Comparative transcriptome analysis of canola carrying a single vs stacked resistance genes against clubroot.

Pyramiding resistance genes may expand the efficacy and scope of a canola variety against clubroot (Plasmodiophora brassicae), a serious threat to canola production in western Canada. However, the mechanism(s) of multigenic resistance, especially the potential interaction among clubroot resistance (CR) genes, are not well understood. In this study, transcriptome was compared over three canola (Brassica napus L.) inbred/hybrid lines carrying a single CR gene in chromosome A03 (CRaM, Line 16) or A08 (Crr1rutb, Line 20), and both genes (CRaM+Crr1rutb, Line 15) inoculated with a field population (L-G2) of P. brassicae pathotype X, a new variant found in western Canada recently. The line16 was susceptible, while lines 15 and 20 were partially resistant. Functional annotation identified differential expression of genes (DEGs) involved in biosynthetic processes responsive to stress and regulation of cellular process; The Venn diagram showed that the partially resistant lines 15 and 20 shared 1,896 differentially expressed genes relative to the susceptible line 16, and many of these DEGs are involved in defense responses, activation of innate immunity, hormone biosynthesis and programmed cell death. The transcription of genes involved in Pathogen-Associated Molecular Pattern (PAMP)-Triggered and Effector-Triggered Immunity (PTI and ETI) was particularly up-regulated, and the transcription level was higher in line 15 (CRaM + Crr1rutb) than in line 20 (Crr1rutb only) for most of the DEGs. These results indicated that the partial resistance to the pathotype X was likely conferred by the CR gene Crr1rutb for both lines 15 and 20 that functioned via the activation of both PTI and ETI signaling pathways. Additionally, these two CR genes might have synergistic effects against the pathotype X, based on the higher transcription levels of defense-related DEGs expressed by inoculated line 15, highlighting the benefit of gene stacking for improved canola resistance as opposed to a single CR gene alone.

Bioactive Phyto-Compounds with Antimicrobial Effects and AI: Results of a Desk Research Study.

Resistance of microorganisms to antibiotics represents a formidable global challenge, manifesting in intricate public health ramifications including escalated mortality rates and augmented healthcare costs. The current efforts to manage antimicrobial resistance (AMR) are limited mainly to the standard therapeutic approaches. The aim of this study is to present and analyze the role of artificial intelligence (AI) in the search for new phyto-compounds and novel interactions with antimicrobial effects. The ambition of the current research study is to support researchers by providing summarized information and ideas for future research in the battle with AMR. Inevitably, the AI role in healthcare is growing exponentially. The reviewed AI models reveal new data on essential oils (EOs) as potential therapeutic agents. In terms of antibacterial activity, EOs show activity against MDR bacteria, reduce resistance by sensitizing bacteria to the action of antibiotics, and improve therapeutic efficiency when combined with antibiotics. AI models can also serve for the detailed study of other therapeutic applications of EOs such as respiratory diseases, immune diseases, neurodegenerative diseases, and oncological diseases. The last 5 years have seen an increasing application of AI in the search for potential plant sources to control AMR. For the time being, the application of machine-learning (ML) models is greater in the studies of EOs. Future attention of research teams may also be directed toward a more efficient search for plant antimicrobial peptides (PAMPs). Of course, investments in this direction are a necessary preface, but the excitement of new possibilities should not override the role of human intelligence in directing research processes. In this report, tradition meets innovation to address the "silent pandemic" of AMR.

Involvement of metabotropic glutamate receptors in regulation of immune response in the Pacific oyster Crassostrea gigas.

