Microbial pathogenesis最新文献

Phytophthora capsici is a destructive, broad-host oomycete that causes major agricultural losses. Yet how this generalist pathogen tailors its infection program to different plant species, especially at its natural entry site remains poorly understood. We profiled P. capsici during early crown infection of four hosts representing distinct compatibility outcomes (cucumber, melon, chili pepper CM334, and tomato) using pathogen-centered RNA-seq and microscopy. Disease progression and necrosis diverged sharply: tomato collapsed by 27 hpi, followed by melon (54 hpi), cucumber (102 hpi), and chili pepper (120 hpi). Pathogen transcriptomes were strongly host-dependent, with 4470 differentially expressed genes but only a small conserved core shared across hosts (436 induced; 415 repressed). In rapidly collapsing tomato infections, the pathogen upregulated glycolysis and fatty-acid metabolism and repressed HR-associated elicitin INF2B. In cucurbit infections, expression patterns were consistent with prolonged biotrophy, including increased carbohydrate metabolism, transport processes, and nutrient acquisition. In partially resistant CM334, pathogen profiles indicated constrained early colonization, with metabolic stress, cell wall remodeling, and broad effector repression. Co-expression analysis identified modules linked to colonization, nutrient exploitation, and pathogenesis/defense-related functions. dsRNA-mediated silencing supported these patterns: silencing Pc18476 and Pc9358 reduced pathogen growth on cucumber leaves (∼78% and ∼65%), and in stem assays reduced growth and/or prevented necrosis in CM334 and tomato. Together, these findings show that P. capsici achieves broad host range by dynamically tuning effector deployment and metabolism to host-specific constraints, resulting in divergent infection outcomes during early crown invasion.

The Bombyx mori nucleopolyhedrovirus (BmNPV) poses a serious threat to the sericulture industry, and its infection process is highly dependent on the remodeling of the host actin skeleton. When the virus infects Bombyx mori cells, it induces significant reorganization of the actin skeleton, promoting the polymerization of G-actin to form F-actin. During this process, the actin monomer-binding protein thymosin (BmTHY) can regulate the dynamic balance of the cytoskeleton by inhibiting microfilament polymerization. Previous research by our group revealed that after BmNPV infects BmN silkworm cells, the phosphorylation level at S68 of Thymosin significantly increases (1.99 fold), suggesting that the virus may inhibit BmTHY function by altering its charge level, thereby hijacking the host microfilament network to promote its own proliferation. Subsequent experiments demonstrated that the BmTHY S68D mutation, mimicking persistent phosphorylation, reduced the binding of BmTHY to actin monomers and promoted the polymerization of G-actin into F-actin. Thus, it can be concluded that BmTHY S68D might enhance BmNPV proliferation by promoting F-actin formation.

Viral keratitis & conjunctivitis result in multiple ophthalmic symptoms and even progress to vision loss without timely intervention. Although multitudinous pathogens can cause ocular infections, the regulatory mechanisms underlying virus-host interactions remain incompletely defined. Our clinical and mechanistic investigations identify the co-infection of herpes simplex virus type 1 (HSV-1) and adenovirus as a predominant etiology of viral keratoconjunctivitis in Shenzhen, China (2024). The viral co-infection causes both severe symptoms and inflammations in clinical cases and in vitro. Mechanistically, mTORC2-regulated autophagy plays a pivotal role in viral replication, with mTOR-targeted intervention demonstrating superior antiviral and anti-inflammatory efficacy in corneal epithelial cells. This study elucidates a novel regulatory mechanism of mTORC2 in HSV-1 and adenovirus infection, thereby providing novel targets for the development of drugs against viral keratitis & conjunctivitis.

