The innate immune system is the first line of defense, playing a crucial role in sensing viral infections. The recent discovery implicates manganese (Mn) in the activation of the innate immune DNA-sensing cGAS-STING pathway, leading to an anti-DNA virus response. Despite this, the involvement of Mn2+ in bolstering the host's defense mechanisms against RNA viruses is currently uncertain. We observed that Mn2+ exhibited antiviral activity across various animal and human viruses, encompassing RNA viruses like PRRSV and VSV, and DNA viruses including HSV1, in a fashion that correlated with the dose. Additionally, Mn2+'s antiviral effect on cGAS and STING was investigated in CRISPR-Cas9-modified knockout cells. Surprisingly, the outcomes revealed that inactivation of cGAS or STING pathways did not affect Mn2+-mediated antiviral processes. However, we ascertained that the presence of Mn2+ triggered the cGAS-STING signaling pathway. These findings indicate a broad-spectrum antiviral effect of Mn2+, acting independently of the cGAS-STING pathway. Further insights into redundant mechanisms underpinning Mn2+'s antiviral properties are revealed by this study, which also identifies a promising new target for antiviral treatments utilizing Mn2+.
Viral gastroenteritis, a prevalent global issue, is frequently linked to norovirus (NoV), especially among young children under five years old. The study of norovirus (NoV) diversity in middle- and low-income nations, encompassing Nigeria, lacks extensive epidemiological support. Three Ogun State hospitals in Nigeria were the sites for this investigation into the genetic variety of norovirus (NoV) within children under five experiencing acute gastroenteritis. In the period between February 2015 and April 2017, a total of 331 fecal samples were collected. A random subset of 175 samples was then subjected to RT-PCR analysis, followed by partial sequencing and phylogenetic analysis of both the polymerase (RdRp) and capsid (VP1) genes. In a study of 175 samples, NoV was detected in 51% (9 samples) using RdRp and in 23% (4 samples) using VP1 testing. Critically, a high co-infection rate of 556% (5 samples out of 9 NoV positive) was observed with other enteric viruses. A substantial variety of genotypes was observed, in which GII.P4 emerged as the most common RdRp genotype (667%), containing two genetic clusters, and GII.P31 at 222%. A low rate (111%) of the GII.P30 genotype, which is rare, was observed in Nigeria for the first time. In the VP1 gene analysis, GII.4 genotype was the most frequent (75%), co-circulating with both the Sydney 2012 and potentially the New Orleans 2009 variant strains during the study. Potential recombinant strains were detected; these included the intergenotypic strains GII.12(P4) and GII.4 New Orleans(P31), and the intra-genotypic strains GII.4 Sydney(P4) and GII.4 New Orleans(P4). Nigeria's potential first instance of GII.4 New Orleans (P31) is implied by this finding. Furthermore, GII.12(P4) was initially documented in Africa, and subsequently globally, in this investigation, as far as we are aware. This study's analysis of NoV genetic diversity in Nigeria provides essential data for future vaccine designs and for tracking the emergence of new and recombinant strains.
A machine learning framework utilizing genome polymorphisms is presented for prognosticating severe cases of COVID-19. Genomic analysis of 296 innate immunity loci was conducted on 96 Brazilian severe COVID-19 patients and controls. Our model selected the optimal locus subset for classification using recursive feature elimination and a support vector machine. Subsequently, a linear kernel support vector machine (SVM-LK) was used to classify patients into the severe COVID-19 group. The SVM-RFE method's selection process highlighted 12 single nucleotide polymorphisms (SNPs) within 12 genes: PD-L1, PD-L2, IL10RA, JAK2, STAT1, IFIT1, IFIH1, DC-SIGNR, IFNB1, IRAK4, IRF1, and IL10, as the most prominent features. According to the SVM-LK's COVID-19 prognosis calculations, the metrics obtained were 85% accuracy, 80% sensitivity, and 90% specificity. infection fatality ratio The univariate analysis, applied to the 12 selected SNPs, brought to light significant features related to individual variant alleles. Of note were the risk-associated alleles (PD-L1 and IFIT1), and the protective alleles (JAK2 and IFIH1). PD-L2 and IFIT1 genes were identified within the set of variant genotypes associated with risk factors. The complex classification methodology proposed is able to identify individuals at high risk for severe COVID-19 outcomes, even in the absence of infection, offering a disruptive perspective in the realm of COVID-19 prognosis. The genetic environment proves to be a key determinant in the progression of severe COVID-19, as our results demonstrate.