Metabotropic glutamate receptors (mGluRs) play a pivotal role in the neuroendocrine-immune regulation. In this study, eight mGluRs were identified in the Pacific Oyster Crassostrea gigas, which were classified into three subfamilies based on genetic similarity. All CgmGluRs harbor variable numbers of PBP1 domains at the N-terminus. The sequence and structural features of CgmGluRs are highly similar to mGluRs in other species. A uniformly upregulated expression of CgmGluRs was observed during D-shaped larval stage compared to early D-shaped larval stage. The transcripts of CgmGluRs were detectable in various tissues of oyster. Different CgmGluR exhibited diverse expression patterns response against different PAMP stimulations, among which CgmGluR5 was significantly downregulated under these stimulations, reflecting its sensitivity and broad-spectrum responsiveness to microbes. Following LPS stimulation, the mRNA expression of CgmGluR5 and CgCALM1 in haemocytes was suppressed within 6 h and returned to normal levels by 12 h. Inhibition of CgmGluR5 activity resulted in a significant reduction in CgCALM1 expression after 12 h. Further KEGG enrichment analysis suggested that CgmGluR5 might modulate calcium ion homeostasis and metabolic pathways by regulating CgCALM1. This research delivers the systematic analysis of mGluR in the Pacific Oyster, offering insights into evolutionary characteristics and immunoregulatory function of mGluR in mollusks.

Systemic immune response of burns from the acute to chronic phase.

Immune responses that occur following burn injury comprise a series of reactions that are activated in response to damaged autologous tissues, followed by removal of damaged tissues and foreign pathogens such as invading bacteria, and tissue repair. These immune responses are considered to be programmed in living organisms. Developments of modern medicine have led to the saving of burned patients who could not be cured previously; however, the programmed response is no longer able to keep up, and various problems have arisen. This paper describes the mechanism of immune response specific to burn injury and the emerging concept of persistent inflammation, immunosuppression, and catabolism syndrome.

Is preexisting inflamed jaw marrow a "hidden" co-morbidity affecting outcomes of COVID-19 infections? - Clinical comparative study.

Introduction: Exceedingly high levels of the chemokine CCL5/RANTES have been found in fatty degenerated osteonecrotic alveolar bone cavities (FDOJ) and aseptic ischemic osteolysis of the jaw (AIOJ) from toothless regions. Because CCL5/RANTES seems to have a prominent role in creating the COVID-19 "cytokine storm", some researchers have used the monoclonal antibody Leronlimab to block the CCR5 on inflammatory cells.Objective: Is preexisting FDOJ/AIOJ jaw marrow pathology a "hidden" co-morbidity affecting some COVID-19 infections? To what extent does the chronic CCL5/RANTES expression from preexisting FDOJ/AIOJ areas contribute to the progression of the acute cytokine storm in COVID-19 patients?Methods: Authors report on reducing the COVID-19 "cytokine storm" by treating infected patients through targeting the chemokine receptor 5 (CCR5) with Leronlimab and interrupting the activation of CCR5 by high CCL5/RANTES signaling, thus dysregulating the inflammatory phase of the viremia. Surgical removal of FDOJ/AIOJ lesions with high CCL5/RANTES from patients with inflammatory diseases may be classified as a co-morbid disease.Results: Both multiplex analysis of 249 FDOJ/AIOJ bone tissue samples as well as serum levels of CCL5/RANTES displayed exceedingly high levels in both specimens.Discussion: By the results the authors hypothesize that chronic CCL5/RANTES induction from FDOJ/AIOJ areas may sensitize CCR5 throughout the immune system, thus, enabling it to amplify its response when confronted with the virus. As conventional intraoral radiography does little to assess the quality of the alveolar bone, ultrasonography units are available to help dentists locate the FDOJ/AIOJ lesions in an office setting.Conclusion: The authors propose a new approach to containment of the COVID-19 cytokine storm by a prophylactic focus for future viral-related pandemics, which may be early surgical clean-up of CCL5/RANTES expression sources in the FDOJ/AIOJ areas, thus diminishing a possible pre-sensitization of CCR5. A more complete dental examination includes trans-alveolar ultrasono-graphy (TAU) for hidden FDOJ/AIOJ lesions.

Immune profiling reveals umbilical cord blood mononuclear cells from South India display an IL-8 dominant, CXCL-10 deficient polyfunctional monocyte response to pathogen-associated molecular patterns (PAMPs) that is distinct from adult blood cells.

