Role of Microbiota-Derived Metabolites in Alcoholic and Non-Alcoholic Fatty Liver Diseases

Chronic liver disease encompasses diseases that have various causes, such as alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). Gut microbiota dysregulation plays a key role in the pathogenesis of ALD and NAFLD through the gut–liver axis. The gut microbiota consists of various microorganisms that play a role in maintaining the homeostasis of the host and release a wide number of metabolites, including short-chain fatty acids (SCFAs), peptides, and hormones, continually shaping the host’s immunity and metabolism. The integrity of the intestinal mucosal and vascular barriers is crucial to protect liver cells from exposure to harmful metabolites and pathogen-associated molecular pattern molecules. Dysbiosis and increased intestinal permeability may allow the liver to be exposed to abundant harmful metabolites that promote liver inflammation and fibrosis. In this review, we introduce the metabolites and components derived from the gut microbiota and discuss their pathologic effect in the liver alongside recent advances in molecular-based therapeutics and novel mechanistic findings associated with the gut–liver axis in ALD and NAFLD.

Functional Characterization of the Nep1-Like Protein Effectors of the Necrotrophic Pathogen – Alternaria brassicae

Alternaria brassicae is an important necrotrophic pathogen that infects the Brassicaceae family. A. brassicae, like other necrotrophs, also secretes various proteinaceous effectors and metabolites that cause cell death to establish itself in the host. However, there has been no systematic study of A. brassicae effectors and their roles in pathogenesis. The availability of the genome sequence of A. brassicae in public domain has enabled the search for effectors and their functional characterization. Nep1-like proteins (NLPs) are a superfamily of proteins that induce necrosis and ethylene biosynthesis. They have been reported from a variety of microbes including bacteria, fungi, and oomycetes. In this study, we identified two NLPs from A. brassicae viz. AbrNLP1 and AbrNLP2 and functionally characterized them. Although both AbrNLPs were found to be secretory in nature, they localized differentially inside the plant. AbrNLP2 was found to induce necrosis in both host and non-host species, while AbrNLP1 could not induce necrosis in both species. Additionally, AbrNLP2 was shown to induce pathogen-associated molecular pattern (PAMP)-triggered immunity in both host and non-host species. Overall, our study indicates that AbrNLPs are functionally and spatially (subcellular location) distinct and may play different but important roles during the pathogenesis of A. brassicae.

Viral Strain-Specific Activation of Pathogen-Associated Molecular Pattern-Triggered Immunity Enhances Symptom Severity in Broad Bean Wilt Virus 2 Infection

Broad bean wilt virus 2 (BBWV2) is an emerging virus in various economically important crops, especially pepper (Capsicum annuum L.), worldwide. Recently, the emergence of various BBWV2 strains that induce severe symptoms has increased damage to pepper crops. While the symptomatic variations among virus strains should be associated with differences in the transcriptomic reprogramming of host plants upon infection, underlying molecular mechanisms and associated genes are largely unknown. In the present study, we employed transcriptome analysis to identify responsible host factors for symptom enhancement in the BBWV2-pepper pathosystem using two distinct BBWV2 strains, PAP1 (a severe strain) and RP1 (a mild strain). Comparative analysis of the differentially expressed genes (DEGs) revealed that various genes associated with pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) and ethylene signaling were significantly upregulated upon infection with the severe PAP1 strain, but not with the mild RP1 strain. Indeed, hormone analysis revealed that ethylene emission was significantly increased in pepper plants infected with PAP1. These observations imply that the activation of the PTI-associated defense responses reinforce symptom formation during BBWV2 infection in a virus strain-specific manner.

Induction of transposable element expression is central to innate sensing

SUMMARYEvidence indicates that transposable elements (TEs) stimulate innate sensing pathways in various pathologies but it is not clear whether they are sensed during normal physiological responses. Here we show that, during activation with an exogenous pathogen associated molecular pattern (PAMP), dendritic cells (DCs) epigenetically remodel heterochromatin at TEs by depleting the methyltransferase Suv39h1 and reducing histone-3 lysine-9 trimethylation (H3K9me3). TLR4 signaling activates TE expression to enhance innate responses through the DNA sensor cGAS. Cytosolic cGAS-bound DNA comprised LINE1 TEs as the predominant endogenous ligands. Concordantly, LINE1 inhibition attenuated the type-I IFN response to LPS and rescued influenza virus infection. We propose that in healthy cells, exogenous PAMPs epigenetically activate self-derived PAMPs (LINE1) that engage cGAS to enhance responses. These data explain why pathogens employ redundant and broad innate immune countermeasures, to suppress activation of host PAMPs and illustrate a hitherto unappreciated role for host genome-derived PAMPs in response to pathogens.

