Virulence最新文献

Sindbis virus (SINV), a widely distributed alphavirus, is both a foundational model for viral replication studies and an underrecognized human pathogen. Despite its typically mild presentation, SINV can lead to prolonged joint pain and, in rare cases, neurological complications. This review explores SINV's molecular biology and clinical manifestations, particularly its role in causing Sindbis Fever - a self-limiting but potentially chronic arthritic disease. Molecular insights reveal mechanisms of immune evasion, neurovirulence, and persistent infection, highlighting SINV's potential for broader public health impact, especially under changing climatic conditions. This review also identifies key virulence determinants and discusses the virus's utility as a model for studying alphaviral encephalitis. Continued research is essential to better understand SINV pathogenesis and to prepare for potential outbreaks.

The oral cavity contains the second most diverse bacterial community after the intestines, with bacteria and viruses coexist. Streptococcus mutans is a major pathogenic bacterium in the oral cavity, commonly associated with dental caries. We investigated the effects of S. mutans-derived extracellular vesicles (Sm EVs) on herpes simplex virus 1 (HSV-1) infection, which is prevalent in the oral cavity. We performed our experiments in human oral keratinocyte (HOK) cells and mucosal tissue-derived organoids, and analyzed human whole saliva (n = 50) for associations between S. mutans and HSV-1 envelope glycoprotein D (gD) mRNA levels by qPCR. Sm EVs significantly enhanced HSV-1 production in mucosal organoids. Indeed, mRNA and/or protein levels of type I (IFN-α and IFN-β), type II (IFN-γ), and type III (IFN-λ₁, IFN-λ₂, and IFN-λ₃) interferons were significantly lower in Sm EV-treated mucosal organoids compared with the vehicle control under mock-infection. When HSV-1 was introduced after Sm EV pretreatment, these IFN levels showed a general trend of statistically significant reduction compared with those in the vehicle control. Moreover, Sm EVs suppressed IFN mRNA and protein levels by upregulating the EGFR - ERK pathway in mucosal cells, creating an environment that enhances HSV-1 production. Interestingly, a positive correlation was noted between S. mutans and HSV-1 detected in human whole saliva samples. These results suggest that S. mutans can negatively modulate the host innate antiviral responses by secreting EVs, thereby enhancing viral production. This study might provide a new perspective for controlling viral infections in humans.

Bacterial metabolism is important for antibiotic resistance and tolerance. However, the impact of indole on bacterial metabolism and antibiotic efficacy has not been fully elucidated. In this study, we investigated the effect and specific mechanism of exogenous indole on the antibiotic susceptibility of Edwardsiella tarda, a common pathogen in freshwater and marine fish farming. We found that exogenous indole promoted E. tarda tolerance to the antibiotic florfenicol, and reprogrammed the E. tarda metabolome. A total of 108 metabolites were detected, including 66 differential metabolites that regulate various metabolic pathways, such as the tricarboxylic acid (TCA) cycle and nucleotide metabolism. Exogenous indole disrupted the TCA cycle in E. tarda by increasing the intracellular NADH contents and activating the respiratory chain to increase the reactive oxygen species levels, thereby increasing the intracellular Fe²⁺ content to activate the Fenton reaction, which in turn promotes the oxidative stress response. Furthermore, indole inhibited antibiotic entry into the cell and activated efflux pumps to reduce the intracellular antibiotic content, ultimately promoting antibiotic tolerance. In vivo, exogenous indole compromised the ability of florfenicol to protect fish survival and eliminate pathogenic bacteria. These results shed light on the metabolic changes induced by indole and suggest future directions for addressing antibiotic tolerance and clinical infections of E. tarda in aquaculture. This study serves as a reminder of the adverse effects of combining antibiotics with metabolites in aquaculture.

Small extracellular vesicles (sEVs) play a role in the pathophysiology of viral respiratory infections and may be suitable biomarkers for COVID-19 and Influenza infections, or targets for treatment. We investigated differences in the surface proteome of plasma sEVs in patients with COVID-19 and Influenza. In a discovery cohort with 117 patients, we used a random forest (RF) classifier in order to discriminate COVID-19 and Influenza patients based on routine clinical parameters. Furthermore, plasma samples from these patients were analyzed with an EV Array containing 33 antibodies to capture sEVs, which were then visualized with a combination of CD9, CD63, and CD81 antibodies. We applied an RF classifier and a random depth-first search (RDFS) approach to extract markers with the best discriminatory potential. Data were then validated in an independent set of patient samples on a chip-based ExoView platform.In the initial cohort of 117 patients, leukocyte numbers, and heart rate discriminated best between COVID-19 and Influenza infection. In the plasma samples, 32 EV surface markers could be detected. Feature panels containing CD9, CD81, and CD141 allowed a discrimination between COVID-19 and Influenza. Consecutively, increased CD9 abundance was validated in a second, independent cohort, with the ExoView technology. The increased CD9 signal in Influenza patients was confirmed and shown to be mostly driven by CD9/CD41a double positive sEVs, hinting at a thrombocyte origin.We identified leukocyte numbers and heart rate, as well as CD9 as a sEV surface marker to differentiate COVID-19 from Influenza patients.