Neonate responses to pathogen-associated molecular patterns (PAMPS) differ from adults; such understanding is poor in Indian neonates, despite recognised significant infectious risk. Immune profiling analysis was undertaken of ten secreted mediators contextualised with cellular source induced by six PAMPs in umbilical cord (CB; n=21) and adult-blood (PBMC, n=14) from a tertiary care hospital in South India. Differential cytokine expression analysis (minimum log2-fold difference; adj p-value<0.05) identified bacterial PAMPs induced higher concentrations of IL-1ß, IL-10, TNF-α in adults versus IL-8, GM-CSF, IFN-γ and IL-2 in CB. CB responded to poly I:C and SARS-CoV-2 lysate with a dominant IL-8 response, whereas, in PBMC, CXCL-10 dominated poly I:C, but not SARS-CoV-2, responses, highlighting potential IL-8 importance, in absence of Type I Interferons, in antiviral CB immunity. Candida albicans was the only PAMP to uniformly induce higher secretion of effectors in CB. The predominant source of IL-8/IL-6/TNF-α/IL-1ß in both CB and PBMC was polyfunctional monocytes and IFN-γ /IL-2/IL-17 from innate lymphocytes. Correlation matrix analyses revealed IL-8 to be the most differentially regulated, correlating positively in CB versus negatively in PBMC with IL-6, GM-CSF, IFN-γ, IL-2, consistent with more negatively regulated cytokine modules in adults, potentially linked to higher anti-inflammatory IL-10. Cord and adult blood from India respond robustly to PAMPs with unique effector combinations. These data provide a strong foundation to monitor, explore, mechanisms that regulate such immunity during the life course, an area of significant global health importance given infection-related infant mortality incidence.

Porphyromonas gingivalis, a bridge between oral health and immune evasion in gastric cancer.

Porphyromonas gingivalis (P. gingivalis) is a gram-negative oral pathogen associated with chronic periodontitis. Previous studies have linked poor oral health and periodontitis with oral cancer. Severe cases of periodontal disease can result in advanced periodontitis, leading to tissue degradation, tooth loss, and may also correlate with higher gastric cancer (GC) risk. In fact, tooth loss is associated with an elevated risk of cancer. However, the clinical evidence for this association remains inconclusive. Periodontitis is also characterized by chronic inflammation and upregulation of members of the Programmed Death 1/PD1 Ligand 1 (PD1/PDL1) axis that leads to an immunosuppressive state. Given that chronic inflammation and immunosuppression are conditions that facilitate cancer progression and carcinogenesis, we hypothesize that oral P. gingivalis and/or its virulence factors serve as a mechanistic link between oral health and gastric carcinogenesis/GC progression. We also discuss the potential impact of P. gingivalis' virulence factors (gingipains, lipopolysaccharide (LPS), and fimbriae) on inflammation and the response to immune checkpoint inhibitors in GC which are part of the current standard of care for advanced stage patients.

Structure-activity relationship in NOD2 agonistic muramyl dipeptides.

Nucleotide-binding oligomerization domain 2 (NOD2) is a receptor of the innate immune system that is capable of perceiving bacterial and viral infections. Muramyl dipeptide (MDP, N-acetyl muramyl L-alanyl-d-isoglutamine), identified as the minimal immunologically active component of bacterial cell wall peptidoglycan (PGN) is recognized by NOD2. In terms of biological activities, MDP demonstrated vaccine adjuvant activity and stimulated non-specific protection against bacterial, viral, and parasitic infections and cancer. However, MDP has certain drawbacks including pyrogenicity, rapid elimination, and lack of oral bioavailability. Several detailed structure-activity relationship (SAR) studies around MDP scaffolds are being carried out to identify better NOD2 ligands. The present review elaborates a comprehensive SAR summarizing structural aspects of MDP derivatives in relation to NOD2 agonistic activity.

Decoding Toll-like receptors: Recent insights and perspectives in innate immunity.

Toll-like receptors (TLRs) are an evolutionarily conserved family in the innate immune system and are the first line of host defense against microbial pathogens by recognizing pathogen-associated molecular patterns (PAMPs). TLRs, categorized into cell surface and endosomal subfamilies, recognize diverse PAMPs, and structural elucidation of TLRs and PAMP complexes has revealed their intricate mechanisms. TLRs activate common and specific signaling pathways to shape immune responses. Recent studies have shown the importance of post-transcriptional regulation in TLR-mediated inflammatory responses. Despite their protective functions, aberrant responses of TLRs contribute to inflammatory and autoimmune disorders. Understanding the delicate balance between TLR activation and regulatory mechanisms is crucial for deciphering their dual role in immune defense and disease pathogenesis. This review provides an overview of recent insights into the history of TLR discovery, elucidation of TLR ligands and signaling pathways, and their relevance to various diseases.

