Search Results (73)

This study investigated the therapeutic potential of a novel probiotic combination consisting of Lactococcus cremoris subsp. cremoris MP01 and Lacticaseibacillus paracasei subsp. paracasei MP02, collectively referred to as LCP, in the treatment of canine atopic dermatitis (CAD). In a 60-day open-label, single-arm trial involving eight dogs, notable clinical improvements were observed following daily LCP treatment, as evidenced by decreasing trends in Canine Atopic Dermatitis Extent and Severity Index and Pruritus Visual Analogue Scale scores, as well as a significant reduction in serum immunoglobulin E levels (p < 0.05). Microbiome and short-chain fatty acid (SCFA) analyses were subsequently conducted in a representative subset of six dogs to explore the effects of LCP on the fecal and skin microbial ecosystems. Concomitant alterations in gut and skin microbiome were observed, including a significant reduction in abundance of Erysipelotrichaceae (p < 0.05) and non-significant decreasing trends in Romboutsia, Escherichia/Shigella spp., and Shigella flexneri, along with a trend toward increased SCFA production. Functional prediction using PICRUSt suggested potential involvement of immune- and infection-related signaling pathways, including those associated with nucleotide-binding oligomerization domain-like receptors, retinoic acid-inducible gene I-like receptors and Shigellosis, supporting the hypothesis that LCP may exert its effects through modulation of the gut–skin axis. These findings support LCP as a safe and promising adjunct therapy for CAD, offering a novel microbiome-targeted approach targeting both clinical symptoms and underlying dysbiosis. Further investigation is warranted to optimize probiotic formulations and better understand the mechanisms underlying microbiome-mediated immune modulation in canine allergy. Full article

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is recognized by pattern recognition receptors (PRRs), which play a vital role in triggering innate immune responses such as the production of type I and III interferons (IFNs). While modest PRR activation helps to defend against SARS-CoV-2, excessive or sustained activation can cause harmful inflammation and contribute to severe Coronavirus Disease 2019 (COVID-19). Altered expression of Toll-like receptors (TLRs), which are among the most important members of the PRR family members, particularly TLRs 2, 3, 4, 7, 8 and 9, has been strongly linked to COVID-19 severity. Furthermore, retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5), collectively known as RLRs (RIG-I-like receptors), act as sensors that detect SARS-CoV-2 RNA. The expression of these receptors, as well as that of different DNA sensors, varies in patients infected with SARS-CoV-2. Changes in PRR expression, particularly that of TLRs, cyclic GMP-AMP synthase (cGAS), and the stimulator of interferon genes (STING), have also been shown to play a role in the development and persistence of long COVID (LC). However, SARS-CoV-2 has evolved strategies to evade PRR recognition and subsequent signaling pathway activation, contributing to the IFN response dysregulation observed in SARS-CoV-2-infected patients. Nevertheless, PRR agonists and antagonists remain promising therapeutic targets for SARS-CoV-2 infection. This review aims to describe the PRRs involved in recognizing SARS-CoV-2, explore their expression during SARS-CoV-2 infection, and examine their role in determining the severity of both COVID-19 and long-term manifestations of the disease. It also describes the strategies developed by SARS-CoV-2 to evade PRR recognition and activation. Moreover, given the considerable interest in modulating PRR activity as a novel immunotherapy approach, this review will provide a description of PRR agonists and antagonists that have been investigated as antiviral strategies against SARS-CoV-2. This review aims to explore the complex interplay between PRRs and SARS-CoV-2 in depth, considering its implications for prognostic biomarkers, targeted therapeutic strategies and the mechanistic understanding of long LC. Additionally, it outlines future perspectives that could help to address knowledge gaps in PRR-mediated responses during SARS-CoV-2 infection. Full article

