Çagla Tükel
Temple University
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Publication
Featured researches published by Çagla Tükel.
Trends in Microbiology | 2009
Renato L. Santos; Manuela Raffatellu; Charles L. Bevins; L. Garry Adams; Çagla Tükel; Renée M. Tsolis; Andreas J. Bäumler
The lower gastrointestinal tract is densely populated with resident microbial communities (microbiota), which do not elicit overt host responses but rather provide benefit to the host, including niche protection from pathogens. However, introduction of bacteria into the underlying tissue evokes acute inflammation. Non-typhoidal Salmonella serotypes (NTS) elicit this stereotypic host response by actively penetrating the intestinal epithelium and surviving in tissue macrophages. Initial responses generated by bacterial host cell interaction are amplified in tissue through the interleukin (IL)-18/interferon-gamma and IL-23/IL-17 axes, resulting in the activation of mucosal barrier functions against NTS dissemination. However, the pathogen is adapted to survive antimicrobial defenses encountered in the lumen of the inflamed intestine. This strategy enables NTS to exploit inflammation to outcompete the intestinal microbiota, and promotes the Salmonella transmission by the fecal/oral route.
Molecular Microbiology | 2005
Çagla Tükel; Manuela Raffatellu; Andrea D. Humphries; R. Paul Wilson; Helene Andrews-Polymenis; Tamara Gull; Josely F. Figueiredo; Michelle H. Wong; Kathrin S. Michelsen; Mustafa Akçelik; L. Garry Adams; Andreas J. Bäumler
Knowledge about the origin and identity of the microbial products recognized by the innate immune system is important for understanding the pathogenesis of inflammatory diseases. We investigated the potential role of Salmonella enterica serotype Typhimurium fimbriae as pathogen‐associated molecular patterns (PAMPs) that may stimulate innate pathways of inflammation. We screened a panel of 11 mutants, each carrying a deletion of a different fimbrial operon, for their enteropathogenicity using the calf model of human gastroenteritis. One mutant (csgBA) was attenuated in its ability to elicit fluid accumulation and GROα mRNA expression in bovine ligated ileal loops. The mechanism by which thin curled fimbriae encoded by the csg genes contribute to inflammation was further investigated using tissue culture. The S. Typhimurium csgBA mutant induced significantly less IL‐8 production than the wild type in human macrophage‐like cells. Purified thin curled fimbriae induced IL‐8 expression in human embryonic kidney (HEK293) cells transfected with Toll‐like receptor (TLR) 2/CD14 but not in cells transfected with TLR5, TLR4/MD2/CD14 or TLR11. Fusion proteins between the major fimbrial subunit of thin curled fimbriae (CsgA) and glutathione‐S‐transferase (GST) elicited IL‐8 production in HEK293 cells transfected with TLR2/CD14. Proteinase K treatment abrogated IL‐8 production elicited in these cells by GST–CsgA, but not by synthetic lipoprotein. GST–CsgA elicited more IL‐6 production than GST in bone marrow‐derived macrophages from TLR2+/+ mice, while there was no difference in IL‐6 secretion between GST–CsgA and GST in macrophages from TLR2–/– mice. These data suggested that CsgA is a PAMP that is recognized by TLR2.
Cellular Microbiology | 2008
R. Paul Wilson; Manuela Raffatellu; Daniela Chessa; Sebastian E. Winter; Çagla Tükel; Andreas J. Bäumler
The viaB locus enables Salmonella enterica serotype Typhi to reduce Toll‐like receptor (TLR) dependent cytokine production in tissue culture models. This DNA region contains genes involved in the regulation (tviA), biosynthesis (tviBCDE) and export (vexABCDE) of the Vi capsule. Expression of the Vi capsule in S. Typhimurium, but not expression of the TviA regulatory protein, reduced tumour necrosis factor‐alpha (TNF‐α) and IL‐6 production by murine bone‐marrow derived macrophages. Production of TNF‐α and IL‐6 was dependent on expression of TLR4 as stimulation of macrophages from TLR4−/− mice with S. Typhimurium did not result in expression of these cytokines. Intraperitoneal infection of mice with S. Typhimurium induced expression of TNF‐α and inducible nitric oxide synthase (iNOS) in the liver. Introduction of the cloned viaB region into S. Typhimurium reduced TNF‐α and iNOS expression to levels observed after infection with a S. Typhimurium msbB mutant. In contrast, no differences in TNF‐α expression between the S. Typhimurium wild type and strains expressing the Vi‐capsule or carrying a mutation in msbB were observed after infection of TLR4−/− mice. We conclude that the Vi capsule prevents both in vitro and in vivo recognition of S. Typhimurium lipopolysaccharide by TLR4.