Pathogen-associated molecular patterns (PAMPs) derived from Leishmania and bacteria increase gene expression of antimicrobial peptides and gut surface proteins in sand flies.

The interaction between pathogens and vectors' physiology can impact parasite transmission. Studying this interaction at the molecular level can help in developing control strategies. We study leishmaniases, diseases caused by Leishmania parasites transmitted by sand fly vectors, posing a significant global public health concern. Lipophosphoglycan (LPG), the major surface glycoconjugate of Leishmania, has been described to have several roles throughout the parasite's life cycle, both in the insect and vertebrate hosts. In addition, the sand fly midgut possesses a rich microbiota expressing lipopolysaccharides (LPS). However, the effect of LPG and LPS on the gene expression of sand fly midgut proteins or immunity effectors has not yet been documented. We experimentally fed Lutzomyia longipalpis and Phlebotomus papatasi sand flies with blood containing purified LPG from Leishmania infantum, Leishmania major, or LPS from Escherichia coli. The effect on the expression of genes encoding gut proteins galectin and mucin, digestive enzymes trypsin and chymotrypsin, and antimicrobial peptides (AMPs) attacin and defensins was assessed by quantitative PCR (qPCR). The gene expression of a mucin-like protein in L. longipalpis was increased by L. infantum LPG and E. coli LPS. The gene expression of a galectin was increased in L. longipalpis by L. major LPG, and in P. papatasi by E. coli LPS. Nevertheless, the gene expression of trypsins and chymotrypsins did not significantly change. On the other hand, both L. infantum and L. major LPG significantly enhanced expression of the AMP attacin in both sand fly species and defensin in L. longipalpis. In addition, E. coli LPS increased the expression of attacin and defensin in L. longipalpis. Our study showed that Leishmania LPG and E. coli LPS differentially modulate the expression of sand fly genes involved in gut maintenance and defence. This suggests that the glycoconjugates from microbiota or Leishmania may increase the vector's immune response and the gene expression of a gut coating protein in a permissive vector.

The dsRNA isolated from Escherichia coli infected with the MS2 bacteriophage induces the production of interferons.

Viral infections pose a significant threat to public health, and the production of interferons represents one of the most critical antiviral innate immune responses of the host. Consequently, the screening and identification of compounds or reagents that induce interferon production are of paramount importance. This study commenced with the cultivation of host bacterium 15,597, followed by the infection of Escherichia coli with the MS2 bacteriophage. Utilizing the J2 capture technique, a class of dsRNA mixtures (MS2+15,597) was isolated from the E. coli infected with the MS2 bacteriophage. Subsequent investigations were conducted on the immunostimulatory activity of the MS2+15,597 mixture. The results indicated that the dsRNA mixtures (MS2+15,597) extracted from E. coli infected with the MS2 bacteriophage possess the capability to activate innate immunity, thereby inducing the production of interferon-ß. These dsRNA mixtures can activate the RIG-I and TLR3 pattern recognition receptors, stimulating the expression of interferon stimulatory factors 3/7, which in turn triggers the NF-κB signaling pathway, culminating in the cellular production of interferon-ß to achieve antiviral effects. This study offers novel insights and strategies for the development of broad-spectrum antiviral drugs, potentially providing new modalities for future antiviral therapies.

Mincle as a potential intervention target for the prevention of inflammation and fibrosis (Review).