Respiratory syncytial virus (RSV) remains a leading cause of acute lower respiratory tract infections globally, particularly affecting infants, older adults, and immunocompromised individuals. While recent advances in prophylaxis, such as long-acting monoclonal antibodies and maternal immunization, offer promise for prevention, therapeutic options for active infection remain limited. Severe RSV disease is often driven not solely by viral replication but by dysregulated host immune responses, including excessive cytokine production, T helper type 2 (Th2) and T helper type 17 (Th17) cell polarization, and impaired interferon signaling. RSV has evolved sophisticated immune evasion strategies, such as inhibition of dendritic cell maturation, degradation of signal transducer and activator of transcription 2 (STAT2) via nonstructural proteins 1 and 2 (NS1/NS2), and interference with pattern recognition receptor signaling, particularly Toll-like receptors (TLRs) and retinoic acid-inducible gene I (RIG-I)-like receptors. These mechanisms result in attenuated innate immune responses and defective adaptive immunity, contributing to viral persistence, immunopathology, and recurrent infections. Moreover, age-dependent vulnerabilities, such as immune immaturity in infants and immunosenescence in older adults, exacerbate disease severity. Excessive immune activation leads to bronchiolitis, airway remodeling, and long-term sequelae including wheezing and asthma. Emerging immunomodulatory therapies aim to restore immune balance, targeting cytokines (e.g., interleukin-6 [IL-6], interleukin-1 beta [IL-1β]), the Janus kinase–signal transducer and activator of the transcription (JAK-STAT) pathway, or inflammasome activity. Host-directed therapies and direct-acting antivirals are also under investigation. A better understanding of RSV–host immune interactions is critical for optimizing therapeutic strategies and designing effective vaccines. This review synthesizes current knowledge on RSV immunopathogenesis and highlights immunomodulation as a promising frontier for therapeutic intervention. Full article

Sediment burial generated by deep-sea mining is usually lethal to echinoderms, which are ecologically important in marine environments. However, their molecular mechanisms responding to sediment burial are still rarely investigated. In this study, Patiria pectinifera was investigated for sediment burial research to analyze its gene expression variations by using comparative transcriptomes and to probe into shared molecular mechanisms of echinoderms under sediment burial. During sediment burial experiments, dissolved oxygen continuously decreased, which had a significant impact on Patiria pectinifera, which suffered from hypoxic stress. Based on functional annotations of differentially expressed genes (DEGs), its metabolic patterns altered with the upregulated DEGs related to glycolysis and fatty acid degradation and the downregulated ones in the citrate cycle, and its immune responses also varied with the upregulated DEGs of apoptosis and the downregulated ones defending against pathogens. Meanwhile, the peroxisome proliferator-activated receptor signaling pathway and retinoic acid-inducible gene I-like receptor signaling pathway were also upregulated, indicating metabolic and immune changes. Furthermore, combined with functional annotations of twelve echinoderm reference genomes, those DEGs related to lipid metabolism and the immune response were also universally present in the echinoderm genomes. Our study probes into shared molecular mechanisms of echinoderms under sediment burial, which advances our understanding of echinoderms affected by deep-sea mining. Full article

As an evolutionarily conserved and ubiquitous mechanism of host defense, non-immune cells in vertebrates possess the intrinsic ability to autonomously detect and combat intracellular pathogens. This process, termed cell-autonomous immunity, is distinct from classical innate immunity. In this review, we comprehensively examine the defense mechanisms employed by non-immune cells in response to intracellular pathogen invasion. We provide a detailed analysis of the cytosolic sensors that recognize aberrant nucleic acids, lipopolysaccharide (LPS), and other pathogen-associated molecular patterns (PAMPs). Specifically, we elucidate the molecular mechanisms underlying key signaling pathways, including the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, the retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs)-mitochondrial antiviral signaling (MAVS) axis, and the guanylate-binding proteins (GBPs)-mediated pathway. Furthermore, we critically evaluate the involvement of these pathways in the pathogenesis of various diseases, including autoimmune disorders, inflammatory conditions, and malignancies, while highlighting their potential as therapeutic targets. Full article

