transforming-growth-factor-beta and Streptococcal-Infections

We have previously postulated that surviving invasive streptococcal infections may have been a factor in psoriasis becoming a common skin disease in some parts of the world. Many of the candidate genes linked to psoriasis are associated with the acquired or innate immune system, which are also important in host defence to invasive streptococcal infections. High rates of positive streptococcal throat swabs among patients with chronic plaque psoriasis suggest that they are efficient at internalizing/carrying beta-haemolytic streptococci. Internalization of streptococci in the throat is dependent upon the transforming growth factor (TGF)-beta/fibronectin/alpha 5 beta 1 integrin pathway. The immune cell Th17 and its related cytokine network are important in mucosal defence, being very effective against extracellular microbes but having little effect on intracellular organisms. The TGF-beta/fibronectin/alpha 5 beta 1 integrin pathway and the Th17 cell network also appear to be operative in psoriasis, animal models of both TGF-beta and alpha 5 beta 1 cutaneous overexpression being associated with characteristic psoriasis lesions. We postulate that some of the genotypic/phenotypic changes in different immunological pathways in psoriasis, including the acquired T-cell response, the innate immune response, the TGF-beta/fibronectin/alpha 5 beta 1 integrin pathway and the Th17 cell system, confer protection against mortality during epidemics of invasive streptococcal infections, heightened efficiency in internalizing and allowing carriage of streptococci as well as predisposition to the development of psoriasis.

Topics: Disease Outbreaks; Humans; Psoriasis; Selection, Genetic; Streptococcal Infections; Th1 Cells; Transforming Growth Factor beta

Pleural fibrosis (PF) is a chronic and progressive lung disease which affects approximately 30,000 people per year in the United States. Injury and sustained inflammation of the pleural space can result in PF, restricting lung expansion and impairing oxygen exchange. During the progression of pleural injury, normal pleural mesothelial cells (PMCs) undergo a transition, termed mesothelial mesenchymal transition (MesoMT). While multiple components of the fibrinolytic pathway have been investigated in pleural remodeling and PF, the role of the urokinase type plasminogen activator receptor (uPAR) is unknown. We found that uPAR is robustly expressed by pleural mesothelial cells in PF. Downregulation of uPAR by siRNA blocked TGF-β mediated MesoMT. TGF-β was also found to significantly induce uPA expression in PMCs undergoing MesoMT. Like uPAR, uPA downregulation blocked TGF-β mediated MesoMT. Further, uPAR is critical for uPA mediated MesoMT. LRP1 downregulation likewise blunted TGF-β mediated MesoMT. These findings are consistent with in vivo analyses, which showed that uPAR knockout mice were protected from S. pneumoniae-mediated decrements in lung function and restriction. Histological assessments of pleural fibrosis including pleural thickening and α-SMA expression were likewise reduced in uPAR knockout mice compared to WT mice. These studies strongly support the concept that uPAR targeting strategies could be beneficial for the treatment of PF.

Topics: Actins; Animals; Cells, Cultured; Epithelial-Mesenchymal Transition; Epithelium; Fibrosis; Humans; Mice; Mice, Inbred C57BL; Pleura; Pneumonia, Bacterial; Receptors, Urokinase Plasminogen Activator; Streptococcal Infections; Transforming Growth Factor beta; Urokinase-Type Plasminogen Activator

Influenza infection predisposes the host to secondary bacterial pneumonia, which is a major cause of mortality during influenza epidemics. The molecular mechanisms underlying the bacterial coinfection remain elusive. Neuraminidase (NA) of influenza A virus (IAV) enhances bacterial adherence and also activates TGF-β. Because TGF-β can up-regulate host adhesion molecules such as fibronectin and integrins for bacterial binding, we hypothesized that activated TGF-β during IAV infection contributes to secondary bacterial infection by up-regulating these host adhesion molecules. Flow cytometric analyses of a human lung epithelial cell line indicated that the expression of fibronectin and α5 integrin was up-regulated after IAV infection or treatment with recombinant NA and was reversed through the inhibition of TGF-β signaling. IAV-promoted adherence of group A Streptococcus (GAS) and other coinfective pathogens that require fibronectin for binding was prevented significantly by the inhibition of TGF-β. However, IAV did not promote the adherence of Lactococcus lactis unless this bacterium expressed the fibronectin-binding protein of GAS. Mouse experiments showed that IAV infection enhanced GAS colonization in the lungs of wild-type animals but not in the lungs of mice deficient in TGF-β signaling. Taken together, these results reveal a previously unrecognized mechanism: IAV NA enhances the expression of cellular adhesins through the activation of TGF-β, leading to increased bacterial loading in the lungs. Our results suggest that TGF-β and cellular adhesins may be potential pharmaceutical targets for the prevention of coinfection.

