Search Results (18,536)

African swine fever virus (ASFV) is a high-consequence pathogen that causes African swine fever (ASF), for which mortality rates can reach 90–100%, with death typically occurring within 14 days. ASF is currently a highly contagious pandemic disease responsible for extensive losses in pig production in multiple affected countries suffering from extended outbreaks. While a limited number of vaccines to prevent ASF are in use in south-east Asia, vaccines are not widely available, are only effective against highly homologous strains of ASFV, and must be used prior to an outbreak on a farm. Currently, there is no treatment for ASF and culling affected farms is the only response to outbreaks on farms to try and prevent spreading. CRISPR/Cas systems evolved as an adaptive immune response in bacteria and archaea that function by cleaving and disrupting the genomes of invading bacteriophage pathogens. CRISPR technology has since been leveraged into an array of endonuclease-based systems used for nucleic acid detection, targeting, genomic cleavage, and gene editing, making them particularly well-suited for development as sequence-specific therapeutic modalities. The programmability of CRISPR-based therapeutics offers a compelling new way to rapidly and specifically target pathogenic viral genomes simply by using different targeting guide RNAs (gRNA) as an adaptable antiviral modality. Here, we demonstrate for the first time a specific CRISPR/Cas9 multiplexed gRNA system that targets the African swine fever viral genome, resulting in sequence-specific cleavage, leading to the reduction in the viral load in infected animals, and subsequent recovery from an otherwise lethal dose of ASFV. Moreover, animals that recovered had protective immunity to subsequent homologous ASFV infection. Full article

Background: Cystic echinococcosis (CE) is a globally distributed zoonosis triggered by the larval stage of Echinococcus granulosus (E. granulosus), impacting humans and an extensive array of mammalian intermediate hosts. EGR-01664 is the major egg antigen of E. granulosus, but almost nothing is currently known about the function of EGR-01664 from E. granulosus. Methods: This study aimed to investigate the E. granulosus EGR-01664 gene (GenBank ID: 36337379), and the recombinant EGR-01664 protein was expressed successfully. Next, the transcription of the EGR-01664 gene across various developmental stages of E. granulosus was analyzed. Its spatial expression patterns in adult worms and protoscoleces were characterized using both quantitative PCR (qPCR) and immunofluorescence assays. Furthermore, the immunomodulatory effects of rEGR-01664 on cell proliferation, nitric oxide production, and cytokine secretion were examined by co-culturing the recombinant protein with canine PBMCs. Results: The rEGR-01664 could be recognized by sera from dogs infected with E. granulosus. Immunofluorescence assay (IFA) localization revealed the protein’s presence in the epidermis of protoscoleces, the adult epidermis, and some parenchymal tissues. qPCR revealed that EGR-01664 mRNA levels were significantly higher in protoscoleces compared to adults (p < 0.0001). At a concentration of 20 μg/mL, rEGR-01664 could significantly activate the transcription and expression of IL-10, TGF-β1, IL-17A, and Bax in canine PBMCs. However, with an increase in concentration, it inhibited the expression of IFN-γ, Bcl-2, GSDMD, IL-18, and IL-1β. These results suggest that the EGR-01664 gene plays a crucial role in the development, parasitism, and reproduction of E. granulosus. In vitro studies have shown that rEGR-01664 protein regulates the immune regulation function of canine PBMCs, suggesting its potential as a vaccine adjuvant or immunotherapy target. Conclusions: EGR-01664 may modulate canine PBMC functions to regulate host immune responses, thereby facilitating our understanding of how E. granulosus EGR-01664 contributes to the mechanism of parasitic immune evasion. Full article

Cardiovascular morbidity and mortality rise precipitously during the 6th–9th decades of life, identifying aging as a critical risk factor. Simultaneously, older individuals are susceptible to severe viral infection, raising the question whether shared mechanisms exist that predispose to both cardiovascular disease (CVD) and failing anti-viral immunity. The aging process causes steady decline in immune fitness (immune aging), which undermines the ability to generate protective anti-viral immune responses. Paradoxically, the aging immune system supports unopposed inflammatory pathways (inflammaging), which exacerbates tissue inflammation in CVD, specifically atherosclerosis. Here, we review the current evidence of how innate and adaptive immune aging promotes tissue-destructive inflammation in atherosclerosis while failing to fight viral infections. Further, we consider how these two disease processes mutually influence each other. We propose that mounting an effective anti-viral response induces off-target bystander activation and exhausts immune cells, ultimately exacerbating CVD. Additionally, we explore how atherosclerotic CVD impacts innate immunity through epigenetic modification of hematopoietic precursors and metabolically conditioning immune cells, leading to a dysfunctional immune system that accelerates plaque inflammation while simultaneously impairing host defense. Full article

