Molecular characterization and functional analysis of interferon regulatory factor 8 in the sea cucumber Apostichopus japonicus during Vibrio splendidus challenge.

The host PYHIN (pyrin and HIN domain family) protein IFN-γ-inducible protein 16 (IFI16) was first discovered as a nuclear sensor of double-stranded DNA (dsDNA). Since then its roles in innate immunity have expanded to include restriction of infection of both DNA and RNA viruses. Mechanistically, IFI16 restricts DNA viruses through four principal mechanisms: (i) direct repression of viral gene expression by binding viral genomes and promoting epigenetic-mediated silencing; (ii) sequestration of host transcription factor Sp1; (iii) induction of interferons (IFNs) after sensing viral genomes in the nucleus and cytosol; and (iv) assembly of apoptosis-associated speck-like protein containing a CARD (ASC)-dependent inflammasomes that activates caspase-1 leading to maturation of interleukin-1 beta (IL-1β) and interleukin-18 (IL-18) and pyroptosis. These mechanisms have been reported across dsDNA virus families, including Herpesviridae, Papillomaviridae, Hepadnaviridae, Parvoviridae, Polyomaviridae, and Poxviridae. For RNA viruses, IFI16 can: (i) directly bind viral genomes or sequester Sp1; (ii) amplify antiviral signalling by promoting RIG-I transcription or activation or cooperating with cyclic GMP-AMP synthase (cGAS)- stimulator of IFN genes (STING), and (iii) in some settings activate inflammasomes and pyroptosis. These mechanisms were reported for RNA virus families including, Togaviridae, Flaviviridae, Picornaviridae, Caliciviridae, Arteriviridae, Orthomyxoviridae, Paramyxoviridae and Retroviridae. Consistent with these antiviral roles, many viruses have evolved both destructive (IFI16 degradation) and non-destructive mechanisms to evade IFI16. This review summarizes the current understanding of how IFI16 mediates broad antiviral restriction and how diverse viruses subvert this role to facilitate their replication.

Genome-wide identification, expression analysis and antiviral function of RIG-I-like receptors (RLRs) in basal chordate Branchiostoma japonicum.

CcFTR54 restricts spring viremia of carp virus replication by promoting p62-mediated autophagic degradation of N protein.

In addition to fibrinogens canonical function in hemostasis, alternate roles in innate immunity have emerged. However, interactions with bacterial protein toxins, the main virulence factors of many medically relevant bacteria and causative agents of life-threatening diseases, have not been described so far. Here, we identified human fibrinogen as an inhibitor of the enterotoxic Clostridium (C.) botulinum C2 toxin. Our results indicate that fibrinogen specifically interacts with the binding subunit of C2 toxin in vitro and that N-linked glycans of fibrinogen are crucial for this interaction. This prevents receptor-binding and cellular uptake of the toxin. Related toxins from Bacillus anthracis (lethal toxin), C. perfringens (iota) or Clostridioides difficile (CDT) do not bind to fibrinogen and are therefore not inhibited. Furthermore, C2 toxin had no effect on coagulation of human blood ex vivo. In conclusion, we identified fibrinogen as an inhibitor of a highly potent bacterial protein toxin, highlighting an unexpected role for this blood coagulation factor in innate immunity.

IFI16 (the murine homologue is IFI204) is an intracellular double-stranded DNA (dsDNA) pattern recognition receptor (PRR) that plays a crucial role in bridging innate and adaptive immunity. However, its function in dendritic cell (DC) activation and anti-hepatocellular carcinoma (HCC) efficacy remains poorly characterised. This study demonstrates that IFI16 promotes DC maturation, functional activation and antitumor immunity. This effect occurs through activation of the STING-TBK1-IRF3 signalling pathway. Our findings establish IFI16 as a key molecule enabling DCs to sense dsDNA and initiate antitumor responses. Consequently, targeting IFI16 and its downstream STING-TBK1-IRF3 signalling pathway represents a potential therapeutic strategy for hepatocellular carcinoma.

Design, semi-synthesis and biological evaluation of grandiflorenic acid derivatives as potent covalent NLRP3 inhibitors.

Stimulator of Interferon Genes (STING) is a transmembrane homodimer protein located in the endoplasmic reticulum membrane and plays an essential role in human innate immunity. Hyperactivation of STING has been found in many autoimmune and inflammatory diseases. Therefore, STING has been recognized as a promising target for the treatment of these diseases. Many efforts have been devoted to identifying STING inhibitors and degraders. However, development of STING drug candidates is still challenging and in its infancy, and no candidates have been advanced into clinical trials. In this perspective, we comprehensively summarize recent advances in the development of STING inhibitors and degraders and highlight their design strategies. We also discuss the challenges and opportunities of STING inhibition and expect to shed light on future STING drug discovery.

