A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis.
Chiea Chuen Khor,Stephen J Chapman,Stephen J Chapman,Fredrik O. Vannberg,Aisling Dunne,Caroline Murphy,Edmund Y. S. Ling,Angela J. Frodsham,Andrew Walley,Andrew Walley,Otto Kyrieleis,Amir R. Khan,Christophe Aucan,Shelley Segal,Catrin E. Moore,Kyle Knox,Sarah J. Campbell,Christian Lienhardt,Anthony Scott,Peter Aaby,Oumou Sow,Robert T Grignani,Robert T Grignani,Jackson Sillah,Giorgio Sirugo,N Peshu,Thomas N. Williams,Kathryn Maitland,Robert J. O. Davies,Dominic P. Kwiatkowski,Dominic P. Kwiatkowski,Dominic P. Kwiatkowski,Nicholas P. J. Day,Djamel Yala,Derrick W. Crook,Kevin Marsh,James A. Berkley,Luke A. J. O'Neill,Adrian V. S. Hill +38 more
TLDR
In this paper, a case-control study of 6,106 individuals from the UK, Vietnam and several African countries with invasive pneumococcal disease, bacteremia, malaria and tuberculosis was conducted.Abstract:
Toll-like receptors (TLRs) and members of their signaling pathway are important in the initiation of the innate immune response to a wide variety of pathogens. The adaptor protein Mal (also known as TIRAP), encoded by TIRAP (MIM 606252), mediates downstream signaling of TLR2 and TLR4 (refs. 4-6). We report a case-control study of 6,106 individuals from the UK, Vietnam and several African countries with invasive pneumococcal disease, bacteremia, malaria and tuberculosis. We genotyped 33 SNPs, including rs8177374, which encodes a leucine substitution at Ser180 of Mal. We found that heterozygous carriage of this variant associated independently with all four infectious diseases in the different study populations. Combining the study groups, we found substantial support for a protective effect of S180L heterozygosity against these infectious diseases (N = 6,106; overall P = 9.6 x 10(-8)). We found that the Mal S180L variant attenuated TLR2 signal transduction.read more
Citations
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Pathogen Recognition and Inflammatory Signaling in Innate Immune Defenses
TL;DR: This review presents current knowledge on pathogen recognition through different families of PRRs and the increasingly complex signaling pathways responsible for activation of an inflammatory and antimicrobial response and medical implications are discussed.
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The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling
TL;DR: The function of the fifth adaptor, SARM, has been revealed, which negatively regulates TRIF, and it is shown that it acts as a bridging adaptor in the initiation of TLR signalling.
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Immunity to malaria: more questions than answers.
TL;DR: This review will highlight key aspects of immunity to malaria, about which surprisingly little is known and which will prove critical in the search for effective malaria vaccines.
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Targeting Toll-like receptors: emerging therapeutics?
TL;DR: This work focuses on TLRs that hold the most promise for drug discovery research, highlighting agents that are in the discovery phase and in clinical trials, and on the emerging new aspects of TLR-mediated signalling — such as control by ubiquitination and regulation by microRNAs that might offer further possibilities of therapeutic manipulation.
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Pathogenesis, treatment, and prevention of pneumococcal pneumonia.
Tom van der Poll,Steven M. Opal +1 more
TL;DR: Versatility of the genome of pneumococci and the bacteria's polygenic virulence capabilities show that a multifaceted approach with many vaccine antigens, antibiotic combinations, and immunoadjuvant therapies will be needed to control this microbe.
References
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Haploview: analysis and visualization of LD and haplotype maps
TL;DR: Haploview is a software package that provides computation of linkage disequilibrium statistics and population haplotype patterns from primary genotype data in a visually appealing and interactive interface.
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Shizuo Akira,Kiyoshi Takeda +1 more
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Alexander Poltorak,Xiaolong He,Irina Smirnova,Mu Ya Liu,Christophe Van Huffel,Xin Du,Dale Birdwell,E. Alejos,M. Silva,Chris Galanos,Marina Freudenberg,Paola Ricciardi-Castagnoli,Betsy Layton,Bruce Beutler +13 more
TL;DR: The mammalian Tlr4 protein has been adapted primarily to subserve the recognition of LPS and presumably transduces the LPS signal across the plasma membrane.
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