NLRC3 belongs to the NOD-like receptor family and is recognized as a modulator of innate immune mechanisms. In this study, we firstly report that Ctenopharyngodon idelus NLRC3 (CiNLRC3) acts as a negative regulator in the antiviral immune response. Cinlrc3 is ubiquitously expressed across tested tissues, displaying particularly high expression in the intestine, spleen, gill and kidney. Notably, Cinlrc3 expression is markedly upregulated following grass carp reovirus (GCRV) infection both in vivo and in vitro. Functional assays reveal that the overexpression of CiNLRC3 hampers cellular antiviral responses, thereby facilitating viral replication. Conversely, the silencing of CiNLRC3 through siRNA transfection enhances these antiviral activities. Additionally, CiNLRC3 substantially diminishes the retinoic acid-inducible gene I (RIG-I)-like receptor (RLR)-mediated interferon (IFN) response in fish. Subsequent molecular investigations indicates that CiNLRC3 interacts with the RLR molecule node, IRF7 but not IRF3, by degrading the IRF7 protein in a proteasome-dependent manner. Furthermore, CiNLRC3 co-localizes with CiIRF7 in the cytoplasm and impedes the IRF7-induced IFN response, resulting in impairing IRF7-mediated antiviral immunity. Summarily, these findings underscore the critical inhibitory role of teleost NLRC3 in innate immunity, offering new perspectives on its regulatory functions and potential as a target for resistant breeding in fish. Full article

Inhibition of menin in acute myeloid leukemia (AML) harboring histone-lysine-N-methyltransferase 2A rearrangement (KMT2Ar) or the mutated Nucleophosmin gene (NPM1c) is considered a novel and effective treatment approach in these patients. However, rapid acquisition of resistance mutations can impair treatment success. In patients with elevated retinoic acid receptor alpha (RARA) expression levels, promising effects are demonstrated by the next-generation RARalpha agonist tamibarotene, which restores differentiation or induces apoptosis. In this study, the combination of revumenib and tamibarotene was investigated in various KMT2Ar or NPM1c AML cell lines and patient-derived blasts, focusing on the potential synergistic induction of differentiation or apoptosis. Both effects were analyzed by flow cytometry and validated by Western blot analysis. Synergy calculations were performed using viability assays. Regulation of the relevant key mediators for the MLL complex were quantified by RT-qPCR. In MV4:11 cells characterized by the highest relative mRNA levels of RARA, highly synergistic induction of apoptosis is demonstrated upon combination treatment. Induction of apoptosis by combined treatment of MV4:11 cells is accompanied by pronounced induction of the pro-apoptotic protein BAX and a synergistic reduction in CDK6 mRNA levels. In MOLM13 and OCI-AML3 cells, an increase in differentiation markers like PU.1 or a decreased ratio of phosphorylated to total CEBPA is demonstrated. In parts, corresponding effects were observed in patient-derived AML cells carrying either KMT2Ar or NPM1c. The impact of revumenib on KMT2Ar or NPM1c AML cells was significantly enhanced when combined with tamibarotene, demonstrating synergistic differentiation or apoptosis initiation. These findings propose promising strategies for relapsed/refractory AML patients with defined molecular characteristics. Full article