Collectin-11 (CL-11) is a complement-activating pattern recognition molecule with structural and functional similarities to mannose-binding lectin (MBL), produced in different tissues, including lung epithelium. Given its tissue localization and role in innate immunity, we investigated its potential to recognize and neutralize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and to activate complement. We produced recombinant CL-11, MBL, as well as wild-type, variant, and glycan-mutated SARS-CoV-2 Spike (S) proteins. We evaluated CL-11 binding to the S protein, complement activation, and inhibition of S protein-receptor binding using ELISA, as well as neutralization of SARS-CoV-2 in cell-based neutralization assays. CL-11 bound different SARS-CoV-2 S protein variants with similar binding preferences as MBL, targeting multiple glycan sites. Upon S protein binding, CL-11 mediated activation of both the lectin and alternative complement pathways, and inhibited S protein-receptor binding. Notably, CL-11 neutralized SARS-CoV-2, inhibiting infection of permissive cells. CL-11 binds different SARS-CoV-2 variants and neutralizes SARS-CoV-2 in an antibody-independent manner, suggesting a crucial role in early-stage infection control.

The role of HIF-1α in innate immune mechanisms and autoimmunity: A double-edged sword.

The spleen plays a significant role in innate and adaptive immunity. We aimed to evaluate the prognostic significance of the splenic volume in patients with diffuse large B-cell lymphoma (DLBCL), research on which is limited. We retrospectively analyzed 175 patients diagnosed with DLBCL. Based on optimal thresholds, patients were stratified into small (< 185 cm3), medium (185-315 cm3), and large (≥ 315 cm3) splenic volume groups. Survival analysis was performed using Kaplan-Meier and Cox proportional hazards model. A significant decrease in progression-free survival (PFS) (P < 0.0001) and overall survival (OS) (P < 0.0001) was observed in the large group that received cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (CHOP) without or with rituximab (R-CHOP) treatment. Among the 139 patients who received R-CHOP, significant adverse effects on PFS (P < 0.0036) and OS (P < 0.0035) were observed in the large group. Univariate and multivariate analyses demonstrated that enlarged splenic volume (≥ 315 cm3) was associated with decreased PFS (P < 0.0001, P < 0.01, respectively) and OS (P < 0.001, P < 0.01, respectively). In terms of peripheral blood inflammatory markers, patients with enlarged splenic volume (≥ 315 cm3) exhibited lymphocytopenia, increased monocyte-to-lymphocyte ratio (MLR), increased neutrophil-to-lymphocyte ratio (NLR), and higher red blood cell distribution width (RDW) compared to that in those with smaller splenic volumes (P < 0.001, P < 0.001, P = 0.01, and P < 0.005, respectively). Splenic volume exceeding 315 cm3 is a poor prognostic factor for PFS and OS in patients with DLBCL. An enlarged splenic volume may be associated with compromised anti-cancer immune responses and aberrant inflammatory conditions.

Inhibition of SUMOylation by anacardic acid inhibits adaptive immunity and the development of EAE.

Common carp Ftr82 positively regulates antiviral innate immunity by promoting Irf3 K63-linked ubiquitination.

TRIM25 enhances hypoxia signaling by catalyzing K11-linked polyubiquitination and stabilization of HIF-α.

Comparative molecular characterisation of myeloid cathelicidins reveals subspecies-level diversification in indigenous livestock.

Identification and expression analysis of scavenger receptor SCARA4 in Nibea albiflora.

SFPQ prevents MDA5-mediated activation of innate immunity and preserves cell viability.

Functional Characterization of a Canonical C-Type Lectin from Mytilus coruscus: Roles in Innate Immunity and Feeding Processes.

Human cathelicidin peptide LL-37 is encoded by the CAMP gene and plays a key role in innate immunity. It maintains intestinal homeostasis through antibacterial, immunomodulation, and tissue repair functions. This paper reviews the multiple functions of LL-37 in the intestinal-immune axis and its contribution to intestinal immune homeostasis. A large amount of evidence shows that the biological effect of LL-37 is highly dependent on the environmental background, and its effects vary with peptide concentration, receptor binding status, disease stage, and local microenvironment. This article reviews the latest findings of the dual role of LL-37 in inflammatory bowel disease (IBD) and colorectal cancer (CRC), and focuses on the conditional mechanism of the transformation of its activity from protective to pathogenic. We also discuss the interaction between LL-37 and intestinal microbiota, focusing on how microbial signals and host peptides can coordinate to regulate mucosal immunity. At the same time, this article examines the key obstacles to the therapeutic application of LL-37 and its clinical promotion: cytotoxicity, rapid degradation by proteases, and drug resistance. We have further explored new strategies to overcome these challenges in the near future, including peptide engineering, nanocarrier delivery systems, and combined therapy. These findings together position LL-37 at the intersection of intestinal immunity and microbial ecology, providing a theoretical basis for its therapeutic application in IBD, CRC and infectious colitis.

Sequential infection with rhinovirus followed by Influenza Virus led to an increased antiviral response in A549 cells.