The Vertebrate TLR Supergene Family Evolved Dynamically by Gene Gain/Loss and Positive Selection Revealing a Host–Pathogen Arms Race in Birds

Imran Khan,Stephen J O’Brien,Erich D Jarvis,Guojie Zhang,M Thomas P Gilbert,Warren E Johnson,Liliana Silva,Agostinho Antunes,Daniela Almeida,Emanuel Maldonado

doi:10.3390/d11080131

Abstract

The vertebrate toll-like receptor (TLRs) supergene family is a first-line immune defense against viral and non-viral pathogens. Here, comparative evolutionary-genomics of 79 vertebrate species (8 mammals, 48 birds, 11 reptiles, 1 amphibian, and 11 fishes) revealed differential gain/loss of 26 TLRs, including 6 (TLR3, TLR7, TLR8, TLR14, TLR21, and TLR22) that originated early in vertebrate evolution before the diversification of Agnatha and Gnathostomata. Subsequent dynamic gene gain/loss led to lineage-specific diversification with TLR repertoires ranging from 8 subfamilies in birds to 20 in fishes. Lineage-specific loss of TLR8-9 and TLR13 in birds and gains of TLR6 and TLR10-12 in mammals and TLR19-20 and TLR23-27 in fishes. Among avian species, 5–10% of the sites were under positive selection (PS) (omega 1.5–2.5) with radical amino-acid changes likely affecting TLR structure/functionality. In non-viral TLR4 the 20 PS sites (posterior probability PP > 0.99) likely increased ability to cope with diversified ligands (e.g., lipopolysaccharide and lipoteichoic). For viral TLR7, 23 PS sites (PP > 0.99) possibly improved recognition of highly variable viral ssRNAs. Rapid evolution of the TLR supergene family reflects the host–pathogen arms race and the coevolution of ligands/receptors, which follows the premise that birds have been important vectors of zoonotic pathogens and reservoirs for viruses.

Highlights

The toll-like receptor (TLRs) supergene family members are type-I transmembrane glycoproteins belonging to the pathogen recognition receptor (PRRs) class of proteins expressed in the cell membrane and intracellular vesicles, including the endoplasmic reticulum, endosomes, lysosomes, and endolysosomes [1,2]
Overall these results show that the number and (TLR4) toll-like receptors (TLRs) evolved strong strength of positive selection sites varies in the family and diacyl that both viral (TLR7)
Our results show that the TLR supergene family is broadly divided into six major families, including TLR1, TLR3, TLR4, TLR5, TLR7, and TLR11, with each having different numbers of subfamilies—e.g., 10 subfamilies in TLR1, 10 subfamilies in TLR11, 3 subfamilies in TLR7, and a single subfamily in families TLR3, TLR4, and TLR5

Summary

Introduction

The toll-like receptor (TLRs) supergene family members are type-I transmembrane glycoproteins belonging to the pathogen recognition receptor (PRRs) class of proteins expressed in the cell membrane and intracellular vesicles, including the endoplasmic reticulum, endosomes, lysosomes, and endolysosomes [1,2]. TLRs constitute one of the first lines of the immune defense system and recognize a variety of pathogen-associated-molecular patterns (PAMPs) during pathogen invasion, triggering the cascade of signaling pathways leading to the adaptive immune response [3,4,5]. The diverse mechanisms used by TLRs paralogs for TLR-ligand recognition and the formation of a m-shaped homo or heterodimeric complex, lead to activation of downstream signaling cascades by. The TIR dimer is recognized by the TIR domain present in different signaling adaptor proteins—including MyD88, MAL, TRIF, and TRAM [16]—and resulting in the activation of NFkB, the expression of various inflammatory and anti-pathogenic proteins [17], the initiation of the adaptive immune response, and the elimination of the invading pathogens [5,18,19,20]

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Conclusion