TLR4) triggered the cellular immune responses when it interacted with APEC EVs. APEC EVs induced a significant release of proinflammatory cytokines in THP-1 macrophages. APEC EVs induced the macrophage inflammatory response via the TLR4/MYD88/NF-κB signaling pathway, which participated in the activation of the APEC-EV-induced NLRP3 inflammasome. However, the loss of lipopolysaccharide (LPS) from APEC EVs reduced the activation of the NLRP3 inflammasome mediated by TLR4/MYD88/NF-κB signaling. Because APEC EVs activated the macrophage inflammatory response and cytokines release, we speculated that the interaction between APEC EVs and macrophages activated and promoted neutrophil migration during APEC extraintestinal infection. This study is the first to report that APEC EVs induce the formation of neutrophil extracellular traps (NETs) and chicken heterophil extracellular traps. Treatment with APEC EVs induced SAPK/JNK activation in neutrophils. The inhibition of TLR4 signaling suppressed APEC-EV-induced NET formation. However, although APEC EVs activated the immune response of macrophages and initiated NET formation, they also damaged macrophages, causing their apoptosis. The loss of LPS from APEC EVs did not prevent this process. Conclusion APEC-derived EVs induced inflammatory responses in macrophages and NETs in neutrophils, and that TLR4 was involved in the APEC-EV-activated inflammatory response. These findings provided a basis for the further study of APEC pathogenesis.

Bacteriophage are sophisticated cellular parasites that can not only parasitize bacteria but are increasingly recognized for their direct interactions with mammalian hosts. Phage adherence to mucus is known to mediate enhanced antimicrobial effects in vitro. However, little is known about the therapeutic efficacy of mucus-adherent phages in vivo. Here, using a combination of in vitro gastrointestinal cell lines, a gut-on-a-chip microfluidic model, and an in vivo murine gut model, we demonstrated that a E. coli phage, øPNJ-6, provided enhanced gastrointestinal persistence and antimicrobial effects. øPNJ-6 bound fucose residues, of the gut secreted glycoprotein MUC2, through domain 1 of its Hoc protein, which led to increased intestinal mucus production that was suggestive of a positive feedback loop mediated by the mucus-adherent phage. These findings extend the Bacteriophage Adherence to Mucus model into phage therapy, demonstrating that øPNJ-6 displays enhanced persistence within the murine gut, leading to targeted depletion of intestinal pathogenic bacteria. Authors profile the antimicrobial activity of an Escherichia coli bacteriophage (in vivo and in vitro), isolated from chicken faeces.

Escherichia coli ( E. coli ) O157:H7 bacterial infection causes severe disease in mammals and results in substantial economic losses worldwide. Due to the development of antibiotic resistance, bacteriophage (phage) therapy has become an alternative to control O157:H7 infection. However, the therapeutic effects of phages are frequently disappointing because of their low resistance to the gastrointestinal environment. In this study, to improve the stability of phages in the gastrointestinal tract, E. coli O157:H7 phages were microencapsulated and their in vitro stability and in vivo therapeutic efficiency were investigated. The results showed that compared to free phages, the resistance of microencapsulated phages to simulated gastric fluid and bile salts significantly increased. The microencapsulated phages were efficiently released into simulated intestinal fluid, leading to a better therapeutic effect in rats infected with E. coli O157:H7 compared to the effects of the free phages. In addition, the microencapsulated phages were more stable during storage than the free phages, showing how phage microencapsulation can play an essential role in phage therapy.

Mycotoxins such as zearalenone (ZEN), deoxynivalenol (DON) and T-2 toxin (T-2) are the most poisonous biological toxins in food pollution. Mycotoxin contaminations are a global health issue. The aim of the current study was to use porcine Leydig cells as a model to explore the toxic effects and underlying mechanisms of ZEN, DON and T-2. The 50% inhibitory concentration (IC50) of ZEN was 49.71 μM, and the IC50 values of DON and T-2 were 2.49 μM and 97.18 nM, respectively. Based on the values of IC50, ZEN, DON and T-2 exposure resulted in increased cell apoptosis, as well as disrupted mitochondria membrane potential and cell cycle distribution. The results also showed that ZEN and DON significantly reduced testosterone and progesterone secretion in Leydig cells, but T-2 only reduced testosterone secretion. Furthermore, the expression of steroidogenic acute regulatory (StAR) protein and 3β-hydroxysteroid dehydrogenase (3β-HSD) were significantly decreased by ZEN, DON and T-2; whereas the protein expression of cholesterol side-chain cleavage enzyme (CYP11A1) was only significantly decreased by ZEN. Altogether, these data suggest that the ZEN, DON and T-2 toxins resulted in reproductive toxicity involving the inhibition of steroidogenesis and cell proliferation, which contributes to the cellular apoptosis induced by mitochondrial injury in porcine Leydig cells.