Macrophage­inducible C­type lectin receptor (Mincle) is predominantly found on antigen­presenting cells. It can recognize specific ligands when stimulated by certain pathogens such as fungi and Mycobacterium tuberculosis. This recognition triggers the activation of the nuclear factor­κB pathway, leading to the production of inflammatory factors and contributing to the innate immune response of the host. Moreover, Mincle identifies lipid damage­related molecules discharged by injured cells, such as Sin3­associated protein 130, which triggers aseptic inflammation and ultimately hastens the advancement of renal damage, autoimmune disorders and malignancies by fostering tissue inflammation. Presently, research on the functioning of the Mincle receptor in different inflammatory and fibrosis­associated conditions has emerged as a popular topic. Nevertheless, there remains a lack of research on the impact of Mincle in promoting long­lasting inflammatory reactions and fibrosis. Additional investigation is required into the function of Mincle receptors in chronological inflammatory reactions and fibrosis of organ systems, including the progression from inflammation to fibrosis. Hence, the present study showed an overview of the primary roles and potential mechanism of Mincle in inflammation, fibrosis, as well as the progression of inflammation to fibrosis. The aim of the present study was to clarify the potential mechanism of Mincle in inflammation and fibrosis and to offer perspectives for the development of drugs that target Mincle.

Identification and functional analysis of Toll-like receptor 2 from razor clam Sinonovacula constricta.

Toll-like receptor 2 (TLR2) is a member of TLR family that plays important roles in the innate immune system, such as pathogen recognition and inflammation regulation. In this study, the TLR2 homologue was cloned from razor clam Sinonovacula constricta (denoted as ScTLR2) and its immune function was explored. The full-length cDNA of ScTLR2 comprised 2890 nucleotides with a 5'-UTR of 218 bp, an open reading frame of 2169 bp encoding 722 amino acids and a 3'-UTR of 503 bp. The deduced amino acid of ScTLR2 showed similar structure to TLR2 homologue with a conserved signal peptide, four LRR domains, one LRR-TYP domain, one LRR-CT domain, one transmembrane domain and a conserved TIR domain. ScTLR2 mRNA was detected in all examined tissues with the highest expression in the gill. After Vibrio parahaemolyticus challenge, the mRNA expression of ScTLR2 was significantly induced both in gill and haemocytes. The recombinant ScTLR2-LRR protein could bind all tested PAMPs including LPS, PGN and MAN. Bacterial agglutination assay showed that rScTLR2 could agglutinate the six tested bacteria with a calcium dependent manner. More importantly, ScTLR2 silencing by siRNA transfection could significantly depress the mRNA expression of Myd88, NF-κB, Tollip, IRF1, and IRF8. The survival rate of S. constricta was markedly decreased after V. parahaemolyticus challenge under this condition. Our current study demonstrated that ScTLR2 served as a pattern recognition receptor to induce immune response against invasive pathogen.

A comprehensive model for the biochemistry of ageing, senescence and longevity.

Various models for ageing, each focussing on different biochemical and/or cellular pathways have been proposed. This has resulted in a complex and non-coherent portrayal of ageing. Here, we describe a concise and comprehensive model for the biochemistry of ageing consisting of three interacting signalling hubs. These are the nuclear factor kappa B complex (NFκB), controlling the innate immune system, the mammalian target for rapamycin complex, controlling cell growth, and the integrated stress responses, controlling homeostasis. This model provides a framework for most other, more detailed, biochemical pathways involved in ageing, and explains why ageing involves chronic inflammation, cellular senescence, and vulnerability to environmental stress, while starting with the spontaneous formation of advanced glycation end products. The totality of data underlying this model suggest that the gradual inhibition of the AMPK-ISR probably determines the maximal lifespan. Based on this model, anti-ageing drugs in general, are expected to show hormetic dose response curves. This complicates the process of dose-optimization. Due to its specific mechanism of action, the anti-aging drug alkaline phosphatase is an exception to this rule, because it probably exhibits saturation kinetics.

Accelerating the understanding of Aspergillus terreus: Epidemiology, physiology, immunology and advances.

