TolCV1 inhibition by NPPB renders less virulent and more susceptible to antibiotics.

Bacterial efflux pumps play important roles in the antibiotic resistance and excretion of virulence factors. We previously characterized that TolCV1, a component of efflux pumps, plays critical roles in resistance to antibiotics and bile and also RtxA1 toxin secretion of . In this context, we speculated that TolCV1 blockers would have a dual effect of enhancing susceptibility to antibiotics and suppressing virulence of .

A Flagellin-Adjuvanted Trivalent Mucosal Vaccine Targeting Key Periodontopathic Bacteria.

Periodontal disease (PD) is caused by microbial dysbiosis and accompanying adverse inflammatory responses. Due to its high incidence and association with various systemic diseases, disease-modifying treatments that modulate dysbiosis serve as promising therapeutic approaches. In this study, to simulate the pathophysiological situation, we established a "temporary ligature plus oral infection model" that incorporates a temporary silk ligature and oral infection with a cocktail of live (), (), and () in mice and tested the efficacy of a new trivalent mucosal vaccine.

Development of an anti-tauopathy mucosal vaccine specifically targeting pathologic conformers.

Alzheimer's disease (AD) and related tauopathies are associated with pathological tau protein aggregation, which plays an important role in neurofibrillary degeneration and dementia. Targeted immunotherapy to eliminate pathological tau aggregates is known to improve cognitive deficits in AD animal models. The tau repeat domain (TauRD) plays a pivotal role in tau-microtubule interactions and is critically involved in the aggregation of hyperphosphorylated tau proteins.

Enhancing cancer immunotherapy with photodynamic therapy and nanoparticle: making tumor microenvironment hotter to make immunotherapeutic work better.

Cancer immunotherapy has made tremendous advancements in treating various malignancies. The biggest hurdle to successful immunotherapy would be the immunosuppressive tumor microenvironment (TME) and low immunogenicity of cancer cells. To make immunotherapy successful, the 'cold' TME must be converted to 'hot' immunostimulatory status to activate residual host immune responses.

Developmental self-reactivity determines pathogenic Tc17 differentiation potential of naive CD8 T cells in murine models of inflammation.

The differentiation of naive CD8 T cells into effector cells is important for establishing immunity. However, the effect of heterogeneous naive CD8 T cell populations is not fully understood. Here, we demonstrate that steady-state naive CD8 T cells are composed of functionally heterogeneous subpopulations that differ in their ability to differentiate into type 17 cytotoxic effector cells (Tc17) in a context of murine inflammatory disease models, such as inflammatory bowel disease and graft-versus-host disease.

Deglycosylation of eukaryotic-expressed flagellin restores adjuvanticity.

Flagellin, the TLR5 agonist, shows potent adjuvant activities in diverse vaccines and immunotherapies. Vibrio vulnificus flagellin B expressed in eukaryotic cells (eFlaB) could not stimulate TLR5 signaling. Enzymatic deglycosylation restored eFlaB's TLR5 stimulating functionality, suggesting that glycosylation interferes with eFlaB binding to TLR5.

Synergistic cancer immunotherapy utilizing programmed Salmonella typhimurium secreting heterologous flagellin B conjugated to interleukin-15 proteins.

The use of appropriately designed immunotherapeutic bacteria is an appealing approach to tumor therapy because the bacteria specifically target tumor tissue and deliver therapeutic payloads. The present study describes the engineering of an attenuated strain of Salmonella typhimurium deficient in ppGpp biosynthesis (SAM) that could secrete Vibrio vulnificus flagellin B (FlaB) conjugated to human (hIL15/FlaB) and mouse (mIL15/FlaB) interleukin-15 proteins in the presence of L-arabinose (L-ara). These strains, named SAMphIF and SAMpmIF, respectively, secreted fusion proteins that retained bioactivity of both FlaB and IL15.

Deimmunization of flagellin adjuvant for clinical application.

Flagellin is the cognate ligand for host pattern recognition receptors, toll-like receptor 5 (TLR5) in the cell surface, and NAIP5/NLRC4 inflammasome in the cytosol. TLR5-binding domain is located in D1 domain, where crucial amino acid sequences are conserved among diverse bacteria. The highly conserved C-terminal 35 amino acids of flagellin were proved to be responsible for the inflammasome activation by binding to NAIP5.

TLR5 agonists enhance anti-tumor immunity and overcome resistance to immune checkpoint therapy.

Primary and adaptive resistance to immune checkpoint therapies (ICT) represent a considerable obstacle to achieving enhanced overall survival. Innate immune activators have been actively pursued for their antitumor potential. Herein we report that a syngeneic 4T1 mammary carcinoma murine model for established highly-refractory triple negative breast cancer showed enhanced survival when treated intra-tumorally with either the TLR5 agonist flagellin or CBLB502, a flagellin derivative, in combination with antibodies targeting CTLA-4 and PD-1.

Flagellin synergistically enhances anti-tumor effect of EGFRvIII peptide in a glioblastoma-bearing mouse brain tumor model.

Background: Glioblastoma (GBM) is the most aggressive type of brain tumor with heterogeneity and strong invasive ability. Treatment of GBM has not improved significantly despite the progress of immunotherapy and classical therapy. Epidermal growth factor receptor variant III (EGFRvIII), one of GBM-associated mutants, is regarded as an ideal therapeutic target in EGFRvIII-expressed GBM patients because it is a tumor-specific receptor expressed only in tumors.