Mathematical modeling is essential for understanding the complex regulatory pathways governing cell death and survival, including apoptosis, necroptosis, pyroptosis, ferroptosis, autophagy, and immunogenic cell death (ICD)—a functional category comprising diverse morphological types capable of activating immune responses. The growing number of models describing individual signaling pathways poses the challenge of integrating them into a cohesive framework. This review aims to identify common components across existing ordinary differential equation models that could serve as key nodes to merge distinct signaling modalities. Proposed models highlight Bcl-2, Bax, Ca², and p53 as shared regulators linking autophagy and apoptosis. Necroptosis and apoptosis are interconnected via TNF signaling network and modulated by caspase-8, c-FLIP, and NFκB, with RIPK1 acting as a critical hub directing pathway choice. Pyroptosis and apoptosis are co-regulated by NFκB, tBid, and caspases, while ferroptosis is modeled exclusively as an independent process, separate from other forms of cell death. Furthermore, existing models indicate that ICD intersects with necroptosis during oncolytic virotherapy, with pyroptosis in SARS-CoV-2 infection, and with apoptosis in the context of chemotherapy. Although several models address crosstalk between pairs of cell fate decisions, creating comprehensive frameworks that encompass three or more death modes remains an open challenge. Full article

Pierce’s disease (PD), caused by the xylem-limited bacterium Xylella fastidiosa, poses a significant threat to global grapevine (Vitis vinifera) production. Despite its economic importance, the dynamic molecular mechanisms underlying grapevine responses to infection remain poorly understood. This study re-analyzed the publicly available RNA-seq dataset GSE152164 to characterize phase-dependent transcriptional reprogramming during PD progression. Differential expression analysis using DESeq2 identified 1093 differentially expressed genes (DEGs) during the early infection phase (Phase I) and 136 in the intermediate phase (Phase II), indicating a strong early defense response followed by transcriptional downregulation as symptoms progressed. Comparative analysis distinguished 991 Phase-I-specific and 34 Phase-II-specific genes, along with 167 infection-specific temporal DEGs, underscoring a coordinated early immune response and subsequent metabolic repression. Protein–protein interaction network analysis identified 21 high-confidence hub genes, including chitinase (VIT_16s0050g02220), thaumatin-like protein (VIT_02s0025g04250), and EDS1 (VIT_17s0000g07560), which represent core regulators of defense and stress adaptation pathways. Collectively, this study elucidates the transcriptional dynamics underlying V. vinifera responses to X. fastidiosa and provides valuable insights for developing disease-resistant cultivars to mitigate Pierce’s disease. Full article

Shewanella putrefaciens is a significant bacterial pathogen causing high mortality in farmed largemouth bass (Micropterus salmoides). This study investigated the molecular immune responses in its primary target organs, the liver and spleen, via transcriptomic profiling at 24 h post-infection. We identified 458 significantly differentially expressed genes (DEGs) in the liver and 1405 in the spleen. Gene Ontology enrichment analysis revealed organ-specific immune strategies: the liver response was characterized by type I interferon signaling pathway, whereas the spleen response centered on the regulation of innate immune response. Furthermore, Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that fatty acid metabolism and cytokine-cytokine receptor interaction were significantly enriched in the liver. In contrast, the C-type lectin receptor signaling pathway and cytokine-cytokine receptor interaction were the most prominent in the spleen. Several key DEGs (e.g., stat1a, rsad2, pglyrp5, pglyrp6, acaca, stat2, lepb) associated with immune response, metabolic adaptation, and cellular stress were identified, suggesting a coordinated host mechanism involving pathogen recognition, immunomodulation, and tissue repair. These results provide crucial insights into the immunomodulatory processes in largemouth bass against S. putrefaciens infection. Full article

