Virulence最新文献

Staphylococcus aureus is a major human opportunistic pathogen that causes significant morbidity and mortality, particularly in immunocompromised individuals. SaeRS is a two-component system in S. aureus that regulates signal transduction related to virulence, including hemolysis and coagulation. Metal ions are essential nutrients that support bacterial virulence and survival against host immune cells and are intricately interconnected with regulatory systems. The SaeRS system has long been studied for its function in bacterial virulence and invasive infections. However, its interactions with other regulators and metal ions remain unelucidated. Thus, this study evaluated the effects of the S. aureus SaeRS system on virulence, specifically its association with oxidative stress resistance and staphyloxanthin (STX) production. saeS deletion reduced STX production via the SigB-CrtOPQMN pathway, increasing vulnerability to oxidative stress and susceptibility to host immune cells. Supplementation with metal ions, specifically zinc, inhibited STX-associated gene expression, attenuating antioxidative activity in vitro. Experiments on mice with S. aureus bloodstream infection verified that SaeS was crucial for bacterial survival in vivo. Furthermore, zinc contributed to weakened bacterial virulence and altered host immune defense mechanisms. Collectively, our results established a novel mechanistic interconnection between SaeRS and STX biosynthesis and demonstrated that SaeRS inhibition combined with zinc supplementation promotes innate immune system-mediated killing of S. aureus.

There are no prophylactic vaccines for preventing the disease gonorrhea, caused by sexually transmitted infection with the Gram-negative pathogen Neisseria gonorrhoeae. In this study, we examined the antigenicity in mice of a recombinant rMafA 2/3 outer membrane protein (OMP). Mice were immunized with rMafA 2/3 with different adjuvants and delivery vehicles, which induced high levels of antibody that recognized the MafA 2/3 protein in i) antigen and OM-ELISA, ii) OM-western blots and iii) on whole bacteria examined with flow cytometry. Antisera to rMafA 2/3 in liposomes with monophosphoryl lipid A (MPLA) and with Zwittergent 3-14 ± MPLA, were bactericidal in vitro for homologous P9-17 (Allele 193) gonococcal strain (median 50% bactericidal titers of 256). Analysis of MafA 2/3 alleles among gonococcal isolates in the PubMLST database showed that ~50% and 26% of gonococci expressed Allele 90 and Allele 88-encoded protein respectively, and these proteins were identical bar one amino acid substitution. Murine antisera to Allele 193 rMafA 2/3 expressing strain P9-17 (~98% homology with Alleles 88/90 MafA 2/3 protein) showed bactericidal activity against heterologous strain FA1090 (Allele 88, 50% median titers from 4 to 64), but not to heterologous strain AR205 (Allele 90). By contrast, a rabbit anti-rMafA 2/3 serum was bactericidal for P9-17, FA1090, and AR205 (50% titers of 2048-4096), and inhibited significantly (p <0.05) the association of gonococci to human Chang conjunctival epithelial cells in vitro. These findings suggest that MafA 2/3 could be a promising OMP for further study as a component of future subunit gonococcal vaccines.

Viral myocarditis, often caused by Coxsackievirus B (CVB), is the leading cause of dilated cardiomyopathy and heart failure. Despite extensive research, the pathogenesis of CVB infection remains incompletely understood. Our previous study found that Anisomycin inhibits CVB replication by promoting the degradation of eukaryotic translation elongation factor 1 alpha 1 (eEF1A1). However, the precise mechanism through which eEF1A1 facilitates the replication of CVB remains to be fully elucidated. Here, we demonstrated that upregulated eEF1A1 is required for CVB3 replication. In vitro transcription and RNA pulldown assay demonstrated that eEF1A1 binds to the 5' cloverleaf region of CVB3 RNA. We observed that eEF1A1 interacts with double-stranded viral RNA, viral precursor protein 3 CD, and poly(A)-binding protein (PABP), which enhances its interaction with 3 CD. We show that CVB3 upregulates eEF1A1 expression by activating NF-κB. Chromosome-immunoprecipitation assay confirmed that NF-κB p65 binds to the EEF1A1 promoter. Luciferase reporter assays validated that NF-κB up-regulates EEF1A1 transcription. We further showed that eEF1A1 promotes CVB3 replication through interacting with viral RNA, 3 CD, and cellular protein PABP. This study highlights that eEF1A1, which is essential for cellular translation, is manipulated by CVB3 to promote viral replication. These findings suggest that targeting eEF1A1 could be a potential antiviral strategy against CVB infection.

