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Tiffany C Scharschmidt
Inherited TIRAP deficiency confers susceptibility to staphylococcal disease via impaired TLR2 and TLR4 responses, which can be rescued by bacteria-specific antibodies.
March 22, 2017: Science Translational Medicine
Xiaolin Zhao, Wen Xiong, Shuyan Xiao, Tuo-Xian Tang, Jeffrey F Ellena, Geoffrey S Armstrong, Carla V Finkielstein, Daniel G S Capelluto
Pathogen-activated Toll-like receptors (TLRs), such as TLR2 and TLR4, dimerize and move laterally across the plasma membrane to phosphatidylinositol (4,5)-bisphosphate-enriched domains. At these sites, TLRs interact with the TIR domain-containing adaptor protein (TIRAP), triggering a signaling cascade that leads to innate immune responses. Membrane recruitment of TIRAP is mediated by its phosphoinositide (PI)-binding motif (PBM). We show that TIRAP PBM transitions from a disordered to a helical conformation in the presence of either zwitterionic micelles or monodispersed PIs...
February 22, 2017: Scientific Reports
David Martínez-Méndez, Evelyn Rivera-Toledo, Enrique Ortega, Ileana Licona-Limón, Leonor Huerta
Enveloped viruses induce cell-cell fusion when infected cells expressing viral envelope proteins interact with target cells, or through the contact of cell-free viral particles with adjoining target cells. CD4(+) T lymphocytes and cells from the monocyte-macrophage lineage express receptors for HIV envelope protein. We have previously reported that lymphoid Jurkat T cells expressing the HIV-1 envelope protein (Env) can fuse with THP-1 monocytic cells, forming heterokaryons with a predominantly myeloid phenotype...
March 1, 2017: Experimental Cell Research
Pardis Pedram, Guangju Zhai, Wayne Gulliver, Hongwei Zhang, Guang Sun
Food addiction (FA) is a distinguished clinical feature affecting about 5% adults of the general population in Canada. FA contributes to obesity, however, the underlying genes in FA are largely unknown. The aim of the current study was to search for FA candidate genes using an exome sequencing followed by a verification study using the most significantly associated identified genes. From a total of 752 adults, 24 subjects were selected including 8 obese with high and 8 obese with low/zero FA clinical symptom score (FAO, NFO), and 8 healthy controls with normal BMI and low/zero FA symptom score (Ctrl)...
January 20, 2017: Appetite
Ariana Aparecida Ferreira Pereira, Keny Gonçalves Tirapeli, Antonio Hernandes Chaves-Neto, Matheus da Silva Brasilino, Cláudia Quintino da Rocha, Adriane Belló-Klein, Suzana Francisca Llesuy, Rita Cássia Menegati Dornelles, Ana Cláudia de Melo Stevanato Nakamune
Perimenopause is a period in a woman's life that precedes menopause and is characterized by hormonal changes that result in increased oxidative stress. Since oxidative stress is associated with age-related diseases and perimenopausal symptoms including somato-vegetative manifestations, nutritional antioxidant supplementation may be an effective approach to minimizing this stress. Mate tea (MT) (Ilex paraguariensis), a typical and inexpensive beverage consumed in the Brazilian south-east, Argentina and Uruguay, increases antioxidant defense...
April 2017: Experimental Gerontology
Samer Halabi, Eiki Sekine, Brett Verstak, Nicholas J Gay, Martin C Moncrieffe
Ligand binding to Toll-like receptors (TLRs) results in dimerization of their cytosolic Toll/interleukin-1 receptor (TIR) domains and recruitment of post-receptor signal transducers into a complex signalosome. TLR activation leads to the production of transcription factors and pro-inflammatory molecules and the activation of phosphoinositide 3-kinases (PI3K) in a process that requires the multimodular B-cell adaptor for phosphoinositide 3-kinase (BCAP). BCAP has a sequence previously proposed as a "cryptic" TIR domain...
January 13, 2017: Journal of Biological Chemistry
Imran H Chowdhury, Sue-Jie Koo, Shivali Gupta, Lisa Yi Liang, Bojlul Bahar, Laura Silla, Julio Nuñez-Burgos, Natalia Barrientos, Maria Paola Zago, Nisha Jain Garg
BACKGROUND: Chronic inflammation and oxidative stress are hallmarks of chagasic cardiomyopathy (CCM). In this study, we determined if microparticles (MPs) generated during Trypanosoma cruzi (Tc) infection carry the host's signature of the inflammatory/oxidative state and provide information regarding the progression of clinical disease. METHODS: MPs were harvested from supernatants of human peripheral blood mononuclear cells in vitro incubated with Tc (control: LPS treated), plasma of seropositive humans with a clinically asymptomatic (CA) or symptomatic (CS) disease state (vs...