Background/Objectives: Following the global spread of SARS-CoV-2, there was an urgent need for vaccine development to support immune protection. This study aimed to evaluate the impact of active and hybrid immunity on the durability of immunoglobulin G (IgG), neutralizing antibodies, and cellular immune responses over a two-year period. Methods: This longitudinal study was conducted from February 2021 to December 2023 at the Public Health Institute in Ostrava, Czech Republic. Anti-S IgG was measured using ELISA (Euroimmun), neutralizing antibodies via an in-house virus neustralization test (VNT), and cellular immune response using the IGRA test (ELISA, Euroimmun). Participants also completed a questionnaire on demographics, COVID-19 history, symptoms, and vaccination. Statistical analysis included descriptive and non-parametric tests (Mann–Whitney U, Kruskal–Wallis) at a 5% significance level. Results: The cohort included 149 individuals, 97.3% of whom were vaccinated with Comirnaty (Pfizer/BioNTech). A total of 17% had confirmed infection prior to vaccination and showed up to two-fold higher neutralizing antibody levels (p < 0.001) within 2–6 weeks postvaccination. Postvaccination infection was reported in 35% of participants. Although antibody levels declined over the 2–100 week period, participants remained seropositive across all three parameters. Cellular immune response (interferon-γ) remained consistently high throughout follow-up. Conclusions: The study demonstrates long-term durability of IgG and neutralizing antibodies and confirms durable cellular immunity up to two years postvaccination. Hybrid immunity significantly enhanced neutralizing antibody levels, supporting its added value in protective immunity against SARS-CoV-2. Full article

This study aimed to evaluate the pathogenic potential of the 2024 Vietnam PRRSV genotype 2 (NA01/2024, isolate). Fifteen 6-week-old piglets were intramuscularly inoculated with 1 × 10^5.5 TCID₅₀/mL of PRRSV, while fifteen control piglets remained uninfected. Blood and nasal swabs were collected every 3 days until 21 days post-infection (dpi). Necropsies were performed on piglets at 6, 15, and 21 dpi. Infected piglets exhibited fever, blue ear, weight loss, respiratory distress, diarrhea, and leucopenia between 3 and 12 dpi. PRRSV was detected in serum and nasal secretions up to 21 dpi, peaking between 6 and 9 dpi. Seroconversion began at 6 dpi, with the highest antibody titers at 21 dpi. Virus load was highest in lung tissues at all intervals, while the spleen and lymph nodes showed higher viral load at later stages. Routine blood tests indicated a slight decrease in red blood cells, hemoglobin, and reticulocytes, along with a notable increase in monocytes in infected piglets. Cytokine levels (IFN-γ, IL-6, and IL-10) in serum and lung tissues were significantly higher in infected piglets compared to controls. Additionally, the PRRSV infection triggered innate immune responses, including cytokines, growth factors, and chemokines in whole blood and tissues such as IFN-α, IFN-β, TNF-α, IL-1β, etc. These findings highlight the pathogenicity of the Vietnam PRRSV NA01/2024 isolate and its impact on the immune response, providing insights into PRRSV infection mechanisms and strategies for prevention and control. Full article

Sepsis poses a significant global health burden, with millions of cases and high mortality rates annually, largely due to challenges in early diagnosis and monitoring. Traditional methods, reliant on nonspecific clinical manifestations and limited biomarkers like C-reactive protein and procalcitonin, often fail to distinguish infection from non-infectious inflammation or capture disease heterogeneity. This review synthesizes recent progress in omics technologies—genomics, transcriptomics, proteomics, and metabolomics—for advancing sepsis management. Genomics, via metagenomic next-generation sequencing, enables rapid pathogen identification and genetic variant analysis for susceptibility and prognosis. Transcriptomics reveals molecular subtypes and immune dynamics through RNA sequencing and single-cell approaches. Proteomics and metabolomics uncover protein and metabolite profiles linked to immune imbalance, organ damage, and metabolic disorders. Multi-omics integration, enhanced by artificial intelligence and machine learning, facilitates biomarker discovery, patient stratification, and predictive modeling, bridging laboratory findings to bedside applications like rapid diagnostic tools and clinical decision support systems. Despite advancements, challenges including data heterogeneity, high costs, and ethical concerns persist. Future directions emphasize single-cell and spatial omics, AI-driven personalization, and ethical frameworks to transform sepsis care from reactive to proactive, ultimately improving outcomes. Full article