Mycoviruses are increasingly recognized for their potential applications in crop protection, particularly in biocontrol of phytopathogenic fungi and in enhancement of the environmental competence and virulence of entomopathogenic ascomycetes (EA) to optimize their pest control potential. Here, we provide the first evidence of a functional switch between insect-pathogenic and nonpathogenic states in a strain of the EA Beauveria bassiana, driven by a Beauveria bassiana victorivirus 1 (BbVV-1) acting as an essential virulence determinant. The mycovirus-infected wild-type strain (WMI) demonstrated broad-spectrum virulence across insect orders, whereas the isogenic mycovirus-free strain (MFr) was entirely nonpathogenic, exhibiting a complete suppression of cuticle penetration capability, which was restored only through injection of conidia into the hemocoel, bypassing the cuticle barrier. A comprehensive analysis of mycovirus-related inhibition of cuticle penetration revealed that WMI exhibited strong activity in extracellular cuticle-degrading enzymes (ECEs) relevant to virulence, with emphasis on Pr1 protease, whereas ECE secretion, and notably Pr1, were markedly suppressed in MFr. Insect infection by WMI showed a time-dependent increase in the number of pr1 gene copies and quantity of fungal DNA, while neither pr1 expression nor fungal DNA were detected in MFr during the infection cycle. Downregulation of the pr1 gene in MFr suggests a direct effect of mycovirus on fungal transcriptional regulation, highlighting the potential to deploy this BbVV-1 to produce hypervirulent EA strains but also to transition EA from entomopathogens to solely plant-beneficial microorganisms.

Influenza H3N8 viruses have been frequently isolated from chicken farms. However, comprehensive characterization of their virological properties, molecular evolution, virulence, and risk of spillover into mammals remains limited. In particular, little attention has been given to the transmission efficiency of H3N8 avian influenza viruses among chickens and their spillover risk. Here, we systematically characterized H3N8 isolates obtained from asymptomatic chickens through multidisciplinary approaches, including genomic surveillance, receptor binding profiling, and in vivo pathogenicity and transmission assays. All strains showed >98% nucleotide homology with human-infecting strains. Phylogenetic analysis revealed that their internal genes were derived from H9N2, while HA and PB2 genes shared high homology (bootstrap support >98%) with the novel H3N3 virus. All isolates maintained avian-type receptor-binding motifs (HA-Q226/G228) while exhibiting dual α2,3/α2,6-sialic acid binding and robust replication in mammalian cells (peak MDCK titer: 10⁷·⁵ TCID₅₀/mL). ZJ07 demonstrated exceptional thermostability (HA activity persisting >3 hr at 56°C), while JS13 showed 1.8-fold elevated neuraminidase activity versus controls (p < 0.05). In vivo, all strains caused subclinical infections with broad tissue tropism in chickens and mice without adaptation, transmitting efficiently among direct-contact poultry. Strikingly, AH12 achieved 100% airborne transmission in chickens. These findings confirm H3N8's capacity for silent poultry circulation and identify key features conducive to cross-species infection, including dual receptor binding, infection in a mammalian model, and high genetic homology with human strains. The airborne transmissibility of AH12 underscores a heightened spillover risk, necessitating enhanced surveillance and vaccines targeting avian-human interface strains.

Peste des petits ruminants (PPR) is a WOAH notifiable disease affecting sheep and goats, caused by Peste des petits ruminants virus (PPRV), a morbillivirus of the Paramyxoviridae family. Infection with PPRV leads to immunosuppression, creating conditions for opportunistic infections that can result in animal mortality. Although goats generally exhibit more severe clinical signs than sheep, the underlying mechanisms driving this species-specific difference remain poorly understood. Dendritic cells (DC), which play a pivotal role in initiating immune responses, are among the immune targets of PPRV in small ruminants. In this study, we examined the impact of PPRV on caprine immune cells, focusing on CD14⁺ monocytes and monocyte-derived dendritic cells (MoDC). Our findings indicate that PPRV infects goat monocytes without preventing their differentiation into DC. Infected MoDC displayed increased expression of maturation markers and reduced phagocytic activity, suggesting a transition toward an activated phenotype. However, mixed lymphocyte reaction assays revealed that PPRV-infected MoDCs have a diminished capacity to promote T cell proliferation. This impaired function was associated with elevated IL-10 production and reduced conjugation between DCs and T cells. Overall, PPRV infection induces an atypical maturation stage in goat MoDCs, characterized by partial activation but impaired antigen presentation. These findings demonstrate that PPRV-driven modulation of DC function contributes to the immunosuppression observed during PPRV infection in goats.

