Virulence最新文献

Chronic kidney and urinary tract diseases, including glomerulonephritis, nephrotic syndrome, and chronic kidney disease (CKD), present significant global health challenges. Recent studies suggest a complex interplay between infectious pathogens and immune-mediated kidney damage. This study employs Generalized Summary data-based Mendelian Randomization (GSMR) to explore causal relationships between pathogen-derived antibodies and major urinary and kidney diseases.We conducted a two-sample MR analysis using summary statistics from large-scale Genome-Wide Association Studies (GWAS) to assess associations between 46 pathogen-specific antibodies and seven urinary system diseases. We utilized robust statistical methods, including inverse variance weighting, to ascertain causal effects while controlling for potential confounders.Significant associations were identified between several pathogen-specific antibodies and disease risk. Notably, Epstein-Barr virus (EBNA-1) antibody levels were inversely associated with glomerulonephritis and nephrotic syndrome, indicating a potential protective effect. Conversely, Anti-Merkel cell polyomavirus IgG seropositivity was linked to increased risks of CKD and glomerulonephritis. Additionally, immune-mediated mechanisms were highlighted, with certain antibodies exhibiting dual roles as risk factors or protective agents.This study underscores the complex role of pathogen antibodies in the pathogenesis of kidney and urinary tract diseases, revealing significant implications for future research and potential therapeutic strategies. The findings advocate for further investigation into specific pathogen interactions with the immune system, aiming to inform targeted interventions.

Severe dengue often presents as shock syndrome with enhanced vascular permeability and plasma leakage into tissue spaces. In vitro studies have documented the role of Src family kinases (SFKs) and RhoA-kinases (ROCK) in dengue virus serotype 2 (DENV2)-induced endothelial permeability. Here, we show that the FDA-approved SFK inhibitors Bosutinib, Vandetanib and Ponatinib, as well as the ROCK inhibitors, Netarsudil and Ripasudil significantly inhibit DENV2-induced endothelial permeability. In cultured telomerase immortalized human microvascular endothelial cells (HMEC-1), treatment with these inhibitors reduced the phosphorylation of VE-Cadherin, Src and myosin light chain 2 (MLC2) proteins that were upregulated during DENV2 infection. It also prevented the loss of VE-Cadherin from the inter-endothelial cell junctions induced by viral infection. In in-vivo studies using DENV2-infected AG129 IFN receptor-α/β/γ deficient mice, ponatinib, when administered 24 h post-infection onwards, demonstrated significant benefits in improving body weight, clinical outcomes, and survival rates. While all virus-infected, untreated mice died by day-10 post-infection, 80% of the ponatinib-treated mice survived, and approximately 60% were still alive at the end of the 15-day observation period. The treatment also significantly reduced disease severity factors such as vascular leakage, thrombocytopenia; mRNA transcript levels of proinflammatory cytokines such as IL-1β and TNF-α; and restored liver function. Comparable effects were observed even when ponatinib treatment was initiated after symptom onset. The results highlight ponatinib as an effective therapeutic option in severe dengue; and also a similar potential for other FDA- approved SFK and ROCK inhibitors.

One of the most common hospital-acquired infections is caused by toxigenic Clostridioides difficile. Although C. difficile ST37 only produces a functional toxin B, it causes disease as severe as that caused by hypervirulent ST1. We aim to compare the differences in virulence and drug resistance between ST37 and ST1 isolates. We conducted whole-genome sequencing on ST37 and ST1 isolates, analyzing their type-specific genes, and the distribution and mutation of genes related to virulence and antibiotic resistance. We compared the in vitro virulence-related phenotypes of ST37 and ST1 isolates, including: TcdB concentration, number of spores formed, aggregation rate, biofilm formation, swimming diameter in semi-solid medium, motility diameter on the surface of solid medium, and their resistance to 14 CDI-related antibiotics. We detected 4 ST37-specific genes related to adherence, including lytC, cbpA, CD3246, and srtB. We detected 97 virulence-related genes in ST37 isolates that exhibit genomic differences compared to ST1. ST37 isolates showed increased aggregation, biofilm formation, and surface motility compared to ST1 in vitro. Chloramphenicol resistance gene catQ and tetracycline resistance gene tetM are present in ST37 but absent in ST1 strains. The resistance rates of ST37 to chloramphenicol and tetracycline were 45.4% and 81.8%, respectively, whereas ST1 isolates were sensitive to both antibiotics. ST1 was more resistant to rifaximin than ST37. ST37 isolates showed stronger aggregation, biofilm formation and surface motility, and had higher resistance rates to chloramphenicol and tetracycline. ST1 isolates showed stronger ability to produce toxin and sporulation, and was highly resistant to rifaximin.