Interstitial lung diseases (ILDs) represent a group of lung disorders that primarily affect the lung parenchyma. These disorders are usually progressive, may be debilitating and life threatening, and often pose diagnostic and therapeutic challenges. Exhaled breath analyses offer opportunity for diagnosis, differential diagnosis, and to predict prognosis and treatment outcomes. Numerous studies have been published using various exhaled biomarker analyses, including exhaled nitric oxide, exhaled breath condensate, and exhaled volatile organic compounds. This review summarises and critically appraises the literature and offers suggestions for further research to apply exhaled biomarker analyses in clinical practice. Full article

The Influenza A Virus (IAV) is known to hijack cellular proteins during its replication. IAV infection increases the expression of Heat-shock-protein family A (Hsp70) member 5 (HSPA5) in human cells, but its specific function in the viral life cycle remains unclear. This study aims to elucidate the function of HSPA5 in IAV replication, by implementing HSPA5 knockdown (KD) in A549 cells and assessing its impact on IAV’s viral protein translation, genomic RNA transcription, and the host cellular proteome. HSPA5 KD significantly reduced progeny virus release, although viral RNA levels were unaffected. Interestingly, levels of viral structural proteins increased in HSPA5 KD cells after infection. Treatment with HSPA5 inhibitor also suppressed IAV replication, confirming its role as a host dependency factor. Proteomic profiling revealed 116 proteins altered in wild-type cells and 223 in HSPA5 KD cells, with 32 uniquely dysregulated in wild-type and 139 unique to HSPA5 KD cells. In HSPA5 knockdown cells, the altered proteins were linked to pathways such as EIF2, EGF, PEDF, CNTF, IL-13, and G-protein receptor signaling, as well as to cellular processes like lymphocyte activation and regulation of immune and blood cell death, which were not affected in wild-type cells after IAV infection. Overall, this study suggests that HSPA5 contributes to late stages of IAV replication, likely assembly or maturation, and represents a promising target for antiviral drug development. Full article

Equine herpesvirus (EHV) infections represent a significant global veterinary and economic challenge affecting both horses and donkeys across all inhabited continents. This narrative review comprehensively examines the nine distinct EHV species (EHV-1 through EHV-9), their taxonomic classification within Alphaherpesvirinae and Gammaherpesvirinae subfamilies, and their diverse host tropism patterns. The complex molecular pathogenesis involves sophisticated viral glycoproteins (gK, gB, gC, gH, gM, gL, gG, gD, gI, gE) that orchestrate cellular invasion, immune evasion, and intercellular transmission. Clinical manifestations vary considerably, ranging from respiratory diseases and reproductive failures to severe neurological disorders, with EHV-1 demonstrating the most severe presentations including myeloencephalopathy. Global distribution analysis reveals widespread circulation across Europe, Asia, Africa, the Americas, and Oceania, with species-specific clinical patterns. Current therapeutic options remain largely supportive, with experimental compounds like berbamine and cepharanthine, celastrol, blebbistatin, and hyperoside showing promise in preclinical studies. Vaccination programs demonstrate limited effectiveness, failing to prevent transmission at population levels despite inducing individual immune responses. The sophisticated immune evasion strategies employed by EHVs, including the “Trojan horse” mechanism utilizing infected leukocytes, highlight the complexity of host–pathogen interactions and underscore the urgent need for innovative prevention and treatment strategies. Full article