The fungal priority pathogen and basidiomycete, Cryptococcus neoformans (Cn), causes lung and brain infection in predominantly immuno-compromised individuals and there is an urgent need for new treatment options. The pyrazolopyrimidine-based cyclin dependent kinase (CDK)7 inhibitor, BS-181, has anticancer properties, but its antifungal activity has not been investigated. We show that cryptococcal CDK7 more closely resembles the human enzyme than that of ascomycetes, and that BS-181 inhibits its activity. BS-181 inhibited growth of both Cn and Cryptococcus gattii (Cg), but not ascomycete fungi and delayed progression through the G₂/M phase of the cell cycle. Transcriptomic analysis revealed that BS-181 induces splicing defects leading to elevated intron retention within the transcriptome and also suppresses translational processes. BS-181 displayed additive or synergistic activity with licensed antifungals against laboratory and clinical Cn and Cg strains, most notably with amphotericin B where synergy (2-4-fold reduction in the amphotericin B MIC) was achieved using low-sub micromolar concentrations of BS-181. Compared with either drug alone, BS-181-AmB combination therapy provided greater protection against Cn infection in a wax moth model (p ≤ 0.032) and extended survival of Cn-infected mice. These findings demonstrate that CDK7 inhibitors, already of interest as anticancer agents, could be repurposed to prevent or treat opportunistic fungal infections in cancer patients when combined with licensed antifungals limited by either toxicity or resistance.

The emergence and global spread of antimicrobial resistant (AMR) pathogens represent a critical challenge to global public health security. The ESKAPE pathogens refer to a group of highly troublesome multidrug-resistant bacteria responsible for hospital-acquired infections. Of particular concern are Gram-negative ESKAPE pathogens, which pose a significant threat to patient health and healthcare systems worldwide. Systematic investigation into antimicrobial resistance mechanisms and pathogenicity regulation is therefore imperative for developing effective infection control strategies. Emerging evidence highlights small regulatory RNAs (sRNAs) as pivotal post-transcriptional modulators in bacterial physiology, particularly in governing virulence determinant expression and host-pathogen interactions during infection. This review summarizes recent advances in sRNA-mediated regulatory mechanisms in Gram-negative ESKAPE pathogens, with emphasis on Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. We discuss the classification of sRNAs, their regulatory mechanisms, their roles in modulating virulence factors and pathogenicity, as well as the challenges and opportunities in targeting sRNAs for antimicrobial therapy. Evidence accumulated across the studies reviewed indicates that sRNAs exert their function through base pairing with target mRNAs or other sRNA, through interactions with proteins, or as dual-function sRNA. sRNAs have emerged as essential regulators of virulence in the ESKAPE pathogens, influencing capsular polysaccharide production, iron acquisition, biofilm formation, regulation of catabolic pathway genes, cell adhesion and invasion, as well as host immune responses during infection. This review provides a framework for understanding bacterial adaptive evolution through sRNA-mediated regulation and identifies novel intervention targets against multidrug-resistant pathogens.

Gut microbiota has been considered as a key bridge between phytochemicals and host immunity. Prevotella copri (P. copri) showed a close correlation with inflammation, and protocatechuic acid (PCA) has potential protective effects in our previous studies. To understand the underlying mechanism, a total of 108 healthy Duroc × Landrace × Yorkshire weaned piglets, aged 21 d, were randomly assigned into 3 groups, with 6 replicates and 6 piglets per replicate. The piglets were fed a basal diet, a basal diet containing 1.0 × 10⁸ CFU/kg P. copri or 1.0 × 10⁸ CFU/kg P. copri +400 mg/kg PCA for 28 d. Results showed that P. copri decreased the final body weight and average daily gain (ADG), while increased the feed-to-gain ratio (F/G), with increased serum levels of interleukin (IL)-2 and IL-8 in piglets (p < 0.05), and reduced the expression of intestinal tight junction protein (p < 0.05). Dietary supplementation of PCA increased the ADG by suppressing inflammation and enhancing intestinal integrity. In vitro experiments demonstrated that argininosuccinic acid, indole-3-aldehyde, and N-acetylputrescine are critical metabolites produced by P. copri, which initiated inflammatory responses by upregulating pro-inflammatory cytokines and downregulating tight junction proteins in MODE-K cells. PCA was found to effectively attenuate these effects in a dose-dependent manner. In conclusion, PCA can improve the growth performance in weaned piglets by attenuating inflammation caused by P. copri and its metabolites.