Lumpy skin disease virus (LSDV) is a critical transboundary pathogen that causes devastating infections in cattle, buffalo, and other ruminants. The virus induces characteristic clinical manifestations, including cutaneous nodules, marked reduction in milk yield, and impaired production performance, leading to severe economic losses in the global livestock sector. Although LSDV exhibits remarkable multi-tissue tropism and persistent viral shedding in various organs, posing significant challenges for disease control, the molecular mechanisms underlying its tissue-specific adaptation remain poorly understood. Here, we established both bovine cell models and golden hamster models to elucidate the tissue-specific pathogenic mechanisms of LSDV, and further validated these findings in bovine kidney and mammary tissue samples to demonstrate their relevance in natural hosts. Our findings revealed that LSDV employs distinct cell death pathways in different tissues to facilitate host adaptation. In kidney tissue, the viral envelope protein ORF117 specifically interacts with host GAPDH, triggering its nuclear translocation and subsequent activation of the GAPDH-Siah1/p53 signaling cascade, culminating in Caspase-3-mediated apoptosis. Conversely, in mammary tissue, LSDV induces Caspase-8-dependent cleavage of Gasdermin C, promoting pyroptosis in mammary epithelial cells and substantial release of inflammatory cytokines IL-1β and IL-18. This study provides the first mechanistic insight into the molecular basis of LSDV’s tissue-specific activation of distinct cell death pathways, establishing a theoretical framework for developing targeted therapeutic interventions against lumpy skin disease.

EBV genomic variation has been shown to contribute to the development of certain EBV-associated cancers. While EBV genomic variation has been extensively studied at the nucleotide level, it remains unclear how synonymous codon usage contributes to viral adaptation across epithelial cancer contexts. Here, we analyzed 1148 EBV genomes with annotated tumor origins to investigate genome-wide genetic differentiation and codon usage patterns of 13 core genes across NPC- and GC-associated viruses and EBV types. SNP-based analyses revealed partial genetic separation between NPC-EBV and GC-EBV, characterized by both rare GC-associated risk variants and common protective haplotypes. Codon usage patterns, however, showed strong gene-specific structure: EBNA2 and EBNA3 clustered primarily by EBV type, whereas EBNA1 and LMP2A were more sensitive to tumor background. Codon bias analyses suggested heterogeneous contributions of mutational pressure and natural selection across genes and lineages, whereas lytic BALF genes displayed highly conserved codon usage despite cancer-associated variants. Collectively, this study demonstrates that codon usage patterns of specific EBV genes are associated with tumor background and are jointly shaped by gene function and viral lineage structure.

Merbecovirus, a subgenus of coronaviruses that includes the highly pathogenic Middle East respiratory syndrome coronavirus (MERSr-CoV), poses a significant zoonotic threat. To better understand its host adaptation and potential for cross-species transmission, we conducted a comprehensive analysis of codon usage patterns in 1967 Merbecovirus sequences. Phylogenetic analysis confirmed the division of Merbecoviruses into seven distinct clusters. Codon usage bias was found to be low and predominantly shaped by natural selection, with a consistent A/U-rich composition across the genome. Codon adaptation index (CAI) and relative codon deoptimization index (RCDI) analyses indicate that Merbecovirus exhibits potential host adaptation to Sus scrofa (pigs), Equus caballus (horses), and Oryctolagus cuniculus (rabbits), suggesting a risk of cross-species transmission. Strikingly, this genomic-level adaptation prediction is supported by emerging functional evidence: recent studies have demonstrated that key Merbecovirus lineages utilize diverse cell entry receptors (DPP4 or ACE2), a fundamental determinant of host tropism. For instance, the ability of the HKU5 lineage to utilize ACE2 receptors from mustelids like minks (Neogale vison) provides mechanistic support for the host adaptability trends inferred from our genomic analyses. By integrating existing receptor specificity data, this study provides the first systematic, large-scale analysis of codon usage across the Merbecovirus subgenus, elucidating key mechanisms of genomic adaptation and viral evolution. Our analytical framework provides a novel comparative perspective on host diversity and pinpoints specific surveillance priorities for mitigating future spillover risks.

Neonatal meningitis Escherichia coli (NMEC) breaching the blood-brain barrier (BBB) is a critical event in the development of E. coli meningitis. Brain microvascular endothelial cells (BMECs), the primary structural component of the BBB, play a central role in defending against pathogen invasion. In this study, we employ the NMEC strain RS218 (O18:K1:H7) to investigate the molecular mechanisms of cell death in BMECs and its pivotal contribution to BBB disruption. The study reveals that RS218 infection promotes assembly of the Ripoptosome complex. This leads to the coordinated activation of apoptosis, pyroptosis, and necroptosis. Notably, necroptosis can also occur through RIPK1-independent pathways. By generating Ripk1 D138N/D138N , Gsdmd -/- , and Casp8 -/- Ripk3 -/- mice, we demonstrate that the regulation of BMECs death was an important factor in BBB resistance to infection. Among these models, kinase-dead Ripk1 D138N/D138N mice exhibit the most effective BBB protection, independent of innate immune responses. Inhibition of RIPK1 kinase significantly preserves BBB integrity, and lowers RS218 invasion and neuroinflammation. Moreover, the combination of RIPK1 inhibition with antibiotics yields additive therapeutic effects. Our study advances the understanding of NMEC pathogenesis and supports the potential of RIPK1 as a therapeutic target for E. coli meningitis. In this work, authors elucidate the molecular mechanisms by which neonatal meningitis Escherichia coli facilitates bacterial invasion through inducing multiple programmed cell death pathways in brain microvascular endothelial cells.