The endemic status of goose parvovirus (GPV) continues to devastate the poultry industry in China. Novel GPV (NGPV) and Mutated GPV (MGPV) represent the predominant lineages. However, the comparative pathogenicity between these viruses remains poorly understood. Herein, we selected representative NGPV and MGPV strains as model viruses to assess their pathogenic potential both in vitro and in vivo. In vitro cellular and embryo assays demonstrated that both NGPV and MGPV were capable of replicating in DEF and GEF cells, leading to pronounced cytopathic effects. However, these viruses exhibited distinct levels of intra-embryonic replication capabilities. Furthermore, we conducted in vivo infection experiments and systematically evaluated the pathogenic differences between NGPV and MGPV by examining various indicators, including growth, clinical signs, gross pathology, skeletal development, viral load, and humoral response in the infected animals. The results showed that both NGPV and MGPV inhibited weight gain in goslings and ducklings, with NGPV exerting a more significant suppressive impact. MGPV induced classical gosling plague pathology in goslings, while NGPV led to short beak and dwarfism syndrome in ducklings, notably disrupting skeletal development. Moreover, MGPV and NGPV exhibited diverse host tropisms, with MGPV being more pathogenic to goslings and NGPV to ducklings. Both viruses elicited specific antibody responses, with MGPV being more effective in goslings and NGPV in ducklings. Additionally, MGPV exhibited stronger humoral response compared to NGPV. These findings enhance our understanding of the pathogenicity of prevalent GPV strains in waterfowl, offering a critical theoretical foundation for devising strategies to prevent GPV infections.

The long-term resistance to desiccation on abiotic surfaces is a key determinant of the adaptive success of Acinetobacter baumannii as a healthcare-associated bacterial pathogen. Here, the cellular and molecular mechanisms enabling A. baumannii to resist desiccation and persist on abiotic surfaces were investigated. Experiments were set up to mimic the A. baumannii response to air-drying that would occur when bacterial cells contaminate fomites in hospitals. Resistance to desiccation and transition to the "viable but nonculturable" (VBNC) state were determined in the laboratory-adapted strain ATCC 19606^T and the epidemic strain ACICU. Culturability, membrane integrity, metabolic activity, virulence, and gene expression profile were compared between the two strains at different stages of desiccation. Upon desiccation, ATCC 19606^T and ACICU cells lose culturability and membrane integrity, lower their metabolism, and enter the VBNC state. However, desiccated A. baumannii cells fully recover culturability and virulence in an insect infection model following rehydration in physiological buffers or human biological fluids. Transcriptome and chemical analyses of A. baumannii cells during desiccation unveiled the production of protective metabolites (L-cysteine and L-glutamate) and decreased energetic metabolism consequent to activation of the glyoxylate shunt (GS) pathway, as confirmed by reduced resuscitation efficiency of aceA mutants, lacking the key enzyme of the GS pathway. VBNC cell formation and extensive metabolic reprogramming provide a biological basis for the response of A. baumannii to desiccation, with implications on environmental control measures aimed at preventing the transmission of A. baumannii infection in hospitals.

The gut microbiota maintains host health and shapes immune responses through intricate host-microbe interactions. Bacterial flagellin, a key microbe-associated molecular pattern, is recognized by Toll-like receptor 5 (TLR5) and NOD-like receptor family caspase activation and recruitment domain-containing 4 inflammasome. This dual recognition maintains the delicate balance between immune tolerance and activation, thereby influencing health and disease outcomes. Therefore, we explored the structural and functional evolution of bacterial flagellin to elucidate its role in innate and adaptive immune responses, along with its impact on metabolic processes, particularly via TLR5. In this review, we highlight the diagnostic and therapeutic potential of flagellin, including its application in vaccine development, cancer immunotherapy, and microbiome-based therapies. We integrated perspectives from structural biology, immunology, and microbiome research to elucidate the co-evolutionary dynamics between gut microbiota-derived flagellin and host immunity. Our interpretations provide a basis for the development of innovative strategies to improve health and disease management.

This study presents the genetic structure of two incompatibility (Inc) groups found in Providencia: the newly discovered IncFII_pPROV114-NR and the newly designated Inc_pCHS4.1-3. An extensive genomic comparison was performed on all 14 plasmids (three IncFII_pPROV114-NR plasmids and 11 Inc_pCHS4.1-3 plasmids) from Providencia, including 12 newly sequenced in this study and two from GenBank. Three IncFII_pPROV114-NR plasmids had similar conserved backbones but differed in accessory modules. The 11 Inc_pCHS4.1-3 plasmids fell into two groups according to differences in the conserved genes of the plasmid backbone. The accessory modules of 11 Inc_pCHS4.1-3 plasmids showed significant diversity, indicating numerous gene gains and losses, including in the Tn1696-related region, in Tn7504, in a 17.3-kb sul2 region, and a 63.6-kb bla_NDM-1 region. A minimum of 45 obtained antimicrobial resistance genes (ARGs) were identified in 13 of the 14 plasmids, covering resistance to 14 classes of antimicrobials and heavy metals. Five new mobile genetic elements (MGEs) were identified, including In2168, In1790, Tn7500, Tn7501, and Tn7502. Additionally, three MGEs, Tn7499, Tn7503, and Tn7504 were newly designated. These two Inc group plasmids integrate abundant accessory modules that allow them to accumulate and distribute ARGs and improve the survivability of Providencia under the pressure of drug selection.