Vibrio spp. are important bacterial pathogens in aquaculture and can also cause human infections worldwide. Antimicrobial peptides (AMPs) are natural molecules with broad-spectrum antibacterial activity and are therefore considered promising alternatives to conventional antibiotics. In this study, a potential anti-bacterial peptide (GITIQCILPGFVVSKLSKLK, AMP LRSG08) was identified from Penaeus vannamei using ultra-performance liquid chromatography-mass spectrometry and online software. The minimum inhibitory concentrations of AMP LRSG08 against Vibrio parahaemolyticus, Vibrio alginolyticus, and Vibrio vulnificus were 2 μg/mL, 2 μg/mL, and 125 μg/mL, respectively. Furthermore, over 80 % of these bacteria were killed within 2.5 h. The AMP LRSG08 could selectively accumulate on the V. parahaemolyticus cell surface and disrupt the integrity of their cellular membranes, leading to nucleic acid leakage from these cells by specifically targeting the cell membrane. Additionally, AMP LRSG08 exhibited concentration-dependent binding to genomic DNA. In vivo studies further revealed that AMP LRSG08 significantly increased the 72 h survival rate of zebrafish infected with V. parahaemolyticus to 80.0 %. Moreover, LRSG08 exhibited nonhemolytic activity and low cytotoxicity in vitro, indicating a favorable biosafety. The present study not only offers valuable insights for the screening of potential antimicrobial peptides but also establishes a theoretical framework for effective prevention and control strategies against vibriosis in aquatic products.

Burkholderia pseudomallei, the causative agent of melioidosis, is a recognised bioterrorism threat. This microorganism produces a key quorum molecule, 3-Hydroxy-C₁₀ homoserine lactone (3-OH-C₁₀ HSL), which has shown to modulate host immune responses. This study investigated the impact of 3-Hydroxy-C₁₀ HSL on A549 cell line, with a focus on organelle stress and inflammatory responses. Treatment with 3-Hydroxy-C₁₀ HSL (100 μM, 2 h) induces a significant elevation of cytosolic calcium and endoplasmic reticulum (ER) stress, evidenced by BiP upregulation and activation of the PERK-CHOP axis, indicating activation of the unfolded protein response (UPR). Mitochondrial function was compromised, as shown by reduced ATP production, loss of mitochondrial membrane potential (MMP), and elevated mitochondrial ROS generation. Furthermore, lysosomal dysfunction was observed through decreased acridine orange puncta, along with TFEB upregulation and LAMP1 downregulation. Gene expression analysis (10 μM, 6 h) revealed activation of the inflammasome pathway, with increased expression of NLRP3, NLRC4, IL-1β, and IL-18, and enhanced secretion of pro-inflammatory cytokines IL-6, TNF- α, and INF- γ. Overall, 3-Hydroxy-C₁₀ HSL disrupts host cellular homeostasis and induces inflammatory stress, providing novel insights into the molecular mechanisms underlying B. pseudomallei mediated pathogenesis.

Pseudomonas aeruginosa, which is one of the most common opportunistic pathogenic bacteria, poses severe clinical risks for individuals with compromised immune systems, particularly concerning lung infections. Sodium houttuyfonate (SH), an active constituent isolated from Houttuynia cordata, exhibits limited direct antibacterial efficacy in vitro yet demonstrates notable therapeutic effects against bacterial infections in vivo. Nevertheless, the precise mechanisms underlying in vivo antibacterial pharmacological activity of SH remain unclear. Thus, here we investigate the mechanism by which SH alleviates P. aeruginosa-induced acute pulmonary infection, focusing on its influence on macrophage polarization signaling pathways. First, our findings demonstrate that SH effectively alleviated P. aeruginosa-induced acute pulmonary infection in mice, as evidenced by reduced inflammatory infiltration and alveolar damage in vivo. The results indicate that SH significantly modulated the expression of inflammatory mediators (IL-6, TNF-α, IL-1β, IL-10, TGF-β, Arg-1) and key signaling molecules (NF-κB, TLR4, STAT6, p38MAPK). In vitro, 24-h SH treatment decreased NO production and attenuated macrophage phagocytosis, while shifting cytokine profiles from M1 to M2 phenotypes. Immunofluorescence and flow cytometry confirmed decreased CD86 (M1 marker) and increased CD206 (M2 marker) expression, indicating enhanced M2 polarization. Mechanistically, SH suppressed the TLR-4/MyD88/NF-κB pathway while activating the p38MAPK/STAT6 axis. Genetic manipulation further verified that SH regulates TLR-4 and p38MAPK, thereby controlling downstream signaling and inflammatory responses to combat infection. In conclusion, our study suggests that SH promotes macrophage M2 polarization and reduces excessive inflammation in late-stage P. aeruginosa-induced acute pulmonary infection by modulating macrophage polarization through the suppression of pro-inflammatory signaling via the TLR4/MyD88/NF-κB pathway and activation of the p38 MAPK/STAT6 pathway.

