The Novel Inducer of Innate Immunity HO53 Stimulates Autophagy in Human Airway Epithelial Cells.

Aroylated phenylenediamines (APDs) are novel modulators of innate immunity with respect to enhancing the expression of antimicrobial peptides and maintaining epithelial barrier integrity. Here, we present a new study on induction of autophagy in human lung epithelial cells by the APD HO53. Interestingly, HO53 affected autophagy in a dose-dependent manner, demonstrated by increased microtubule-associated proteins 1A/1B light-chain 3B (LC3B) processing in mature polarized bronchial epithelial cells.

Citrullination Alters the Antibacterial and Anti-Inflammatory Functions of the Host Defense Peptide Canine Cathelicidin K9CATH In Vitro.

K9CATH is the sole cathelicidin in canines (dogs) and exhibits broad antimicrobial activity against both Gram-positive and Gram-negative bacteria. K9CATH also modulates inflammatory responses and binds to LPS. These activities depend on the secondary structure and a net-positive charge of the peptide.

Gut microbiota-CRAMP axis shapes intestinal barrier function and immune responses in dietary gluten-induced enteropathy.

In the gut, cathelicidin-related antimicrobial peptide (CRAMP) has been largely described for its anti-infective activities. With an increasing recognition of its immune regulatory effects in extra-intestinal diseases, the role of CRAMP in gluten-induced small intestinal enteropathy celiac disease remains unknown. This study aimed to investigate the unexplored role of CRAMP in celiac disease.

Immunomodulatory Agents Combat Multidrug-Resistant Tuberculosis by Improving Antimicrobial Immunity.

Background: Multidrug-resistant (MDR) tuberculosis has low treatment success rates, and new treatment strategies are needed. We explored whether treatment with active vitamin D3 (vitD) and phenylbutyrate (PBA) could improve conventional chemotherapy by enhancing immune-mediated eradication of Mycobacterium tuberculosis.

Methods: A clinically relevant model was used consisting of human macrophages infected with M.

Slow radiological improvement and persistent low-grade inflammation after chemotherapy in tuberculosis patients with type 2 diabetes.

Background: Diabetes mellitus type 2 (DM) may impede immune responses in tuberculosis (TB) and thus contribute to enhanced disease severity. In this study, we aimed to evaluate DM-mediated alterations in clinical, radiological and immunological outcomes in TB disease.

Methods: Newly diagnosed pulmonary TB patients with or without DM (TB n = 40; TB-DM n = 40) were recruited in Dhaka, Bangladesh.

Host Directed Therapy Against Infection by Boosting Innate Immunity.

The innate immune system constitutes the first line of defense against invading pathogens, regulating the normal microbiota and contributes to homeostasis. Today we have obtained detailed knowledge on receptors, signaling pathways, and effector molecules of innate immunity. Our research constellation has focused on ways to induce the expression of antimicrobial peptides (AMPs), the production of oxygen species (ROS and NO), and to activate autophagy, during the last two decades.

Innate Effector Systems in Primary Human Macrophages Sensitize Multidrug-Resistant Klebsiella pneumoniae to Antibiotics.

Infections caused by multidrug-resistant (MDR) are difficult to treat with conventional antibiotics. Thus, alternative strategies to control the growth of MDR are warranted. We hypothesized that activation of innate effector systems could sensitize MDR to conventional antibiotics.

The anti-microbial peptide LL-37/CRAMP levels are associated with acute heart failure and can attenuate cardiac dysfunction in multiple preclinical models of heart failure.

: Biomarkers for the diagnosis of heart failure (HF) are clinically essential. Circulating antimicrobial peptides LL-37 has emerged as a novel biomarker in cardiovascular disease, however, its relevance as a biomarker for acute HF are undetermined. : Acute HF patients were enrolled in this study and the serum levels of LL-37/CRAMP (cathelicidin-related antimicrobial peptide) were measured by ELISA.

Studies on citrullinated LL-37: detection in human airways, antibacterial effects and biophysical properties.