Infection and Immunity | 2006
Manuela Raffatellu; Daniela Chessa; R. Paul Wilson; Çagla Tükel; Mustafa Akçelik; Andreas J. Bäumler
The genus Salmonella contains a group of closely related organisms that are pathogenic for humans and other vertebrates. The human disease manifestations caused most frequently by Salmonella serotypes worldwide are typhoid fever and gastroenteritis (reviewed in reference [102][1]). Both illnesses
Cell Host & Microbe | 2009
Çagla Tükel; R. Paul Wilson; Jessalyn H. Nishimori; Milad Pezeshki; Brett A. Chromy; Andreas J. Bäumler
Curli fibrils are proteinaceous bacterial structures formed by amyloid fibrils composed of the major curli subunit CsgA. Like beta-amyloid 1-42, which is associated with brain inflammation and Alzheimers disease, curli fibrils have been implicated in the induction of host inflammatory responses. However, the underlying mechanisms of amyloid-induced inflammation are not fully understood. In a mouse sepsis model, we show that curli fibrils contributed to Nos2 expression, a hallmark of inflammation, by stimulating Toll-like receptor (TLR) 2. The TLR2 agonist activity was reduced by an amyloidogenicity-lowering amino acid substitution (N122A) in CsgA. Amyloid-forming synthetic peptides corresponding to beta-amyloid 1-42 or CsgA 111-151 stimulated Nos2 production in macrophages and microglia cells through a TLR2-dependent mechanism. This activity was abrogated when an N122A substitution was introduced into the synthetic CsgA peptide. The induction of TLR2-mediated responses by bacterial and eukaryotic amyloids may explain the inflammation associated with amyloids and the resulting pathologies.
Cellular Microbiology | 2010
Çagla Tükel; Jessalyn H. Nishimori; R. Paul Wilson; Maria G. Winter; A. Marijke Keestra; Jos P. M. van Putten; Andreas J. Bäumler
Responses to host amyloids and curli amyloid fibrils of Escherichia coli and Salmonella enterica serotype Typhimurium are mediated through Toll‐like receptor (TLR) 2. Here we show that TLR2 alone was not sufficient for mediating responses to curli. Instead, transfection experiments with human cervical cancer (HeLa) cells and antibody‐mediated inhibition of TLR signalling in human macrophage‐like (THP‐1) cells suggested that TLR2 interacts with TLR1 to recognize curli amyloid fibrils. TLR1/TLR2 also serves as a receptor for tri‐acylated lipoproteins, which are produced by E. coli and other Gram‐negative bacteria. Despite the presence of multiple TLR1/TLR2 ligands on intact bacterial cells, an inability to produce curli amyloid fibrils markedly reduced the ability of E. coli to induce TLR2‐dependent responses in vitro and in vivo. Collectively, our data suggest that curli amyloid fibrils from enterobacterial biofilms significantly contribute to TLR1/TLR2‐mediated host responses against intact bacterial cells.
Infection and Immunity | 2011
R. Paul Wilson; Sebastian E. Winter; Alanna M. Spees; Maria G. Winter; Jessalyn H. Nishimori; Jesus F. Sanchez; Sean Paul Nuccio; Robert W. Crawford; Çagla Tükel; Andreas J. Bäumler
ABSTRACT Capsular polysaccharides are important virulence factors of invasive bacterial pathogens. Here we studied the role of the virulence (Vi) capsular polysaccharide of Salmonella enterica serotype Typhi (S. Typhi) in preventing innate immune recognition by complement. Comparison of capsulated S. Typhi with a noncapsulated mutant (ΔtviBCDE vexABCDE mutant) revealed that the Vi capsule interfered with complement component 3 (C3) deposition. Decreased complement fixation resulted in reduced bacterial binding to complement receptor 3 (CR3) on the surface of murine macrophages in vitro and decreased CR3-dependent clearance of Vi capsulated S. Typhi from the livers and spleens of mice. Opsonization of bacteria with immune serum prior to intraperitoneal infection increased clearance of capsulated S. Typhi from the liver. Our data suggest that the Vi capsule prevents CR3-dependent clearance, which can be overcome in part by a specific antibody response.