Physiology disorders of the liver, as it is an important tissue in lipid metabolism, can cause fatty liver disease. The mechanism might be regulated by 17 circadian clock genes and 18 fat metabolism genes, together with a high-fat diet (HFD). Due to their rich nutritional and medicinal value, Chinese soft-shelled turtles (Trionyx sinensis) are very popular among the Chinese people. In the study, we aimed to investigate the influence of an HFD on the daily expression of both the core clock genes and the lipid metabolism genes in the liver tissue of the turtles. The two diets were formulated with 7.98% lipid (the CON group) and 13.86% lipid (the HFD group) to feed 180 juvenile turtles, which were randomly divided into two groups with three replicates per group and 30 turtles in each replicate for six weeks, and the diet experiment was administrated with a photophase regimen of a 24 h light/dark (12L:12D) cycle. At the end of the experiment, the liver tissue samples were collected from nine turtles per group every 3 h (zeitgeber time: ZT 0, 3, 6, 9, 12, 15, 18, 21 and 24) for 24 h to investigate the daily expression and correlation analysis of these genes. The results showed that 11 core clock genes [i.e., circadian locomotor output cycles kaput (Clock), brain and muscle arnt-like protein 1 and 2 (Bmal1/2), timeless (Tim), cryptochrome 1 (Cry2), period2 (Per2), nuclear factor IL-3 gene (Nfil3), nuclear receptor subfamily 1, treatment D, member 1 and 2 (Nr1d1/2) and retinoic acid related orphan receptor α/β/γ β and γ (Rorβ/γ)] exhibited circadian oscillation, but 6 genes did not, including neuronal PAS domain protein 2 (Npas2), Per1, Cry1, basic helix-loop-helix family, member E40 (Bhlhe40), Rorα and D-binding protein (Dbp), and 16 lipid metabolism genes including fatty acid synthase (Fas), diacylglycerol acyltransferase 1 (Dgat1), 3-hydroxy-3-methylglutaryl-CoA reductase (Hmgcr), Low-density lipoprotein receptor-related protein 1-like (Ldlr1), Lipin 1 (Lipin1), Carnitine palmitoyltransferase 1A (Cpt1a), Peroxisome proliferator activation receptor α, β and γ (Pparα/β/γ), Sirtuin 1 (Sirt1), Apoa (Apoa1), Apolipoprotein B (Apob), Pyruvate Dehydrogenase kinase 4 (Pdk4), Acyl-CoA synthase long-chain1 (Acsl1), Liver X receptors α (Lxrα) and Retinoid X receptor, α (Rxra) also demonstrated circadian oscillations, but 2 genes did not, Scd and Acaca, in the liver tissues of the CON group. However, in the HFD group, the circadian rhythms’ expressional patterns were disrupted for the eight core clock genes, Clock, Cry2, Per2, Nfil3, Nr1d1/2 and Rorβ/γ, and the peak expression of Bmal1/2 and Tim showed delayed or advanced phases. Furthermore, four genes (Cry1, Per1, Dbp and Rorα) displayed no diurnal rhythm in the CON group; instead, significant circadian rhythms appeared in the HFD group. Meanwhile, the HFD disrupted the circadian rhythm expressions of seven fat metabolism genes (Fas, Cpt1a, Sirt1, Apoa1, Apob, Pdk4 and Acsl1). Meanwhile, the other nine genes in the HFD group also showed advanced or delayed expression peaks compared to the CON group. Most importantly of all, there were remarkably positive or negative correlations between the core clock genes and the lipid metabolism genes, and their correlation relationships were altered by the HFD. To sum up, circadian rhythm alterations of the core clock genes and the lipid metabolism genes were induced by the high-fat diet (HFD) in the liver tissues of T. sinensis. This result provides experimental and theoretical data for the mass breeding and production of T. sinensis in our country. Full article

Sepsis, a severe global healthcare challenge, is characterized by significant morbidity and mortality. The 2016 redefinition by the Third International Consensus Definitions Task Force emphasizes its complexity as a “life-threatening organ dysfunction caused by a dysregulated host response to infection”. Bacterial pathogens, historically dominant, exhibit geographic variations, influencing healthcare strategies. The intricate dynamics of bacterial immunity involve recognizing pathogen-associated molecular patterns, triggering innate immune responses and inflammatory cascades. Dysregulation leads to immunothrombosis, disseminated intravascular coagulation, and mitochondrial dysfunction, contributing to the septic state. Viral sepsis, historically less prevalent, saw a paradigm shift during the COVID-19 pandemic, underscoring the need to understand the immunological response. Retinoic acid-inducible gene I-like receptors and Toll-like receptors play pivotal roles, and the cytokine storm in COVID-19 differs from bacterial sepsis. Latent viruses like human cytomegalovirus impact sepsis by reactivating during the immunosuppressive phases. Challenges in sepsis management include rapid pathogen identification, antibiotic resistance monitoring, and balancing therapy beyond antibiotics. This review highlights the evolving sepsis landscape, emphasizing the need for pathogen-specific therapeutic developments in a dynamic and heterogeneous clinical setting. Full article