Arginine residues of the antimicrobial peptide LL-37 can be citrullinated by peptidyl arginine deiminases, which reduce the positive charge of the peptide. Notably, citrullinated LL-37 has not yet been detected in human samples. In addition, functional and biophysical properties of citrullinated LL-37 are not fully explored.

Cathelicidin-related antimicrobial peptide protects against ischaemia reperfusion-induced acute kidney injury in mice.

Background And Purpose: Despite recent advances in understanding its pathophysiology, treatment of acute kidney injury (AKI) remains a major unmet medical need, and novel therapeutic strategies are needed. Cathelicidin-related antimicrobial peptide (CRAMP) with immunomodulatory properties has an emerging role in various disease contexts. Here, we aimed to investigate the role of CRAMP and its underlying mechanisms in AKI.

Host-Directed Therapy as a Novel Treatment Strategy to Overcome Tuberculosis: Targeting Immune Modulation.

Tuberculosis (TB) is one of the leading causes of mortality and morbidity, particularly in developing countries, presenting a major threat to the public health. The currently recommended long term treatment regimen with multiple antibiotics is associated with poor patient compliance, which in turn, may contribute to the emergence of multi-drug resistant TB (MDR-TB). The low global treatment efficacy of MDR-TB has highlighted the necessity to develop novel treatment options.

Cathelicidin Contributes to the Restriction of in Human Host Macrophages.

In cutaneous Leishmaniasis the parasitic control in human host macrophages is still poorly understood. We found an increased expression of the human cathelicidin in skin lesions of Ethiopian patients with cutaneous leishmaniasis. Vitamin D driven, Cathelicidin-type antimicrobial peptides (CAMP) play an important role in the elimination of invading microorganisms.

Klebsiella pneumoniae Expressing VIM-1 Metallo-β-Lactamase Is Resensitized to Cefotaxime via Thiol-Mediated Zinc Chelation.

Antibiotic-resistant isolates constitute a great clinical challenge. One important resistance mechanism in is the metallo-β-lactamases (MBLs), which require zinc for their function. Thus, zinc chelation could be a strategy to resensitize to β-lactams.

Low Methoxyl Pectin Protects against Autoimmune Diabetes and Associated Caecal Dysfunction.

Scope: This study aims to examine the protective effects of specific low-methoxyl pectin (LMP) on the development of type 1 diabetes (T1D).

Methods And Results: Female non-obese diabetic (NOD) mice are weaned onto either control or 5% LMP supplemented diets for up to 22 weeks of age. T1D incidence, gut barrier function, and pancreatic-gut immune responses are analyzed.

Modulation of Gut Microbiota by Low Methoxyl Pectin Attenuates Type 1 Diabetes in Non-obese Diabetic Mice.

Intestinal homeostasis underpins the development of type 1 diabetes (T1D), and dietary manipulations to enhance intestinal homeostasis have been proposed to prevent T1D. The current study aimed to investigate the efficacy of supplementing a novel specific low-methoxyl pectin (LMP) dietary fiber in preventing T1D development. Female NOD mice were weaned onto control or 5% (wt/wt) LMP supplemented diets for up to 40 weeks of age, overt diabetes incidence and blood glucose were monitored.

Novel aroylated phenylenediamine compounds enhance antimicrobial defense and maintain airway epithelial barrier integrity.

Aroylated phenylenediamines (APDs) are novel inducers of innate immunity enhancing cathelicidin gene expression in human bronchial epithelial cell lines. Here we present two newly developed APDs and aimed at defining the response and signaling pathways for these compounds with reference to innate immunity and antimicrobial peptide (AMP) expression. Induction was initially defined with respect to dose and time and compared with the APD Entinostat (MS-275).

Innate lymphoid cell type 3-derived interleukin-22 boosts lipocalin-2 production in intestinal epithelial cells via synergy between STAT3 and NF-κB.

and are opportunistic pathogens that are commonly associated with infections at mucosal surfaces, such as the lung or the gut. The host response against these types of infections includes the release of epithelial-derived antimicrobial factors such as lipocalin-2 (LCN-2), a protein that specifically inhibits the iron acquisition of Enterobacteriaceae by binding and neutralizing the bacterial iron-scavenging molecule enterobactin. Regulation of epithelial antimicrobial responses, including the release of LCN-2, has previously been shown to depend on IL-22, a cytokine produced by innate lymphoid cells type 3 (ILC3) during Enterobacteriaceae infections.