2017: Journal of Innate Immunity
Renato Cunha, Marco A Zago, Sergio Querol, Fernanda Volt, Annalisa Ruggeri, Guillermo Sanz, Fabienne Pouthier, Gesine Kogler, José L Vicario, Paola Bergamaschi, Riccardo Saccardi, Carmen H Lamas, Cristina Díaz-de-Heredia, Gerard Michel, Henrique Bittencourt, Marli Tavella, Rodrigo A Panepucci, Francisco Fernandes, Julia Pavan, Eliane Gluckman, Vanderson Rocha
We evaluated the impact of recipient and cord blood unit (CBU) genetic polymorphisms related to immune response on outcomes after unrelated cord blood transplantations (CBTs). Pretransplant DNA samples from 696 CBUs with malignant diseases were genotyped for NLRP1, NLRP2, NLRP3, TIRAP/Mal, IL10, REL, TNFRSF1B, and CTLA4. HLA compatibility was 6 of 6 in 10%, 5 of 6 in 39%, and ≥4 of 6 in 51% of transplants. Myeloablative conditioning was used in 80%, and in vivo T-cell depletion in 81%, of cases. The median number of total nucleated cells infused was 3...
January 26, 2017: Blood
Humberto Doriguêtto Gravina, Alfredo Miranda Goes, Silvane Maria Fonseca Murta, Catherine Ropert
This study continues to explore the plasticity of Toll-like receptor 2 (TLR2) previously described in immune response during Trypanosoma cruzi infection. Here, we have shown that Ly6C(hi)TLR2(hi) monocytes were involved in TNF-α and IL-12 production, whereas Ly6C(lo)TLR2(hi) monocytes were mainly committed to IL-10 and TNF-α production during T. cruzi infection independently of TLR agonist used (i.e. TLR2 or TLR9 agonists). Another difference between the monocyte populations is that the adapter Mal (encoded by TIRAP) has appeared crucial for the cytokine production by Ly6C(lo) but not by Ly6C(hi) monocytes...
November 4, 2016: Journal of Biological Chemistry
Amr Hosny Malash, Aliaa Adel Ali, Rania Mohamed Samy, Radwa Ahmed Shamma
Bronchopulmonary dysplasia (BPD) remains a leading cause of morbidity and mortality during infancy. Evidence suggests that the Toll-like receptor (TLR) signaling pathway plays an integral role in lung inflammation and injury. This study aimed to detect single nucleotide polymorphisms (SNPs) in TLR pathway genes [TLR5 and Toll-interleukin 1 receptor domain-containing adaptor protein (TIRAP)] among preterm neonates and to determine their association with the development and severity of bronchopulmonary dysplasia...
October 30, 2016: Gene
Tianjun Xu, Yanjin Wang, Jinrui Li, Chang Shu, Jingjing Han, Qing Chu
Being indispensable pattern recognition receptors in innate immune responses in host protection, Toll-like receptors (TLRs) play an important role in pathogen recognition. Fish TLRs exhibit high variety and distinct features, although little is known about their function on ligand recognition and signaling pathway in fish. This paper reports the evolutionary spectrum of the TLR1 subfamily (referred to as TLR1, TLR6, and TLR10) as determined using the comparative genomic approach. We hypothesized that the TLR1 subfamily underwent two rounds of gene duplication events; the first duplication occurred prior to the divergence of amphibians, and the second one occurred prior to the divergence of eutherians...
September 2016: Fish & Shellfish Immunology
Wenna Li, Yuehua Ke, Yufei Wang, Mingjuan Yang, Junguang Gao, Shaoxia Zhan, Du Xinying, Liuyu Huang, Wenfeng Li, Zeliang Chen, Juan Li
Brucella spp. are known to avoid host immune recognition and weaken the immune response to infection. Brucella like accomplish this by employing two clever strategies, called the stealth strategy and hijacking strategy. The TIR domain-containing protein (TcpB/Btp1) of Brucella melitensis is thought to be involved in inhibiting host NF-κB activation by binding to adaptors downstream of Toll-like receptors. However, of the five TIR domain-containing adaptors conserved in mammals, whether MyD88 or MAL, even other three adaptors, are specifically targeted by TcpB has not been identified...
August 26, 2016: Biochemical and Biophysical Research Communications
Nuria Martinez, Natkunam Ketheesan, Gregory W Martens, Kim West, Egil Lien, Hardy Kornfeld
Diabetes is associated with increased susceptibility to Klebsiella pneumoniae and poor prognosis with infection. We demonstrate accelerated mortality in mice with streptozotocin-induced diabetes following tracheal instillation of K. pneumoniae. Diabetic mice recruited fewer granulocytes to the alveolar airspace and had reduced early production of CXCL1, CXCL2, IL-1β and TNF-α following tracheal instillation of K. pneumoniae-lipopolysaccharide. Additionally, TLR2 and TIRAP expression following K. pneumoniae-lipopolysaccharide exposure was decreased in hyperglycemic mice...
October 2016: Microbes and Infection
Christian G Meyer, Norbert Reiling, Christa Ehmen, Gerd Ruge, Ellis Owusu-Dabo, Rolf D Horstmann, Thorsten Thye
Toll like receptors (TLR) are key elements of the innate immune response and involved in the recognition of pathogens. To test common and rare TLR variants involved in susceptibility or resistance to infection with Mycobacterium tuberculosis we screened the exons of the genes encoding TLR 1, 2, 4, and the adaptor molecule TIRAP in more than 4500 tuberculosis (TB) cases and controls from Ghana. The analysis yielded 109 variants with possible functional impact, including 101 non-synonymous variants, three stop-variants, and five indels...