Leishmaniasis and Chagas disease, caused by Leishmania spp. and Trypanosoma cruzi, are neglected tropical diseases with significant global health burden, particularly in resource-limited regions. Despite their impact, diagnosis and treatment remain challenging due to limited diagnostic tools and the toxicity of available therapies. Our objective is to propose the incorporation of markers for the diagnosis of leishmaniasis and Chagas disease using ncRNA. This narrative review evaluates studies published between 2010 and 2024 (PubMed, Scopus, Google Scholar) using the SANRA scale to assess the potential of non-coding RNAs (ncRNAs) as biomarkers for these infections. Both parasites release small RNAs via extracellular vesicles that modulate host–pathogen interactions and gene expression. Although RNA interference machinery is absent in T. cruzi and most Leishmania species, it persists in early-diverging lineages. In leishmaniasis, distinct miRNA expression profiles—including miR-155-5p, miR-5011-5p, miR-6785-5p, and miR-361-3p—demonstrate high diagnostic accuracy for detecting infection (AUC up to 1.0). Serum long ncRNAs such as MALAT1 and NUTM2A-AS1 show potential diagnostic value, though clinical validation remains pending. For Chagas disease, the available evidence on ncRNAs primarily addresses the diagnosis of clinical manifestations rather than initial infection. Host miRNAs, including miR-21, miR-145, miR-146a/b, and miR-19a-3p, correlate with cardiac involvement, immune dysregulation, and inflammation during chronic T. cruzi infection. Circulating miRNAs exhibit modest sensitivity (57–67%) and specificity (57–80%) for diagnosing chronic Chagas cardiomyopathy, indicating their utility in assessing disease progression and organ damage rather than detecting early infection. This review distinguishes between ncRNAs that diagnose infection and those that evaluate disease severity or organ involvement. Altered ncRNA expression profiles represent promising biomarkers for species differentiation, treatment monitoring, and assessing cardiac complications in Chagas disease, with broader diagnostic applications emerging for leishmaniasis. Full article

Human herpesvirus-8 (HHV-8) is a gamma herpesvirus linked to the development of Kaposi sarcoma (KS). KS is more common in persons living with HIV (PLWH), but endemic KS in HIV-negative individuals is also common in sub-Saharan Africa. HHV-8 shedding occurs in the oral mucosa and is likely responsible for transmission. The mechanistic drivers of different HHV-8 shedding patterns in infected individuals are unknown. We applied stochastic mathematical models to a longitudinal study of HHV-8 oral shedding in 295 individuals in Uganda who were monitored daily with oral swabs. Participants were divided into four groups based on whether they were HIV-negative or -positive, as well as KS-negative or -positive. In all groups, we observed a wide variance of shedding patterns, including no shedding, brief episodic low viral load shedding, prolonged episodic medium viral load shedding, and persistent high viral load shedding. Our model closely replicates patterns in individual data and attributes higher shedding rates to increased rates of viral reactivation and lower median viral load values to more rapid and effective engagement of cytolytic immune responses. Our model provides a framework for understanding different shedding patterns observed in individuals with HHV-8 infection. Full article

Chronic inflammation constitutes a significant characteristic of sustained infections caused by viral and fungal pathogens, with a strong correlation to the development of cancer, autoimmune disorders, and tissue fibrosis. Viral proteins such as HIV-1 Tat, HBV X (HBx), HPV E6/E7, and EBV LMP1 modulate the host’s immune signaling pathways, primarily through the activation of the NF-κB signaling cascade and the disruption of cytokine equilibrium. These molecular interactions result in a pro-inflammatory microenvironment that facilitates viral persistence, immune evasion, and the process of oncogenesis. Structural investigations have elucidated the mechanisms by which these viral proteins interact with host signaling complexes, thereby highlighting their potential as viable therapeutic targets. Similarly, fungal proteins, including secreted aspartyl proteases (Saps), ribotoxin Asp f1, and chitin-binding proteins, incite chronic inflammation by activating pattern recognition receptors and triggering inflammasome activation. Despite the limited structural information of these fungal proteins, emerging models and bioinformatic analyses identified conserved motifs that are crucial for host interactions. Biologic therapies, encompassing antiviral and antifungal peptides as well as monoclonal antibodies, are currently under development to disrupt these protein-host interactions and modulate inflammatory responses. This review provides structural and functional insight into viral and fungal inflammatory proteins and evaluates the potential of biologics as targeted therapeutic interventions for chronic inflammation associated with infections. We discuss the ongoing clinical trials involving neutralizing antibodies targeting HIV, peptide vaccines aimed at HPV and other promising molecules. Finally, we discuss the current limitations of biologics and possible solutions to translate these promising therapeutics into clinical practice. Full article