Bifidobacterium breve UCC2003 surface exopolysaccharide production is a beneficial trait mediating commensal-host interaction through immune modulation and pathogen protection

Bifidobacteria constitute a substantial proportion of the human gut microbiota. There are currently many bifidobacterial strains with claimed probiotic attributes. The mechanism through which these strains reside within their host and exert benefits to the host is far from fully understood. We have shown in the case of Bifidobacterium breve UCC2003 that a cell surface exopolysaccharide (EPS) plays a role in in vivo persistence. Biosynthesis of two possible EPSs is controlled by a bidirectional gene cluster which guides alternate EPS synthesis by means of a reorienting promoter. The presence of EPS impacts on host immune response: the wild type, EPS-positive B. breve UCC2003 efficiently evades the adaptive B-cell host response, while its isogenic, EPS-deficient equivalent elicits a strong adaptive immune response. Functionally, EPS positive strains were more resilient to presence of acid and bile and were responsible for reduced colonization levels of Citrobacter rodentium, a gut pathogen. In conclusion, we have found that EPS is important in host interactions and pathogen protection, the latter indicative of a probiotic ability for the EPS of B. breve UCC2003.     

Bifidobacterium breve UCC2003 surface exopolysaccharide production is a beneficial trait mediating commensal-host interaction through immune modulation and pathogen protection

Bifidobacteria constitute a substantial proportion of the human gut microbiota. There are currently many bifidobacterial strains with claimed probiotic attributes. The mechanism through which these strains reside within their host and exert benefits to the host is far from fully understood. We have shown in the case of Bifidobacterium breve UCC2003 that a cell surface exopolysaccharide (EPS) plays a role in in vivo persistence. Biosynthesis of two possible EPSs is controlled by a bidirectional gene cluster which guides alternate EPS synthesis by means of a reorienting promoter. The presence of EPS impacts on host immune response: the wild type, EPS-positive B. breve UCC2003 efficiently evades the adaptive B-cell host response, while its isogenic, EPS-deficient equivalent elicits a strong adaptive immune response. Functionally, EPS positive strains were more resilient to presence of acid and bile and were responsible for reduced colonization levels of Citrobacter rodentium, a gut pathogen. In conclusion, we have found that EPS is important in host interactions and pathogen protection, the latter indicative of a probiotic ability for the EPS of B. breve UCC2003.     

Anthrax pathogen evades the mammalian immune system through stealth siderophore production

Systemic anthrax, caused by inhalation or ingestion of Bacillus anthracis spores, is characterized by rapid microbial growth stages that require iron. Tightly bound and highly regulated in a mammalian host, iron is scarce during an infection. To scavenge iron from its environment, B. anthracis synthesizes by independent pathways two small molecules, the siderophores bacillibactin (BB) and petrobactin (PB). Despite the great efficiency of BB at chelating iron, PB may be the only siderophore necessary to ensure full virulence of the pathogen. In the present work, we show that BB is specifically bound by siderocalin, a recently discovered innate immune protein that is part of an antibacterial iron-depletion defense. In contrast, neither PB nor its ferric complex is bound by siderocalin. Although BB incorporates the common 2,3-dihydroxybenzoyl iron-chelating subunit, PB is novel in that it incorporates the very unusual 3,4-dihydroxybenzoyl chelating subunit. This structural variation results in a large change in the shape of both the iron complex and the free siderophore that precludes siderocalin binding, a stealthy evasion of the immune system. Our results indicate that the blockade of bacterial siderophore-mediated iron acquisition by siderocalin is not restricted to enteric pathogenic organisms and may be a general defense mechanism against several different bacterial species. Significantly, to evade this innate immune response, B. anthracis produces PB, which plays a key role in virulence of the organism. This analysis argues for antianthrax strategies targeting siderophore synthesis and uptake.     