Topics: Animals; Bacterial Adhesion; Cell Adhesion Molecules; Coinfection; Colony Count, Microbial; Epithelial Cells; Fibronectins; Humans; Influenza A virus; Influenza, Human; Lung; Mice; Models, Biological; Neuraminidase; Orthomyxoviridae Infections; Protein Binding; Receptors, Cell Surface; Recombinant Proteins; Signal Transduction; Streptococcal Infections; Streptococcus pyogenes; Transforming Growth Factor beta

We measured the neutrophil gelatinase-associated lipocalin (NGAL) concentration in peritoneal dialysate effluent (PDE) collected following an acute episode of continuous ambulatory peritoneal dialysis (CAPD)-related peritonitis.. NGAL concentration in PDE increased in the first 3 days after developing peritonitis and correlated well with the neutrophil count. In patients with culture-negative peritonitis, the NGAL in PDE was lower than that in patients with gram-positive or gram-negative peritonitis. Apart from providing additional diagnostic support to bacterial-induced peritonitis, measurement of NGAL in PDE may be useful to differentiate the neutrophil-dependent culture-negative peritonitis from that associated with non-bacterial or non-cellular etiologies.. Human peritoneal mesothelial cell (HPMC) is another source of NGAL during peritonitis. NGAL was specifically induced in HPMC by IL-1beta. Incubation of HPMC with recombinant NGAL reversed the transforming growth factor-beta-induced up-regulation of Snail and vimentin but rescued the down-regulation of E-cadherin. Our data suggest that NGAL may exert a protective effect in modulating the epithelial-to-mesenchymal transition activated following peritonitis.

Topics: Acute-Phase Proteins; Adult; Ambulatory Care; Biomarkers; Cadherins; Cell Movement; Cells, Cultured; Early Diagnosis; Gene Expression Regulation; Humans; Interleukin-1beta; Kidney Failure, Chronic; Lipocalin-2; Lipocalins; Male; Middle Aged; Neutrophils; Peritoneal Dialysis; Peritonitis; Proto-Oncogene Proteins; Snail Family Transcription Factors; Streptococcal Infections; Streptococcus; Transcription Factors; Transforming Growth Factor beta; Vimentin

Group A Streptococcus (GAS) and other bacterial pathogens are known to interact with integrins as an initial step in a complex pathway of bacterial ingestion by host cells. Efficient GAS invasion depends on the interaction of bound fibronectin (Fn) with integrins and activation of integrin signaling. TGF-beta1 regulates expression of integrins, Fn, and other extracellular matrix proteins, and positively controls the integrin signaling pathway. Therefore, we postulated that TGF-beta1 levels could influence streptococcal invasion of mammalian cells. Pretreatment of HEp-2 cells with TGF-beta1 increased their capacity to ingest GAS when the bacteria expressed fibronectin-binding proteins (M1 or PrtF1). Western blots revealed significant induction of alpha5 integrin and Fn expression by HEp-2 cells in response to TGF-beta1. Increased ingestion of streptococci by these cells was blocked by a specific inhibitor of the TGF-beta1 receptor I and antibodies directed against alpha5 integrin and Fn, indicating that increased invasion depends on TGF-beta1 up-regulation of both the alpha5 integrin and Fn. The capacity of TGF-beta1 to up-regulate integrin expression and intracellular invasion by GAS was reproduced in primary human tonsil fibroblasts, which could be a source of TGF-beta1 in chronically infected tonsils. The relationship between TGF-beta1 and GAS invasion was strengthened by the observation that TGF-beta1 production was stimulated in GAS-infected primary human tonsil fibroblasts. These findings suggest a mechanism by which GAS induce a cascade of changes in mammalian tissue leading to elevated expression of the alpha5beta1 receptor, enhanced invasion, and increased opportunity for survival and persistence in their human host.