Cathelicidin-related antimicrobial peptide protects against myocardial ischemia/reperfusion injury.

Background: Cathelicidins are a major group of natural antimicrobial peptides which play essential roles in regulating host defense and immunity. In addition to the antimicrobial and immunomodulatory activities, recent studies have reported the involvement of cathelicidins in cardiovascular diseases by regulating inflammatory response and microvascular dysfunction. However, the role of cathelicidins in myocardial apoptosis upon cardiac ischemia/reperfusion (I/R) injury remains largely unknown.

A novel cysteine-linked antibacterial surface coating significantly inhibits bacterial colonization of nasal silicone prongs in a phase one pre-clinical trial.

Ventilator associated pneumonia and sepsis are frequent complications in neonatal care. Bacterial colonization of medical devices and interfaces used for respiratory support may contribute by functioning as a bacterial reservoir seeding bacteria into airways. We have developed an antibacterial surface coating based on a cysteine ligand covalently coupled via a spacer to a carboxylic backbone layer on an acrylic acid grafted silicone surface.

Immune responses in the treatment of drug-sensitive pulmonary tuberculosis with phenylbutyrate and vitamin D as host directed therapy.

Background: We have previously shown that 8 weeks' treatment with phenylbutyrate (PBA) (500mgx2/day) with or without vitamin D (vitD) (5000 IU/day) as host-directed therapy (HDT) accelerated clinical recovery, sputum culture conversion and increased expression of cathelicidin LL-37 by immune cells in a randomized, placebo-controlled trial in adults with pulmonary tuberculosis (TB). In this study we further aimed to examine whether HDT with PBA and vitD promoted clinically beneficial immunomodulation to improve treatment outcomes in TB patients.

Methods: Cytokine concentration was measured in supernatants of peripheral blood mononuclear cells (PBMC) from patients (n = 31/group).

The host defense peptide LL-37 is detected in human parotid and submandibular/sublingual saliva and expressed in glandular neutrophils.

The human host defense peptide, LL-37, is an important player in the first line of defense against invading microorganisms. LL-37 and its precursor, hCAP18, have been detected in unstimulated whole saliva but no reports showing hCAP18/LL-37 in isolated, parotid, and/or submandibular/sublingual saliva have been presented. Here, we measured the levels of hCAP18/LL-37 in human parotid and submandibular/sublingual saliva and investigated the expression of hCAP18/LL-37 in parotid and submandibular gland tissue.

Prostaglandin E suppresses hCAP18/LL-37 expression in human macrophages via EP2/EP4: implications for treatment of Mycobacterium tuberculosis infection.

Prostaglandin (PG)E is an arachidonic acid-derived lipid mediator that plays an important role in inflammation and immunity. In this study, we demonstrate that PGE suppresses basal and 1,25-dihydroxy vitamin D (VD)-induced expression of hCAP18/LL-37 via E prostanoid (EP)2 and EP4 receptors. In humans, VD up-regulates vitamin D receptor (VDR) expression and promotes transcription of the cathelicidin hCAP18/LL-37 gene, whereas PGE counteracts this effect.

Treatment with Entinostat Heals Experimental Cholera by Affecting Physical and Chemical Barrier Functions of Intestinal Epithelia.

We have shown previously that oral treatment with sodium butyrate or phenylbutyrate in an experimental model of shigellosis improves clinical outcomes and induces the expression of the antimicrobial peptide CAP-18 in the large intestinal epithelia. In a subsequent study, we found that entinostat, an aroylated phenylenediamine compound, has similar therapeutic potential against shigellosis. In this study, we aimed to evaluate entinostat as a potential candidate for host-directed therapy against cholera in an experimental model.