Replacement of two aminoacids in the bovine Toll-like receptor 5 TIR domain with their human counterparts partially restores functional response to flagellin

Osvaldová, Alena; Woodman, Sally; Patterson, Nicholas J.; Offord, Victoria; Mwangi, Duncan M.; Gibson, Amanda J.; Matiašovic, Ján; Werling, Dirk

doi:10.1016/j.dci.2014.07.002

Cited by 8 publications

(13 citation statements)

References 25 publications

(3 reference statements)

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“…Our earlier studies had indicated that bovine TLR5 contains a number of positively selected sites in the extracellular and intracellular domains 2 , 7 . We also have also recently shown that contrary to some reports 8 , 9 , bovine TLR5 (bTLR5) is functional in both human (HEK293) and bovine epithelial cell lines (EBL), as well as in bovine macrophages. Signalling through bTLR5 with H7 flagellin ligand derived from E. coli O157 resulted in NFκB reporter activation and up-regulation of CXCL8 mRNA in these cells as well as secretion of the chemokine 7 .…”

Section: Introductionmentioning

confidence: 67%

“…S3 ). Osvaldova and colleagues 9 suggested that this difference resulted in an inability of bTLR5 to signal, and replaced FH for YQ in bTLR5 with partial restoration of its activity in HEK cells. However, our data above demonstrates that wild-type bTLR5 is able to signal in both a human and bovine cell background, despite the lack of this putative PI3K motif.…”

Section: Resultsmentioning

confidence: 99%

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Host species adaptation of TLR5 signalling and flagellin recognition

Tahoun

Jensen

Corripio-Miyar

et al. 2017

Sci Rep

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Toll-like receptor 5 (TLR5) recognition of flagellin instigates inflammatory signalling. Significant sequence variation in TLR5 exists between animal species but its impact on activity is less well understood. Building on our previous research that bovine TLR5 (bTLR5) is functional, we compared human and bovine TLR5 activity and signalling in cognate cell lines. bTLR5 induced higher levels of CXCL8 when expressed in bovine cells and reciprocal results were found for human TLR5 (hTLR5) in human cells, indicative of host cell specificity in this response. Analysis of Toll/interleukin-1 receptor (TIR) sequences indicated that these differential responses involve cognate MyD88 recognition. siRNA knockdowns and inhibitor experiments demonstrated that there are some host differences in signalling. Although, PI3K activation is required for bTLR5 signalling, mutating bTLR5 F798 to hTLR5 Y798 within a putative PI3K motif resulted in a significantly reduced response. All ruminants have F798 in contrast to most other species, suggesting that TLR5 signalling has evolved differently in ruminants. Evolutionary divergence between bovine and human TLR5 was also apparent in relation to responses measured to diverse bacterial flagellins. Our results underscore the importance of species specific studies and how differences may alter efficacy of TLR-based vaccine adjuvants.

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Section: Introductionmentioning

confidence: 67%

Section: Resultsmentioning

confidence: 99%

Host species adaptation of TLR5 signalling and flagellin recognition

Tahoun

Jensen

Corripio-Miyar

et al. 2017

Sci Rep

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“…Considering that the ligand-binding region of TLR2 encompasses LRR9-12, the most important change causing amino acid characteristic changes (H326Q) was found in LRR11. In addition, the aa changes identified in the TIR domain (H665Q and E738Q) need to be further investigated, as these might impact on subsequent intracellular signaling events, similar as described recently for bovine TLR5 [39].…”

Section: Discussionmentioning

confidence: 92%

Determination of Genetic Variations of Toll-Like Receptor (TLR) 2, 4, and 6 with Next-Generation Sequencing in Native Cattle Breeds of Anatolia and Holstein Friesian

et al. 2016

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In recent years, the focus of disease resistance and susceptibility studies in cattle have been on determining patterns in the innate immune response of key proteins, such as Toll-like receptors (TLR). In the bovine genome, there are 10 TLR family members and, of these, TLR2, TLR4, and TLR6 are specialized in the recognition of bacterial ligands. Indigenous cattle breeds of Anatolia have been reported to show fewer signs of clinical bacterial infections, such as bovine tuberculosis and mastitis, and it is hypothesized that this might be due to a less stringent genetic selection during breeding. In contrast, Holstein-Friesian cattle have been under strong selection for milk production, which may have resulted in greater susceptibility to diseases. To test this hypothesis, we have compared the TLR2, TLR4, and TLR6 genes of Anatolian Black (AB), East Anatolian Red (EAR), South Anatolian Red (SAR), Turkish Grey (TG), and Holstein (HOL) cattle using next-generation sequencing. The SAR breed had the most variations overall, followed by EAR, AB, TG, and HOL. TG had the most variations for TLR2, whereas SAR had the most variations in TLR4 and TLR6. We compared these variants with those associated with disease and susceptibility traits. We used exon variants to construct haplotypes, investigated shared haplotypes within breeds, and proposed candidate haplotypes for a disease resistance phenotype in Anatolian cattle breeds.

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“…Considering that the ligand-binding region of TLR2 encompasses LRR9-12, the most important change causing amino acid characteristic change (H326Q) was found in LRR11. In addition, the aa changes identified in the TIR domain (H665Q and E738Q) need to be further investigated, as these might impact on subsequent intracellular signaling events, similar as described recently for bovine TLR5 [39].…”

Section: Discussionmentioning

confidence: 99%

Determination of Genetic Variations of Toll-like Receptor (TLR) 2, 4 and 6 with Next Generation Sequencing in Native Cattle Breeds of Anatolia and Holstein Friesian

Bilgen¹,

Kul²,

Offord³

et al. 2016

Preprint

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Abstract:In recent years, the focus of disease resistance and susceptibility studies in cattle have been on determining patterns in the innate immune response of key proteins, such as Toll-like receptors (TLR). In the bovine genome, there are 10 TLR family members and, of these, TLR2, TLR4 and TLR6 are specialized in recognition of bacterial ligands. Indigenous cattle breeds of Anatolia have been reported to show fewer signs of clinical bacterial infections, such as bovine tuberculosis and mastitis, and it is hypothesized that this might be due to a less stringent genetic selection during breeding.In contrast, Holstein-Friesian cattle have been under strong selection for milk production, which may have resulted in greater susceptibility to diseases. To test this hypothesis, we have compared the TLR2, TLR4 and TLR6 genes of Anatolian Black (AB), East Anatolian Red (EAR), South Anatolian Red (SAR), Turkish Grey (TG), and Holstein (HOL) cattle using Next Generation Sequencing. The SAR breed had the most variations overall, followed by EAR, AB, TG and HOL. TG had the most variations for TLR2 whereas SAR had the most variations in TLR4 and TLR6. We compared these variants with those associated with disease and susceptibility traits. We used exon variants to construct haplotypes, investigated shared haplotypes within breeds and determined candidate haplotypes for disease resistance phenotype in Anatolian cattle breeds.

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Replacement of two aminoacids in the bovine Toll-like receptor 5 TIR domain with their human counterparts partially restores functional response to flagellin

Cited by 8 publications

References 25 publications

Host species adaptation of TLR5 signalling and flagellin recognition

Host species adaptation of TLR5 signalling and flagellin recognition

Determination of Genetic Variations of Toll-Like Receptor (TLR) 2, 4, and 6 with Next-Generation Sequencing in Native Cattle Breeds of Anatolia and Holstein Friesian

Determination of Genetic Variations of Toll-like Receptor (TLR) 2, 4 and 6 with Next Generation Sequencing in Native Cattle Breeds of Anatolia and Holstein Friesian

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