Pirfenidone ameliorates chronic pancreatitis in mouse models through immune and cytokine modulation

Chronic pancreatitis (CP) is an irreversible fibro-inflammatory disease of the pancreas with no current targeted therapy. Pirfenidone, an anti-fibrotic and anti-inflammatory drug, is FDA approved for treatment of Idiopathic Pulmonary Fibrosis (IPF). Its efficacy in ameliorating CP has never been evaluated before. We recently reported that pirfenidone improves acute pancreatitis in mouse models. The aim of the current study was to evaluate the therapeutic efficacy of pirfenidone in mouse models of CP. We used caerulein and L-arginine models of CP and administered pirfenidone with ongoing injury, or in well-established disease. We evaluated for fibrosis by Sirius-red staining for collagen, immunohistochemistry, western blotting, and qPCR for fibrosis markers to show the salutary effects of pirfenidone in CP. Our results suggest that treatment with pirfenidone ameliorated CP related changes in the pancreas (i.e., atrophy, acinar cell loss, fibrosis, and inflammation) not only when administered with ongoing injury, but also in well-established models of caerulein as well as L-arginine induced CP. It reduces the pro-fibrotic phenotype of macrophages (in-vivo and in-vitro), reduces macrophage infiltration into the pancreas and alters the intra-pancreatic cytokine milieu preceding changes in histology. The therapeutic effect of pirfenidone is abrogated in absence of macrophages. Furthermore, it reduces collagen secretion, cytokine levels and fibrosis markers in pancreatic stellate cells in-vitro. As it is FDA approved, our findings in mouse models simulating clinical presentation of patients to the clinic, can be used as the basis of a clinical trial evaluating the efficacy of this drug as a therapeutic agent for CP.     

Inotropic agents and immune modulation

Since depression of myocardial contractility forms the basis for the development of heart failure, many attempts have been made to enhance the inotropic state of the failing heart by cardiotonic agent as the therapeutic modality. However, large scale clinical trials conducted in the Western societies revealed excess mortality in patients with heart failure received long-term treatment with inotropic agent. Therefore, all of these agents are now regarded as unsuitable for chronic heart failure treatment. In contrast, some inotropic agents with phosphodiesterase inhibitory properties exhibited potential benefits in Japanese patients. In Japan mortality due to heart disease is substantially lower than that found in all other Western countries. Thereby, chronic treatment with inotropic agent may be justified as the optimal care in the context of relief of symptoms and an improved quality of life. The salutary effects of these phosphodiesterase inhibitorsappear to be related to anticytokine and immunomodulating effects as well as their cardiotonic action. These findings support the recent new concept that immune responses mediated by cytokines play an important role in the pathogenesis of heart failure.     

Fibronectin facilitates the invasion of Orientia tsutsugamushi into host cells through interaction with a 56-kDa type-specific antigen

BACKGROUND: Orientia tsutsugamushi, the causative agent of scrub typhus, is an obligate intracellular bacterium. The pathogen's mechanism of cellular invasion is poorly characterized. METHODS: Through ligand immunoblots, glutathione S-transferase (GST) pull-down assays, and in vitro inhibition assays of intracellular invasion, a bacterial ligand was identified and was shown to interact with fibronectin (Fn) to enhance the intracellular invasion of O. tsutsugamushi. RESULTS: O. tsutsugamushi can bind to immobilized Fn in vitro, and exogenous Fn stimulates bacterial invasion of mammalian host cells. Bacterial invasion in the presence of Fn was abrogated by the addition of Arg-Gly-Asp peptides or by an anti-alpha5beta1 integrin antibody. Through a ligand immunoblot and GST pull-down assay, a 56-kDa type-specific antigen (TSA56) was identified as the bacterial ligand responsible for the interaction with Fn. Antigenic domain III and the adjacent C-terminal region (aa 243-349) of TSA56 interacted with Fn. Furthermore, we found that the enhanced invasion of the pathogen was abrogated by the addition of purified recombinant peptides derived from TSA56. CONCLUSION: Fn facilitates the invasion of O. tsutsugamushi through its interaction with TSA56.     

Enteral nutrition and immune modulation of acute pancreatitis

Enteral nutrition has been strongly recommended by major scientific societies for the nutritional management of patients with acute pancreatitis.Providing severe acute pancreatitis patients with enteral nutrition within the first 24-48 h of hospital admission can help improve outcomes compared to parenteral nutrition and no feeding.New research is focusing in on when and what to feed to best improve outcomes for acute pancreatitis patients.Early enteral nutrition have the potential to modulate the immune responses.Despite this consistent evidence of early enteral nutrition in patients with acute pancreatitis,clinical practice continues to vary due to individual clinician preference.Achieving the immune modulating effects of enteral nutrition heavily depend on proper placement of the feeding tube and managing any tube feeding associated complications.The current article reviews the immune modulating effects of enteral nutrition and pro-and prebiotics and suggests some practical tools that help improve the patient adherence and tolerance to the tube feeding.Proper selection of the type of the tube,close monitoring of the tube for its placement,patency and securing its proper placement and routine checking the gastric residual volume could all help improve the outcome.Using peptide-based and high medium chaintriglycerides feeding formulas help improving feeding tolerance.     