Topics: Cells, Cultured; Epithelial Cells; Fibroblasts; Fibronectins; Humans; Integrin alpha5; Palatine Tonsil; Signal Transduction; Streptococcal Infections; Streptococcus pyogenes; Transforming Growth Factor beta; Transforming Growth Factor beta1; Up-Regulation

Group B streptococci (GBS) are an important cause of neonatal sepsis, pneumonia and meningitis. In some newborns, GBS sepsis may have a severe course, including septic shock with high mortality rate, whereas other newborns are colonized with GBS on their surfaces without any clinical signs of bacterial infections. Interferon (IFN)-gamma is produced in neonatal GBS sepsis, and transforming growth factor (TGF)-beta is also found in the uterus. The involvement of IFN-gamma and TGF-beta in the earliest phase of infection might be a determinant of susceptibility and/or progression of infection in vivo. The aim of this study was to assess the effect of IFN-gamma and TGF-beta on adherence and intracellular viability in ECV304 cells of GBS serotype III isolated from cerebrospinal fluid (CSF) and vagina (strains 90356 and 80340, respectively). Interaction of GBS-ECV304 cells showed that the CSF isolate exhibited a more efficient adherence mechanism than the vagina isolate (P<0.001). Intracellular viability was observed for the CSF 90356 isolate within 2 h incubation. Results suggest the expression of additional bacterial virulence factors that favor some GBS type III strains to cause invasive disease. Detection of genotypic virulence marker (162-kb) in the CSF 90356 isolate by PFGE emphasizes the high risk of invasive infection by some GBS-III strains. Treatment of ECV304 cells with IFN-gamma and/or TGF-beta increased adherence of both GBS strains (P<0.001). Intracellular survival of the CSF 90356 isolate was observed after 24 h incubation following treatment of ECV304 cells with IFN-gamma and TGF-beta. Our data suggest that both IFN-gamma and TGF-beta may favor virulence of GBS strains. Variation of IFN-gamma and TGF-beta producing capacity of host cells of different individuals may influence development of invasive disease by GBS-III.

Topics: Bacterial Adhesion; Carrier State; Cells, Cultured; Cerebrospinal Fluid; Endothelium, Vascular; Female; Humans; Infant, Newborn; Interferon-gamma; Streptococcal Infections; Streptococcus agalactiae; Transforming Growth Factor beta; Umbilicus; Vagina; Veins

Topics: Animals; Arthritis, Psoriatic; Humans; Immunosuppressive Agents; Immunotherapy; Psoriasis; Streptococcal Infections; T-Lymphocytes; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

To determine whether human chorionic gonadotropin (HCG) contributes to pregnancy-associated immunosuppression, as observed clinically by an amelioration of symptoms in human autoimmune diseases, including rheumatoid arthritis, during pregnancy.. Administration of HCG was initiated 2 days prior to an arthritogenic dose of streptococcal cell wall (SCW) in nonpregnant female rats, and the development and severity of SCW-induced arthritis was monitored. Inflammatory mediators, including plasma nitrite/nitrate and cytokine levels, were measured. Inducible nitric oxide synthase (iNOS) protein and cytokine messenger RNA expression in joint tissue were compared between treated and untreated arthritic animals.. Systemic administration of HCG resulted in a dose-dependent reduction in the clinical arthritis index. Consistent with the amelioration of clinical symptoms, HCG significantly reduced the inflammatory cell infiltration, pannus formation, and bone and cartilage degradation. Mechanistically, HCG therapy was associated with suppression of the overzealous production of tumor necrosis factor alpha, interleukin-6 (IL-6), and IL-1beta, which contribute to synovial pathology in animals with SCW-induced arthritis. Circulating nitric oxide and the amount of iNOS protein were also reduced. Furthermore, circulating transforming growth factor beta levels were elevated by the HCG, all of which suggest monocytes/macrophages as a potential target.. These findings indicate that HCG exerts a protective effect in this experimental arthritis model, through modulation of inflammatory mediators.