Immunity | 2015
Paul Matthew Gallo; Glenn J. Rapsinski; R. Paul Wilson; Gertrude O. Oppong; Uma Sriram; Mark Goulian; Bettina A. Buttaro; Roberto Caricchio; Stefania Gallucci; Çagla Tükel
Research on the human microbiome has established that commensal and pathogenic bacteria can influence obesity, cancer, and autoimmunity through mechanisms mostly unknown. We found that a component of bacterial biofilms, the amyloid protein curli, irreversibly formed fibers with bacterial DNA during biofilm formation. This interaction accelerated amyloid polymerization and created potent immunogenic complexes that activated immune cells, including dendritic cells, to produce cytokines such as type I interferons, which are pathogenic in systemic lupus erythematosus (SLE). When given systemically, curli-DNA composites triggered immune activation and production of autoantibodies in lupus-prone and wild-type mice. We also found that the infection of lupus-prone mice with curli-producing bacteria triggered higher autoantibody titers compared to curli-deficient bacteria. These data provide a mechanism by which the microbiome and biofilm-producing enteric infections may contribute to the progression of SLE and point to a potential molecular target for treatment of autoimmunity.
PLOS Pathogens | 2013
David A. Hufnagel; Çagla Tükel; Matthew R. Chapman
Amyloid fibers are β-sheet-rich protein polymers that are highly resistant to denaturation. The distinguishing amyloid fold can be adopted by a variety of proteins, without a shared primary structure, and is found in nearly all cell types. Despite the fact that amyloids have a richly informed scientific history, the diverse biology contributed by amyloids is only beginning to be appreciated. Initial amyloid studies focused on the intimate association of amyloid formation with cytotoxicity and neurodegenerative diseases like Alzheimers, Huntingtons, and the prion encephalopathies. Despite amyloids somewhat sinister past, recent work on “functional” amyloids has revealed numerous ways that amyloids contribute to normal cellular biology [1]. Included among the activities in which amyloids participate are melanin production, the ability to act as non-Mendelian inheritable genetic elements, and as extracellular molecular scaffolds that hold bacterial communities together. The amyloid fold is tailor-made for the extracellular space, as amyloid polymers can self-assemble without requiring exogenous energy and the polymers are resistant to a slew of harsh denaturants that would devastate most protein folds. This article will address questions involving the various roles of bacterial amyloids in host, polymicrobial, and environmental interactions.
Infection and Immunity | 2012
Jessalyn H. Nishimori; Tiffanny N. Newman; Gertrude O. Oppong; Glenn J. Rapsinski; Jui-Hung Yen; Steven G. Biesecker; R. Paul Wilson; Brian P. Butler; Maria G. Winter; Renée M. Tsolis; Doina Ganea; Çagla Tükel
ABSTRACT The Toll-like receptor 2 (TLR2)/TLR1 receptor complex responds to amyloid fibrils, a common component of biofilm material produced by members of the phyla Firmicutes, Bacteroidetes, and Proteobacteria. To determine whether this TLR2/TLR1 ligand stimulates inflammatory responses when bacteria enter intestinal tissue, we investigated whether expression of curli amyloid fibrils by the invasive enteric pathogen Salmonella enterica serotype Typhimurium contributes to T helper 1 and T helper 17 responses by measuring cytokine production in the mouse colitis model. A csgBA mutant, deficient in curli production, elicited decreased expression of interleukin 17A (IL-17A) and IL-22 in the cecal mucosa compared to the S. Typhimurium wild type. In TLR2-deficient mice, IL-17A and IL-22 expression was blunted during S. Typhimurium infection, suggesting that activation of the TLR2 signaling pathway contributes to the expression of these cytokines. T cells incubated with supernatants from bone marrow-derived dendritic cells (BMDCs) treated with curli fibrils released IL-17A in a TLR2-dependent manner in vitro. Lower levels of IL-6 and IL-23 production were detected in the supernatants of the TLR2-deficient BMDCs treated with curli fibrils. Consistent with this, three distinct T-cell populations—CD4+ T helper cells, cytotoxic CD8+ T cells, and γδ T cells—produced IL-17A in response to curli fibrils in the intestinal mucosa during S. Typhimurium infection. Notably, decreased IL-6 expression by the dendritic cells and decreased IL-23 expression by the dendritic cells and macrophages were observed in the cecal mucosa of mice infected with the curli mutant. We conclude that TLR2 recognition of bacterial amyloid fibrils in the intestinal mucosa represents a novel mechanism of immunoregulation, which contributes to the generation of inflammatory responses, including production of IL-17A and IL-22, in response to bacterial entry into the intestinal mucosa.