Chlamydia trachomatis (C. trachomatis) infection is a prevalent sexually transmitted disease worldwide. Although antibiotics are the standard first-line treatment, the rising incidence of treatment failure highlights the need for alternative therapeutic strategies. Baicalin, a natural flavonoid compound extracted from Scutellaria baicalensis, is known to possess antimicrobial properties. This study aimed to evaluate the anti-chlamydial effects of baicalin. Our results showed that baicalin significantly inhibited the growth of multiple C. trachomatis serovars (A, D, and L2) in HeLa cells, as indicated by reductions in inclusion number and size, as well as decreased cHSP60 level. Moreover, baicalin markedly diminished the production of infectious progeny. Mechanistic investigations suggest that the anti-chlamydial effect of baicalin likely involves direct targeting of elementary bodies to impair their infectivity, rather than interfering with host cell pathways. Furthermore, baicalin exhibited a synergistic inhibitory trend when combined with azithromycin. These findings indicate that baicalin is a promising novel therapeutic candidate for combating C. trachomatis infections.

Candidiasis, caused by yeasts of the Candida genus, is increasingly characterized by a high prevalence of clinical isolates resistant to conventional antifungals, rendering the development of novel therapeutic strategies paramount. Drug repurposing has emerged as a key strategy, utilizing established pharmaceuticals for indications beyond their original design; notably, haloperidol (HAL) has shown promising antimicrobial potential. In this context, the present study evaluates the activity of haloperidol, both as a monotherapy and in combination with conventional antifungals, against fluconazole-susceptible and fluconazole-resistant Candida spp. clinical strains. Furthermore, we investigate the underlying mechanisms of its antifungal action. Experimental approaches included broth microdilution assays to determine the Minimum Inhibitory Concentration (MIC), checkerboard assays for synergistic analysis, and cellular assessments via flow cytometry and fluorescence microscopy. Haloperidol displayed MIC values between 26.67 and 256 μg/mL. Synergistic interactions were identified between haloperidol and the azoles fluconazole and itraconazole, alongside a 2.5 % synergy rate with amphotericin B. Additionally, mechanistic assays confirmed that haloperidol induces programmed cell death (apoptosis) in C. albicans and C. auris strains. The oxidative stress caused by haloperidol altered Ca²⁺ homeostasis, followed by mitochondrial membrane depolarization, reduced ATP production, cytochrome c release into the cytosol and metacaspase activation, reduced viability, phosphatidylserine externalization, promoted fragmentation, damage and methylation of DNA. It also induced expression of genes related to oxidative stress. It reduced mitochondrial depolarization and decreased the reduction of glutathione (GSH), causing morphological alterations. The results suggest the apoptotic pathway as the main antifungal mechanism of haloperidol.

The routine utilisation of prophylactic antibiotics in dairy cows during the dry period has been demonstrated to accelerate the rise of antimicrobial resistance, constituting a significant challenge within the One Health framework. The incorporation of essential oils into nanofibre delivery systems provides a sustainable alternative that has become a pivotal instrument in the field of nanotechnology. This approach integrates the inherent antimicrobial properties of specific compounds with a controlled release mechanism and targeted application. It provides a solution for reducing reliance on antibiotics, and the combination of nanoscience and AI further enhances this method. The utilisation of artificial intelligence has the potential to facilitate precise diagnostics, support personalized treatment plans, and enable predictive health monitoring. Consequently, this can lead to improvements in herd management and a reduction in unnecessary pharmaceutical treatments. These innovations have been demonstrated to have a number of benefits, including the promotion of animal health, food security and the strengthening of agricultural systems. In accordance with the EU Green Deal and global sustainability goals, the utilisation of nanofibre-based phytotherapeutics has been demonstrated to assist in the reduction of carbon emissions, the minimisation of drug residues, and the safeguarding of public health. The ethical development of these technologies necessitates a One Health perspective, underpinned by scalable manufacturing techniques, comprehensive environmental impact assessments, and harmonised regulatory frameworks. The integration of nanotechnology, phytotherapy and artificial intelligence has the potential to transform veterinary diagnostics and treatments, thereby establishing sustainable dairy farming as a paradigm for climate-resilient agricultural innovation.