Differential regulation of G protein signaling in Arabidopsis through two distinct pathways that internalize AtRGS1

In animals, endocytosis of a seven-transmembrane GPCR is mediated by arrestins to propagate or arrest cytoplasmic G protein–mediated signaling, depending on the bias of the receptor or ligand, which determines how much one transduction pathway is used compared to another. In Arabidopsis thaliana, GPCRs are not required for G protein–coupled signaling because the heterotrimeric G protein complex spontaneously exchanges nucleotide. Instead, the seven-transmembrane protein AtRGS1 modulates G protein signaling through ligand-dependent endocytosis, which initiates derepression of signaling without the involvement of canonical arrestins. Here, we found that endocytosis of AtRGS1 initiated from two separate pools of plasma membrane: sterol-dependent domains and a clathrin-accessible neighborhood, each with a select set of discriminators, activators, and candidate arrestin-like adaptors. Ligand identity (either the pathogen-associated molecular pattern flg22 or the sugar glucose) determined the origin of AtRGS1 endocytosis. Different trafficking origins and trajectories led to different cellular outcomes. Thus, in this system, compartmentation with its associated signalosome architecture drives biased signaling.

Protective Effects of Fucoxanthin Dampen Pathogen-Associated Molecular Pattern (PAMP) Lipopolysaccharide-Induced Inflammatory Action and Elevated Intraocular Pressure by Activating Nrf2 Signaling and Generating Reactive Oxygen Species

Inflammation and oxidative stress are closely related processes in the pathogenesis of various ocular diseases. Uveitis is a disorder of the uvea and ocular tissues that causes extreme pain, decreases visual acuity, and can eventually lead to blindness. The pharmacological functions of fucoxanthin, isolated from brown algae, induce a variety of therapeutic effects such as oxidative stress reduction and repression of inflammation reactions. However, the specific anti-inflammatory effects of fucoxanthin on pathogen-associated molecular pattern (PAMP) lipopolysaccharide-induced uveitis have yet to be extensively described. Therefore, the aim of present study was to investigate the anti-inflammatory effects of fucoxanthin on uveitis in rats. The results showed that fucoxanthin effectively enhanced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) in ocular tissues. Furthermore, fucoxanthin significantly increased the ocular activities of superoxide dismutase and decreased the levels of malondialdehyde stimulated by PAMP-induced uveitis. Ocular hypertension and the levels of inflammatory cells and proinflammatory cytokine tumor necrosis factor-alpha in the aqueous humor were alleviated with fucoxanthin treatment. Consequently, compared to the observed effects in lipopolysaccharide groups, fucoxanthin treatment significantly preserved iris sphincter innervation and pupillary function. Additionally, PAMP-induced corneal endothelial disruption was significantly inhibited by fucoxanthin treatment. Overall, these findings suggest that fucoxanthin may protect against inflammation from PAMP-induced uveitis by promoting the Nrf2 pathway and inhibiting oxidative stress.

Functional characterisation of the Nep1-like protein effectors of the necrotrophic pathogen - Alternaria brassicae

Alternaria brassicae is an important necrotrophic pathogen that infects the Brassicaceae family. A. brassicae, like other necrotrophs also secretes various proteinaceous effectors and metabolites that cause cell death to establish itself in the host. However, there has been no systematic study of A. brassicae effectors and their roles in pathogenesis. The availability of the genome sequence of A. brassicae has enabled the search for effectors and their functional characterisation. Nep1-like proteins are a superfamily of proteins that induce necrosis and ethylene biosynthesis. They have been reported from a variety of microbes including bacteria, fungi, and oomycetes. In this study, we identified two NLPs from A. brassicae viz. AbrNLP1 and AbrNLP2 and functionally characterised them. Although both AbrNLPs were found to be secretory in nature, they localised differentially inside the plant. AbrNLP2 was found to induce necrosis in both host and nonhost species, while AbrNLP1 could not induce necrosis in both species. Additionally, AbrNLP2 was shown to induce pathogen-associated molecular pattern (PAMP)-triggered immunity in both host and nonhost species. Overall, our study indicates that AbrNLPs are functionally and spatially (subcellular location) distinct and may play different but important roles during the pathogenesis of A. brassicae.

Pathogen-associated molecular pattern active sites of GH45 endoglucanohydrolase from Rhizoctonia solani

A 207-amino acid residue endoglucanohydrolase (EG1) belonging to the glycoside hydrolase 45 (GH45) from Rhizoctonia solani acts as a pathogen associated molecular pattern (PAMP). However, the mechanism of EG1 inducing plant immunity is unclear. Here, we found that EG1 contains two domains related to its PAMP function. Transient expression showed mutation deleting 60 amino acid residuesfrom the N-terminal; EG1-1, still reserved the PAMP function. Further truncation of EG1-1 obtained two truncating mutations, EG1-2 deleting seven amino acid residues from the N-terminal of EG1-1 (SPWAVND) and EG1-3 deleting five amino acid residues from the C-terminal of EG1-1 (GCSRK). Transient expression showed that the two truncating mutations EG1-2 and EG1-3 all lost the PAMP function. Site-directed mutagenesis of EG1-1 showed that the three amino acid residues (P, W, and D) in the region SPWAVND and the two amino acid residues (C and R) in the region GCSRK were involved in the PAMP function. The homology model showed that the two regions were located at a surface on the EG1 and structurally independent. These results demonstrate that there are two functional regions for the plant immune function of the EG1 released by Rhizoctonia solani, and the two functional regions are independent of each other.