Severe fever with thrombocytopenia syndrome virus (SFTSV) causes severe disease in humans, yet the pathogenesis remains poorly understood. A hallmark of fatal SFTS cases is the marked depletion of T cells. Previous studies on T cell depletion have predominantly focused on alterations in blood and peripheral lymphoid organs, while the thymus, a critical site for T cell development, has remained largely overlooked. In this study, we employed a lethal murine infection model to investigate the impact of SFTSV on thymic function. Our results revealed that SFTSV infected the thymus and induced severe cortical atrophy in type I interferon receptor-deficient (IFNAR^-/-) mice, characterized by a dramatic depletion of CD4⁺CD8⁺ double-positive (DP) thymocytes. Transcriptomic analysis indicated that thymic damage is likely attributable to impaired thymocyte proliferation and increased apoptosis, which may be a consequence of SFTSV-induced alterations in the thymic microenvironment. We found SFTSV-infected macrophages and dendritic cells in the thymus, which accumulated in the cortex and exhibited elevated secretion of IFN-γ, a cytokine commonly associated with acute thymic atrophy. These results demonstrate thymic atrophy caused by SFTSV infection and suggest potential therapeutic strategies for restoring thymic function and promoting T cell reconstitution.

Fatty liver disease is prevalent during parturition in dairy cattle. Therefore, there is an urgent need to develop novel, sensitive biomarkers for the early diagnosis of the metabolic disorders. Macroproteomics revealed that the faecal microbial community changes significantly when animal develops fatty liver disease. The microbial changes in cows with severe fatty liver (SFL) were greater than cows with moderate fatty liver (MFL) and normal condition (Norm). This suggests that microorganisms play an important role in the pathogenesis of metabolic disorders. In this study, faeces-sourced microorganisms and microbial proteins were identified and testified as novel biomarkers for the early diagnosis of fatty liver disease in cattle. For example, the AUC (area under curve) values, based on Receiver Operating Characteristics analysis, of using the combination of Lachnoanaerobaculum and Bifidobacterium (at the genus level) to discriminate MFL and SFL animals reached 0.944 and 0.867, respectively, and 0.922 and 0.985, respectively, for the combination of Bifidobacterium pseudolongum and Lachnospiraceae bacterium (at the species level). Interestingly, the differentially expressed microbial proteins are closely related to the identified microorganisms. For example, the majority of the top 20 microbial proteins with significant expression differences were derived from Bifidobacterium pseudolongum. Bifidobacterium pseudolongum was considered a prominent potential biomarker for the diagnosis of metabolic disorders, especially in fatty liver cattle. The results of this study confirm that faecal microbial dysbiosis signatures can serve as a diagnosis biomarker for non-alcoholic fatty liver disease (NAFLD), but also shed light on faecal microbiota transfer (FMT) experiments in treating NAFLD.

Ferroptosis is a novel form of iron-dependent programmed cell death characterized by iron metabolic derangement, an abnormal antioxidant system, and lipid peroxidation. Emerging evidence revealed that viruses modulate ferroptosis to facilitate their replication, dissemination, and pathogenesis, thereby promoting infection or achieving immune evasion by hijacking the host's iron metabolism. However, the interplay between ferroptosis and virus infections remains to be elucidated. This review comprehensively summarizes the core mechanisms of ferroptosis, including iron homeostasis, the system Xc^-/GPX4 pathway, the FSP1/CoQ10 pathway, lipid peroxidation, and their essential roles were discussed in ferroptosis. We highlighted the relationship between the core mechanisms of ferroptosis and virus infection. Furthermore, we revealed the underlying pathogenic mechanisms of viral infections and the prospective applications targeting ferroptosis. This article is conducive to deepening our understanding of the regulatory mechanism of ferroptosis, unraveling the potential therapeutic intervention and pharmacological direction for the development of innovative ferroptosis-dependent antiviral agents.