Topics: Animals; Arthritis, Infectious; Chorionic Gonadotropin; Down-Regulation; Female; Humans; Interleukin-1; Interleukin-6; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Rats; Rats, Inbred Lew; Streptococcal Infections; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Up-Regulation

Acute poststreptococcal glomerulonephritis (APSGN) is characterized by diffuse glomerular hypercellularity, primarily as a result of accumulation of neutrophils (exudative glomerulonephritis), increase in intrinsic glomerular cells, and transient pathological mesangial matrix expansion. Cytokines and growth factors are supposed to play an important role as mediators of inflammation and as progression factors in various renal disorders. Interleukin-8 is a recently described cytokine, defined as a selective activator and chemoattractant of polymorphonuclear leukocytes (PMNL) and transforming growth factor (TGF)-beta plays a central role in the accumulation of pathological extracellular matrix in glomerulonephritis. This study analyzed the biopsies of ten patients with APSGN, using immunohistochemistry (avidin-biotin complex/horseradish peroxidase method) using monoclonal antibodies anti-IL-8, anti-TGF-beta 1, beta 2, beta 3. Controls consisted of non-immune mouse serum, or anti-TGF-beta preabsorbed with human recombinant TGF-beta. Compared with normal renal tissue, and minimal change disease, an increased glomerular IL-8 and TGF-beta staining was observed in all of the biopsies. Furthermore, in one patient, we observed a weak deposit of TGF-beta in tubulointerstitium. Immunoreactive IL-8 and TGF-beta in glomeruli was correlated with light microscopic and clinical features. There was a significant association (P < 0.05), between IL-8 glomerular immunoreactivity and neutrophil infiltration and between TGF-beta glomerular staining and mesangial matrix expansion. Otherwise, there was no correlation with the mesangial cellularity. It was concluded that increased protein expression of IL-8 and TGF-beta are observed in APSGN and may play a role in the acute glomerular inflammation.

Topics: Adolescent; Adult; Animals; Child; Female; Glomerulonephritis; Humans; Immunohistochemistry; Interleukin-8; Kidney Glomerulus; Male; Mice; Middle Aged; Streptococcal Infections; Transforming Growth Factor beta

Intraperitoneal injection of Group A streptococcal cell wall (SCW) fragments into female Lewis rats results in the induction of an acute hepatic inflammation that progresses to granulomatous lesions. Kupffer cells have been shown to rapidly clear circulating SCW which triggers production of TGF-beta. In this study, we examined Kupffer cells for the expression of TGF-beta receptors to determine if these cells might be modulated in an autocrine/paracrine fashion by TGF-beta during SCW-hepatic inflammation. By receptor crosslinking and subsequent SDS-PAGE analysis we demonstrate that Kupffer cells express Type I TGF-beta receptors, but not Types II and III. Scatchard analysis indicated a receptor density of approximately 1100 receptors per cell. Functionally, TGF-beta was found to be chemotactic for Kupffer cells in vitro and this chemotactic response was higher in cells isolated from rats 1-21 days post SCW-injection. Although TGF-beta 1 mRNA is constitutively expressed by Kupffer cells, in vitro stimulation of the cultures with purified TGF-beta augments the expression of TGF-beta 1 mRNA and protein synthesis suggesting autocrine/paracrine regulation. These results indicate that TGF beta secreted by Kupffer cells during SCW-induced hepatic inflammation may amplify its own expression and regulate Kupffer cell functions relevant to the formation of granulomatous lesions within the liver.

Topics: Animals; Cell Wall; Cells, Cultured; Chemotaxis; DNA Probes; Granuloma; Kupffer Cells; Liver Diseases; Male; Rats; Rats, Inbred Lew; Receptors, Cell Surface; Receptors, Transforming Growth Factor beta; RNA, Messenger; Streptococcal Infections; Streptococcus pyogenes; Transforming Growth Factor beta