Monocyte-platelet interaction in immune and nonimmune thrombocytopenia

Platelets from 24 patients with immune thrombocytopenia resistant to standard therapy (refractory ITP), 35 patients with nonimmune thrombocytopenia (non-ITP), and 32 normal donors were studied in regard to platelet surface-bound IgG (PBIgG) and the ability of these platelets to be bound by human monocytes in vitro (monocyte-platelet rosette assay). Fourteen (58%) of the platelet samples from refractory ITP patients but none (0%) from the non-ITP or control donors had PBIgG greater than 800 molecules IgG/platelet. Seventeen of 24 (71%) of the ITP patients had platelets which demonstrated increased monocyte- platelet rosette formation [rosette index (RI) greater than 2], whereas only four (11%) of the non-ITP patients had such platelets. There was a direct correlation between PBIgG and rosette index for the platelets from resistant ITP patients. There was no correlation of severity of thrombocytopenia with PBIgG or rosette index. Monocyte-platelet interaction in the presence of elevated PBIgG is mediated through the monocyte Fc-receptor. Platelets from five of ten refractory ITP patients with PBIgG less than 800 molecules IgG/platelet had increased rosette formation. Monocyte-platelet interaction in the absence of increased PBIgG may be due to small amounts of platelet surface IgG which are still able to mediate monocyte Fc-receptor interaction or to alternate membrane receptor interaction through the monocyte C3 receptor. Our data underscore the pathophysiologic relevance of monocyte/macrophage-mediated interaction in immune platelet destruction syndromes.     

Mast cell modulation of the immune response

Mast cells are present in nearly all vascularized tissues, but not the blood. They are best known for the prominent role they play in atopic disease. However, our current understanding of their direct and indirect roles in the immune response offers a more nuanced picture of both villain and hero. Although they are implicated in many inflammatory disorders, they also defend us from bacterial pathogens, prevent dangerous overreactions by the immune system, and even protect us from snake venom. Perhaps there is more to these maligned cells than we thought.     

Myeloid suppressor cells and immune modulation in lung cancer

Many tumors, including lung cancers, promote immune tolerance to escape host immune surveillance and facilitate tumor growth. Tumors utilize numerous pathways to inhibit immune responses, including the elaboration of immune-suppressive mediators such as PGE2, TGF-β, IL-10, VEGF, GM-CSF, IL-6, S100A8/A9 and SCF, which recruit and/or activate myeloid-derived suppressor cells (MDSCs). MDSCs, a subset of heterogeneous bone marrow-derived hematopoietic cells, are found in the peripheral blood of cancer patients and positively correlate to malignancy. Solid tumors contain MDSCs that maintain an immune-suppressive network in the tumor microenvironment. This review will focus on the interaction of tumors with MDSCs that lead to dysregulation of antigen presentation and T-cell activities in murine tumor models. Specific genetic signatures in lung cancer modulate the activities of MDSCs and impact tumor progression. Targeting MDSCs may have a long-term antitumor benefit and is at the forefront of anticancer therapeutic strategies.     

Clinical effects and immune modulation of biologics in asthma

Asthma is considered a syndrome composed of heterogeneous disorders involving complex chronic airway inflammation. Patients with severe asthma, prolonged symptoms, and frequent asthma exacerbations, despite high doses of inhaled corticosteroids, may benefit from treatment with biologics. Four types of biologics are available for severe asthma, including an anti-immunoglobulin E (IgE) antibody (omalizumab), anti-interleukin (IL)-5 antibody (mepolizumab and reslizumab), anti-IL-5 receptor α antibody (benralizumab), and anti-IL-4 receptor α antibody (dupilumab). Biologics for patients with severe asthma demonstrate high therapeutic efficacy and provide significant clinical benefits, including the prevention of asthma exacerbations, alleviation of symptoms, improvement in the quality of life and respiratory function, and reduction in frequencies of hospitalization and emergency outpatient visits. This review provides an overview of the modulation of immunological features by each of the four established biologics in patients with severe allergic asthma. Given the extensive immunomodulatory effects of biologics, further analyses of their precise effects on the human immune system are warranted.