Optimal long peptide for flagellin-adjuvanted HPV E7 cancer vaccine to enhance tumor suppression in combination with anti-PD-1.

Background: Therapeutic cancer vaccines, which induce or amplify tumor-specific T cell responses, are a critical component of multiple combination cancer immunotherapy regimens. Innovative neoantigen identification continually prompts the development of vaccine platforms. However, vaccine monotherapy is not sufficient to eradicate tumors.

An all-in-one adjuvanted therapeutic cancer vaccine targeting dendritic cell cytosol induces long-lived tumor suppression through NLRC4 inflammasome activation.

Therapeutic cancer vaccines (TCVs) should induce robust tumor-specific T cell responses. To achieve this, TCVs incorporate T cell epitopes and strong adjuvants. Here, we report an all-in-one adjuvanted cancer vaccine platform that targets the intracellular compartment of dentritic cells and subsequently induces effective cytotoxic T cell responses.

Toll-Like Receptor 5 Promotes the Neurogenesis From Embryonic Stem Cells and Adult Hippocampal Neural Stem Cells in Mice.

Toll-like receptors (TLRs) make a crucial contribution to the innate immune response. TLR5 was expressed in embryoid body derived from mouse embryonic stem cells (mESCs) and βIII-tubulin-positive cells under all-trans retinoic acid-treated condition. TLR5 was upregulated during neural differentiation from mESCs and augmented the neural differentiation of mESCs via nuclear factor-κB and interleukin 6/CREB pathways.

Evolution of the Tumor Microenvironment toward Immune-Suppressive Seclusion during Brain Metastasis of Breast Cancer: Implications for Targeted Therapy.

Breast cancer (BC) is the second most common solid malignant tumor that metastasizes to the brain. Despite emerging therapies such as immunotherapy, whether the tumor microenvironment (TME) in breast cancer brain metastasis (BCBM) has potential as a target of new treatments is unclear. Expression profiling of 770 genes in 12 pairs of primary BC and matched brain metastasis (BM) samples was performed using the NanoString nCounter PanCancer IO360 Panel.

Deimmunization of flagellin for repeated administration as a vaccine adjuvant.

Flagellin, a protein-based Toll-like receptor agonist, is a versatile adjuvant applicable to wide spectrum of vaccines and immunotherapies. Given reiterated treatments of immunogenic biopharmaceuticals should lead to antibody responses precluding repeated administration, the development of flagellin not inducing specific antibodies would greatly expand the chances of clinical applications. Here we computationally identified immunogenic regions in Vibrio vulnificus flagellin B and deimmunized by simply removing a B cell epitope region.

TolCV1 Has Multifaceted Roles During Infection.

RtxA1 is a major cytotoxin of () causing fatal septicemia and necrotic wound infections. Our previous work has shown that RpoS regulates the expression and secretion of RtxA1 toxin. This study was conducted to further investigate the potential mechanisms of RpoS on RtxA1 secretion.

Solitary Fibrous Tumor/Hemangiopericytoma Metastasizes Extracranially, Associated with Altered Expression of WNT5A and MMP9.

Solitary fibrous tumor/hemangiopericytoma (SFT/HPC) is a mesenchymal tumor originating from various soft tissues and meninges, which carries the - fusion gene. Meningeal/intracranial SFT/HPCs (SFT/HPC) have a poor clinical outcome with metastatic behavior compared to soft tissue/extracranial SFT/HPCs (SFT/HPC), but the underlying genetic factors are unclear. Differentially expressed genes (DEGs) were analyzed by NanoString nCounter assay using RNA extracted from formalin-fixed paraffin-embedded (FFPE) tissue samples.

Tumor Microenvironment-Regulating Immunosenescence-Independent Nanostimulant Synergizing with Near-Infrared Light Irradiation for Antitumor Immunity.

The combination of photothermal therapy (PTT) and toll-like receptor (TLR)-mediated immunotherapy can elicit antitumor immunity and modulate the immunosuppressive tumor microenvironment (TME). Unlike other TLRs, TLR-5 is a promising target for immune activation, as its expression is well-maintained even during immunosenescence. Here, we developed a unique tumor microenvironment-regulating immunosenescence-independent nanostimulant consisting of TLR-5 adjuvant flagellin B (FlaB) conjugated onto the surface to an IR 780-loaded hyaluronic acid-stearylamine (HIF) micelles.

Bacterial Outer Membrane Vesicle-Mediated Cytosolic Delivery of Flagellin Triggers Host NLRC4 Canonical Inflammasome Signaling.

Bacteria-released components can modulate host innate immune response in the absence of direct host cell-bacteria interaction. In particular, bacteria-derived outer membrane vesicles (OMVs) were recently shown to activate host caspase-11-mediated non-canonical inflammasome pathway deliverance of OMV-bound lipopolysaccharide. However, further precise understanding of innate immune-modulation by bacterial OMVs remains elusive.

Intralymphatic Administration of Metagonimus yokogawai-Extracted Protein Attenuates Experimental Murine Allergic Rhinitis Model.

Objectives: This study aimed to evaluate potential therapeutic effect of Metagonimus yokogawai on the OVA-induced allergic rhinitis model.

Methods: OVA-sensitized mice were used to assess potential therapeutic effect of the extract protein of M. yokogawai (My-TP).