Earth's genetic landscape is characterized by the unparalleled diversity of bacteriophages. Two novel bacteriophages, nACB1 (Podoviridae morphotype) and nACB2 (Myoviridae morphotype), were isolated from sewage samples in this study; these phages specifically infect Acinetobacter beijerinckii and Acinetobacter halotolerans, respectively. Comparison of nACB1 and nACB2 genome sequences revealed genome sizes of 80,310 base pairs for nACB1 and 136,560 base pairs for nACB2. Analysis of the genomes demonstrated that they are novel members of the Schitoviridae and Ackermannviridae families, exhibiting only 40% overall nucleotide identity to any other phage. Amongst other genetic attributes, nACB1 exhibited a substantial RNA polymerase, whereas nACB2 presented three presumptive depolymerases (two capsular, and one esterase) encoded consecutively. In this report, we present the first observation of bacteriophages targeting both *A. halotolerans* and *Beijerinckii* human pathogenic species. The results from these two phages enable a deeper look into phage-Acinetobacter interactions and the evolutionary path of this phage group's genetics.
The hepatitis B virus (HBV), dependent on the core protein (HBc), establishes a productive infection, marked by the formation of covalently closed circular DNA (cccDNA), and executes nearly every subsequent lifecycle stage following cccDNA synthesis. The pregenomic RNA (pgRNA) of the virus is contained by an icosahedral capsid, formed by numerous copies of HBc protein, and this supports the reverse transcription of pgRNA to a relaxed circular DNA (rcDNA) form within the capsid itself. arbovirus infection The HBV virion's entry into human hepatocytes, facilitated by endocytosis, involves its complete structure encompassing an outer envelope and an internal nucleocapsid containing rcDNA. This virion then travels through endosomal compartments and the cytosol, finally releasing its rcDNA into the nucleus, resulting in the production of cccDNA. Furthermore, newly formed rcDNA within cytoplasmic nucleocapsids is also transported to the nucleus of the same cell, where it contributes to the formation of more cccDNA through a process known as intracellular cccDNA amplification or recycling. This paper focuses on recent data demonstrating HBc's varied effects on cccDNA formation during de novo infection compared to cccDNA recycling, achieved through the utilization of HBc mutations and small-molecule inhibitors. The results demonstrate a crucial function of HBc in directing HBV's movement during infection, along with its part in nucleocapsid disassembly (uncoating) to release rcDNA, processes vital for the creation of cccDNA. Interactions with host elements likely underpin HBc's function in these procedures, a critical determinant of HBV's host tropism. A more thorough understanding of the contributions of HBc to HBV cell entry, cccDNA generation, and host selectivity should accelerate the efforts to target HBc and cccDNA as treatment targets for an HBV cure, and help create convenient animal models for both basic research and drug development.
COVID-19, an illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, poses a significant and global public health concern. Using gene set enrichment analysis (GSEA) for drug discovery, we aimed to develop innovative anti-coronavirus therapeutics and preventive strategies. The results indicated that Astragalus polysaccharide (PG2), a blend of polysaccharides from Astragalus membranaceus, efficiently reversed COVID-19 signature genes. Subsequent biological procedures revealed that PG2 could obstruct the fusion of BHK21 cells producing wild-type (WT) viral spike (S) protein with Calu-3 cells expressing ACE2. Furthermore, it explicitly hinders the binding of recombinant viral S glycoproteins from wild-type, alpha, and beta strains to the ACE2 receptor in our non-cellular system. In contrast, PG2 elevates the expression of let-7a, miR-146a, and miR-148b in the cellular lining of the lungs. These results hint at the potential of PG2 to decrease viral replication within the lungs and cytokine storm via the PG2-induced miRNAs. Principally, macrophage activation is a major contributor to the complex challenges faced by COVID-19 patients, and our results demonstrate PG2's capacity to regulate macrophage activation by encouraging the polarization of THP-1-derived macrophages towards an anti-inflammatory phenotype. Stimulation with PG2, as observed in this study, led to the activation of M2 macrophages and an increase in the expression levels of anti-inflammatory cytokines, IL-10 and IL-1RN. Selleck AZD5438 Patients with severe COVID-19 symptoms have recently been treated with PG2, in order to reduce the neutrophil-to-lymphocyte ratio (NLR). Accordingly, our investigation indicates that PG2, a repurposed medication, can prevent WT SARS-CoV-2 S-mediated syncytia formation with host cells; it also inhibits the binding of S proteins from WT, alpha, and beta strains to the recombinant ACE2 and prevents the development of severe COVID-19 by controlling macrophage polarization to the M2 subtype.
The transmission of pathogens, facilitated by contact with contaminated surfaces, significantly contributes to the spread of infections. The contemporary COVID-19 outbreak emphasizes the necessity of diminishing transmission facilitated by surfaces.