Aspergillus species encompass a variety of infections, ranging from invasive aspergillosis to allergic conditions, contingent upon the immune status of the host. In this spectrum, Aspergillus terreus stands out due to its emergence as a notable pathogen and its intrinsic resistance to amphotericin-B. The significance of Aspergillus-associated infections has witnessed a marked increase in the past few decades, particularly with the increasing number of immunocompromised individuals. The exploration of epidemiology, morphological transitions, immunopathology, and novel treatment approaches such as new antifungal drugs (PC945, olorofim) and combinational therapy using antifungal drugs and phytochemicals (Phytochemicals: quercetin, shikonin, artemisinin), also using immunotherapies to modulate immune response has resulted in better outcomes. Furthermore, in the context COVID-19 era and its aftermath, fungal infections have emerged as a substantial challenge for both immunocompromised and immunocompetent individuals. This is attributed to the use of immune-suppressing therapies during COVID-19 infections and the increase in transplant cases. Consequently, this review aims to provide an updated overview encompassing the epidemiology, germination events, immunopathology, and novel drug treatment strategies against Aspergillus terreus-associated infections.

Different roles of Ca2+ and chitohexose in peanut (Arachis Hypogaea) photosynthetic responses to PAMP-immunity.

Background: During active infections, plants prevent further spread of pathogenic microorganisms by inducing the rapid programmed death of cells around the infection point. This phenomenon is called the hypersensitive response and is a common feature of plant immune responses. Plants recognize conserved structures of pathogenic microorganisms, called pathogen-associated molecular patterns (PAMPs), e.g., flagellin 22 (flg22) and chitohexose, which bind to receptors on plant cells to induce various immune-response pathways. Although abiotic stresses are known to alter photosynthesis, the different effects of flg22 and chitohexose, which are involved into PAMP-induced signaling, on photosynthesis needs further study. Methods: In the present study, we assessed the role of PAMPs in peanut (Arachis hypogaea) photosynthesis, particularly, the interaction between PAMPs and Ca2+ signal transduction pathway. Results: Both flg22 and chitohexose significantly promoted the expression of the pathogenesis-related genes PR-4 and PR-10, as did Ca2+. We found that Ca2+ is involved in downregulating the photosystem II (PSII) reaction center activity induced by the flg22 immune response, but the role of chitohexose is not obvious. Additionally, Ca2+ significantly reduced the non-photochemical energy dissipation in the flg22- and chitohexose-induced immune response. Conclusion: These results indicated that flg22 and chitohexose can trigger peanut immune pathways through the Ca2+ signaling pathway, but they differ in their regulation of the activity of the PSII reaction center.

DNA at the center of mammalian innate immune recognition of bacterial biofilms.

Historically, the study of innate immune detection of bacterial infections has focused on the recognition of pathogen-associated molecular patterns (PAMPs) from bacteria growing as single cells in planktonic phase. However, over the past two decades, studies have highlighted an adaptive advantage of bacteria: the formation of biofilms. These structures are complex fortresses that stand against a hostile environment, including antibiotics and immune responses. Extracellular DNA (eDNA) is a crucial component of the matrix of most known biofilms. In this opinion article, I propose that eDNA is a universal PAMP that the immune system uses to recognize biofilms. Outstanding questions concern the discrimination between biofilm-associated eDNA and DNA from planktonic bacteria, the innate receptors involved, and the immune response to biofilms.

PAMPs and DAMPs in Sepsis: A Review of Their Molecular Features and Potential Clinical Implications.

Sepsis is a serious organ dysfunction caused by a dysregulated immune host reaction to a pathogen. The innate immunity is programmed to react immediately to conserved molecules, released by the pathogens (PAMPs), and the host (DAMPs). We aimed to review the molecular mechanisms of the early phases of sepsis, focusing on PAMPs, DAMPs, and their related pathways, to identify potential biomarkers. We included studies published in English and searched on PubMed® and Cochrane®. After a detailed discussion on the actual knowledge of PAMPs/DAMPs, we analyzed their role in the different organs affected by sepsis, trying to elucidate the molecular basis of some of the most-used prognostic scores for sepsis. Furthermore, we described a chronological trend for the release of PAMPs/DAMPs that may be useful to identify different subsets of septic patients, who may benefit from targeted therapies. These findings are preliminary since these pathways seem to be strongly influenced by the peculiar characteristics of different pathogens and host features. Due to these reasons, while initial findings are promising, additional studies are necessary to clarify the potential involvement of these molecular patterns in the natural evolution of sepsis and to facilitate their transition into the clinical setting.