Viral double-stranded RNA (dsRNA) interacts with Retinoic-acid-inducible-gene-1 (RIG-1)-like receptors (RLRs) to induce type 1 interferons. Melanoma-derived-antigen-5 (MDA-5), an RLR, but not RIG-1, is found in chickens. Ducks express both RIG-1 and MDA-5, a possible cause of differences in susceptibility to influenza virus infection between chickens and ducks. Using the HD11 chicken macrophage cell line and an RT² Profiler PCR-array system, we showed that high-molecular-weight poly(I:C), HMW-poly(I:C), upregulates CCL4, interferon-gamma, interleukin-1, and interleukin-6 mRNA transcripts. HMW-poly(I:C), an in vitro surrogate of long dsRNA species, also induces the upregulation of IL-12B and B cell activating factor (BAFF). Conversely, low-molecular-weight poly(I:C), LMW-poly(I:C) did not induce a distinct cytokine expression pattern. Nonetheless, co-transfection of LMW and HMW-poly(I:C) significantly reduced the upregulation of IL12B and BAFF by HMW-poly(I:C). These findings support previous studies that found no expression of RIG-1, a receptor for short dsRNA species, in chicken cells. Surprisingly, however, our data suggested that in the absence of RIG-1 in chicken macrophages, short dsRNA species may inhibit macrophage-mediated B cell development and survival by modulating the expression of BAFF without significantly reducing type 1 interferon response. Full article

The retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) play a crucial role as pattern-recognition receptors within the innate immune system. These receptors, present in various cell and tissue types, serve as essential sensors for viral infections, enhancing the immune system’s capacity to combat infections through the induction of type I interferons (IFN-I) and inflammatory cytokines. RLRs are involved in a variety of physiological and pathological processes, including viral infections, autoimmune disorders, and cancer. An increasing body of research has examined the possibility of RLRs or microRNAs as therapeutic targets for antiviral infections and malignancies, despite the fact that few studies have focused on the regulatory function of microRNAs on RLR signaling. Consequently, our main emphasis in this review is on elucidating the role of microRNAs in modulating the signaling pathways of RLRs in the context of cancer and viral infections. The aim is to establish a robust knowledge base that can serve as a basis for future comprehensive investigations into the interplay between microRNAs and RIG-I, while also facilitating the advancement of therapeutic drug development. Full article

Viral vectors play a pivotal role in the field of gene therapy, with several related drugs having already gained clinical approval from the EMA and FDA. However, numerous viral gene therapy vectors are currently undergoing pre-clinical research or participating in clinical trials. Despite advancements, the innate response remains a significant barrier impeding the clinical development of viral gene therapy. The innate immune response to viral gene therapy vectors and transgenes is still an important reason hindering its clinical development. Extensive studies have demonstrated that different DNA and RNA sensors can detect adenoviruses, adeno-associated viruses, and lentiviruses, thereby activating various innate immune pathways such as Toll-like receptor (TLR), cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING), and retinoic acid-inducible gene I–mitochondrial antiviral signaling protein (RLR-MAVS). This review focuses on elucidating the mechanisms underlying the innate immune response induced by three widely utilized viral vectors: adenovirus, adeno-associated virus, and lentivirus, as well as the strategies employed to circumvent innate immunity. Full article