2016: PloS One
Aditya K Panda, Bidyut K Das, Abhinash Panda, Rina Tripathy, Sarit S Pattnaik, Harishankar Mahto, Sylviane Pied, Sulabha Pathak, Shobhona Sharma, Balachandran Ravindran
Toll-interleukin-1 receptor domain containing adapter protein (TIRAP) plays a crucial role in TLR2 and TLR4 signaling pathways. Glycosylphospatidylinositol (GPI), considered a toxin molecule of Plasmodium falciparum, interacts with TLR2 and 4 to induce an immune inflammatory response. A single nucleotide polymorphism at coding region of TIRAP (S180L) has been reported to influence TLRs signaling. In the present study, we investigated the association of TIRAP (S180L) polymorphism with susceptibility/resistance to severe P...
September 2016: Infection, Genetics and Evolution
Wenji Piao, Lisa W Ru, Vladimir Y Toshchakov
TLR2 heterodimers with TLR1 or TLR6 recognize distinct pathogen-associated molecules such as tri- and di-acylated lipopeptides. The activated TLR2 heterodimers recruit Toll-IL-1R domain- (TIR-) containing adapter proteins, TIRAP and MyD88, through the receptor TIR domains. Molecular recognition mechanisms responsible for agonist-driven, TIR domain-mediated receptor-adapter interactions as well as the structure of resultant signaling complexes remain unknown. We previously reported that the cell-permeable peptide derived from helix D of TLR2 TIR (2R9) specifically binds TIRAP in vitro and in cells and thereby inhibits TIRAP-dependent TLR signaling...
July 2016: Pathogens and Disease
Leilei Gong, Hanxiang Wang, Xiaolei Sun, Chun Liu, Chengwei Duan, Rixin Cai, Xingxing Gu, Shunxing Zhu
Microglial activation, including classical (M1) and alternative (M2) activation, plays important roles in the development of several central nervous system disorders and promotes tissue reconstruction. Toll-like receptor (TLR)4 is important for microglial polarization. TIR domain-containing adaptor protein (TIRAP) is an intracellular adaptor protein, which is responsible for the early phase of TLR4 activation. The role of TIRAP in BV2 cell M1 polarization is still unknown. In this study, we showed that TIRAP expression is greatly elevated in lipopolysaccharide (LPS)/interferon (IFN)-γ-treated microglia...
June 2016: European Journal of Neuroscience
Rémi Planès, Nawal Ben Haij, Kaoutar Leghmari, Manutea Serrero, Lbachir BenMohamed, Elmostafa Bahraoui
UNLABELLED: In this study, we show that the HIV-1 Tat protein interacts with rapid kinetics to engage the Toll-like receptor 4 (TLR4) pathway, leading to the production of proinflammatory and anti-inflammatory cytokines. The pretreatment of human monocytes with Tat protein for 10 to 30 min suffices to irreversibly engage the activation of the TLR4 pathway, leading to the production of tumor necrosis factor alpha (TNF-α) and interleukin-10 (IL-10), two cytokines strongly implicated in the chronic activation and dysregulation of the immune system during HIV-1 infection...
July 1, 2016: Journal of Virology
Megumi Tatematsu, Ryuji Yoshida, Yuka Morioka, Noriko Ishii, Kenji Funami, Ayako Watanabe, Kazuko Saeki, Tsukasa Seya, Misako Matsumoto
The clathrin-dependent endocytic pathway is crucial for endosomal TLR3- and TLR4-mediated Toll-IL-1R domain-containing adaptor molecule-1 (TICAM-1) signaling. TLR4 uses a different signaling platform, plasma membrane and endosomes, for activation of TIRAP-MyD88 and TICAM-2-TICAM-1, respectively. LPS-induced endocytosis of TLR4 is mandatory for TICAM-1-mediated signaling including IFN-β production. Several molecules/mechanisms such as CD14, clathrin, and phosphatidylinositol metabolism have been reported to act as inducers of TLR4 translocation...
May 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Sudipta Biswas, Liang Xin, Soumya Panigrahi, Alejandro Zimman, Hua Wang, Valentin P Yakubenko, Tatiana V Byzova, Robert G Salomon, Eugene A Podrez
A prothrombotic state and increased platelet reactivity are common in dyslipidemia and oxidative stress. Lipid peroxidation, a major consequence of oxidative stress, generates highly reactive products, including hydroxy-ω-oxoalkenoic acids that modify autologous proteins generating biologically active derivatives. Phosphatidylethanolamine, the second most abundant eukaryotic phospholipid, can also be modified by hydroxy-ω-oxoalkenoic acids. However, the conditions leading to accumulation of such derivatives in circulation and their biological activities remain poorly understood...
May 26, 2016: Blood
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