Echovirus 18 (E18) has re-emerged as a global public health concern in recent years because of its association with severe neonatal systemic diseases that pose a risk of high mortality. The lack of effective intervention strategies for E18 infections is largely attributed to limited knowledge regarding molecular epidemiology and recombination patterns. In this study, we obtained seven full-length E18 sequences from infants in Guangdong Province and combined them with representative sequences from GenBank. Using this expanded dataset, we analysed the molecular epidemiological features, genetic characteristics, and recombination patterns of E18. Global statistics reveal a distinct double-peak pattern in the frequency of E18 infections throughout the year in the Northern Hemisphere. All strains isolated from clinical specimens were classified as genotype C2, which has emerged as the predominant circulating strain in Guangdong Province and globally. Several potential recombination events with E30 were identified among these seven strains, particularly in the P2 and P3 non-structural regions. This study offers new insights into the global dissemination, genetic diversity, and phylodynamics of E18, potentially providing valuable information for designing antiviral vaccines and the implementation of sustainable surveillance strategies to enhance virus prevention and control during public health crises.

Porcine deltacoronavirus (PDCoV) is increasingly prevalent in newborn piglets with diarrhea. With the development of research on the virus and the feasibility of PDCoV cross-species transmission, the biosafety and the development of pig industry have been greatly affected. In this study, a PDCoV strain CH/LNFX/2022 was isolated from diarrheal newborn piglets at a farm in China. A genome-wide based phylogenetic analysis suggests that 97.5% to 99.2% homology existed in the whole genomes of other strains. Five amino acid mutations are seen for the first time in the S protein. By constructing 3D models, it was found that the S1-NTD/CTD and S2-HR-C regions produced structural alterations. Protein functional analysis showed that the structural changes of the three regions changed the epitope of S protein, the O-GalNAc glycosylation site and the 3C-like protease cleavage site. In addition, oral administration of 10⁷ TCID₅₀ CH/LNFX/2022 to newborn piglets successfully reproduced obvious clinical signs of piglets, such as diarrhea and dehydration. Meanwhile, PDCoV antigen was detected by immunofluorescence in the small intestine, and microscopic lesions and intestinal mucosal barrier destruction were detected by histological observation and scanning electron microscopy. Our study confirmed that porcine coronavirus strains increased pathogenicity through evolution, damaged the intestinal barrier of newborn piglets, and caused diarrhea in pigs. This study provided the candidate strains and theoretical basis for establishing the prevention and control system of vaccine and diagnostic methods for piglet diarrhea.

We studied the viromes of three dominant mosquito species in Wenzhou, a coastal city in Zhejiang Province, using metavirome sequencing, with 18 viral families identified. Viral sequences were verified by RT-PCR. The JEV E gene was most closely related to the 1988 Korean strain. DENV sequences were most closely related to the 1997 Australian strain. CHIKV-E1-1 was most closely related to the 1983 Senegal strain and belonged to West African genotype CHIKV. Remarkably, this is the first time that a West African genotype of CHIKV has been detected in Zhejiang Province. Mutations in the CHIKV-E1-1 protein A226V may increase infectivity in Ae. albopictus. Three non-conservative mutations of CHIKV-E1-1 (D45H, D70H and V290D) may have an impact on the function. In conclusion, our study reveals the diversity of mosquito-borne viruses and potential emerging outbreaks in the southeast coastal region of China, providing new perspectives for mining the ecological characterization of other important arboviruses.