The innate immune pathway serves as the first line of defense against viral infections and plays a crucial role in the host’s immune response in clearing viruses. Prior research has indicated that the influenza A virus has developed various strategies to avoid host immune responses. Nevertheless, the role of the NS1 protein of the canine influenza virus (CIV) in the innate immune pathway remains unclear. In this study, eukaryotic plasmids of NS1, NP, PA, PB1, and PB2 were constructed, and it was found that these proteins interact with melanoma differentiation-associated gene 5 (MDA5) and antagonize the activation of IFN-β promoters by MDA5. We selected the NS1 protein for further study and found that NS1 does not affect the interaction between the viral ribonucleoprotein (RNP) subunit and MDA5, but that it downregulates the expression of the laboratory of genetics and physiology 2 (LGP2) and retinoic acid-inducible gene-I (RIG-I) receptors in the RIG-I pathway. Additionally, NS1 was found to inhibit the expression of several antiviral proteins and cytokines, including MX dynamin like GTPase 1 (MX1), 2′-5′oligoadenylate synthetase (OAS), Signal Transducers and Activators of Transcription (STAT1), tripartite motif 25 (TRIM25), interleukin-2 (IL-2), IFN, IL-8, and IL-1β. To further investigate the role of NS1, a recombinant H3N2 virus strain (rH3N2) and an NS1-null virus (rH3N2ΔNS1) were rescued using reverse-genetic technology. The rH3N2ΔNS1 virus exhibited lower viral titers compared to rH3N2, but had a stronger activation effect on the receptors LGP2 and RIG-I. Furthermore, when compared to rH3N2, rH3N2ΔNS1 exhibited a more pronounced activation of antiviral proteins such as MX1, OAS, STAT1, and TRIM25, as well as antiviral cytokines such as IL-6, IFN-β, and IL-1β. These findings suggest a new mechanism by which NS1, a nonstructural protein of CIV, facilitates innate immune signaling and provides new avenues for the development of antiviral strategies. Full article

Autophagy plays a homeostatic role in regulating cellular metabolism by degrading unwanted intracellular materials and acts as a host defense mechanism by eliminating infecting pathogens, such as viruses. Upon viral infection, host cells often activate retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) signaling to induce the transcription of type I interferons, thus establishing the first line of the innate antiviral response. In recent years, numerous studies have shown that virus-mediated autophagy activation may benefit viral replication through different actions on host cellular processes, including the modulation of RLR-mediated innate immunity. Here, an overview of the functional molecules and regulatory mechanism of the RLR antiviral immune response as well as autophagy is presented. Moreover, a summary of the current knowledge on the biological role of autophagy in regulating RLR antiviral signaling is provided. The molecular mechanisms underlying the crosstalk between autophagy and RLR innate immunity are also discussed. Full article

Neutrophilia and the production of neutrophil extracellular traps (NETs) are two of many measures of increased inflammation in severe COVID-19 that also accompany its autoimmune complications, including coagulopathies, myocarditis and multisystem inflammatory syndrome in children (MIS-C). This paper integrates currently disparate measures of innate hyperactivation in severe COVID-19 and its autoimmune complications, and relates these to SARS-CoV-2 activation of innate immunity. Aggregated data include activation of Toll-like receptors (TLRs), nucleotide-binding oligomerization domain (NOD) receptors, NOD leucine-rich repeat and pyrin-domain-containing receptors (NLRPs), retinoic acid-inducible gene I (RIG-I) and melanoma-differentiation-associated gene 5 (MDA-5). SARS-CoV-2 mainly activates the virus-associated innate receptors TLR3, TLR7, TLR8, NLRP3, RIG-1 and MDA-5. Severe COVID-19, however, is characterized by additional activation of TLR1, TLR2, TLR4, TLR5, TLR6, NOD1 and NOD2, which are primarily responsive to bacterial antigens. The innate activation patterns in autoimmune coagulopathies, myocarditis and Kawasaki disease, or MIS-C, mimic those of severe COVID-19 rather than SARS-CoV-2 alone suggesting that autoimmunity follows combined SARS-CoV-2-bacterial infections. Viral and bacterial receptors are known to synergize to produce the increased inflammation required to support autoimmune disease pathology. Additional studies demonstrate that anti-bacterial antibodies are also required to account for known autoantigen targets in COVID-19 autoimmune complications. Full article