Gyrovirus galga1 (GyG1) and Gyrovirus homsa1 (GyH1) are the second and third most common gyroviruses identified, respectively, after chicken anaemia virus. They were first reported in 2011 and are currently prevalent worldwide. However, limited research on these pathogens and a lack of prevention and control strategies have necessitated the establishment of a rapid diagnostic technique to address new challenges in infectious diseases. Recombinase acid amplification (RAA) combined with CRISPR - Cas12a or CRISPR - Cas13a technology has major advantages for highly sensitive and rapid diagnosis. Specific targets can activate CRISPR-Cas trans-cleavage activity, resulting in non-specific cleavage of single-stranded DNA by the CRISPR - Cas12a complex and RNA cleavage by the CRISPR - Cas13a complex. In this study, for the first time, we combined RAA-based CRISPR - Cas12a and CRISPR - Cas13a systems for simultaneous differential diagnosis of GyG1 and GyH1 infection. The results showed that dual fluorescence channel RAA-based CRISPR - Cas12a/Cas13a technology could detect GyG1 and GyH1 within one hour, with a minimum detection limit of 1.5 copies of the target DNA standard/µL and no cross-reactivity with other avian pathogens. In addition, this method could be used for clinical detection, with the results exhibiting high consistency with those obtained by qPCR. These findings demonstrate that our RAA-based CRISPR - Cas12a/Cas13a dual-channel detection system can detect two different subtypes of gyrovirus in a sample with good specificity and high sensitivity, improving the detection efficiency and providing a new technique for the study of viral infection dynamics.

Since the outbreak of coronavirus disease 2019 (COVID-19), the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has continuously mutated and evolved, causing several waves of infection. Predicting the evolutionary and epidemiological dynamics of SARS-CoV-2 remains a challenge. This study combines the epidemic data of different variants of SARS-CoV-2 in South Africa to predict their evolutionary and epidemiological dynamics. Based on the susceptible-infectious-recovered-susceptible (SIRS) transmission dynamics, we consider the transmission rate as an evolutionary trait and the disease-deduced mortality and recovery rates as trade-off functions of the trait. Using the adaptive dynamics method, combined with the epidemic data of the five most recent variants in South Africa, we find that South Africa will be continuously invaded and infected by the new mutant strain with a higher transmission rate. In addition, we find that changing the recovery rate by enhancing treatment, for example, will alter the trade-off function and thereby affect the evolutionary dynamics of SARS-CoV-2, which may evolve into a continuously stable strategy. This study is the first to use evolutionary dynamics theory to predict the future evolutionary and epidemiological dynamics of SARS-CoV-2, which is helpful for the government to predict the epidemic dynamics of COVID-19 and to take effective measures in advance, and it is proposed that advancing treatment time and improving treatment efficiency will contribute to disease control.

Duck enteritis virus (DEV) was identified as the etiological agent responsible for an outbreak of morbidity and mortality in adult ducks on a farm in Jiangsu, China. Diagnostic approaches confirmed that the outbreak was caused by the highly pathogenic DEV-JS2024 isolate. The clinical progression of the disease, characterized by lethargy, anorexia, ocular discharge, and high mortality, was accompanied by extensive hemorrhagic lesions in critical organs such as the liver, spleen, lungs, and bursa of Fabricius, consistent with known signs of DEV infection. Genomic analysis of DEV-JS2024 revealed a 45% G+C content and 76 open reading frames. BLASTn analysis revealed that the genome of DEV-JS2024 shares the highest sequence similarity with the Chinese virulent strain CV and the DEV attenuated vaccine strain C-KCE in the database. These results indicate a close genetic relationship between DEV-JS2024 and both the virulent and attenuated strains, suggesting potential similarities in their genomic architecture. Comparative genomic analysis identified 28 nucleotide mutations, including 15 non-synonymous mutations potentially related to virulence factors. The study also highlighted the first reported 528 base pairs deletion in the UL2 gene of a virulent strain, challenging its utility as a marker for distinguishing virulent from attenuated strains. Phylogenetic analysis suggested that DEV-JS2024 may result from recombination between the vaccine and virulent strains, further complicating our understanding of DEV pathogenicity. This study provides new insights into the molecular evolution of DEV and stresses the importance of continued genomic surveillance to enhance vaccine development and control measures for duck plague.