Pan-Vertebrate Toll-Like Receptors During Evolution

Abstract

Human toll-like receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs) to raise innate immune responses. The human TLR family was discovered because of its sequence similarity to fruit fly (Drosophila) Toll, which is involved in an anti-fungal response. In this review, we focus on the origin of the vertebrate TLR family highlighted through functional and phylogenetic analyses of TLRs in non-mammalian vertebrates. Recent extensive genome projects revealed that teleosts contain almost all subsets of TLRs that correspond to human TLRs (TLR1,2,3,4,5,7,8,and 9), whereas the urochordate Ciona intestinalis contains only a few TLR genes. Therefore, mammals likely obtained almost all TLR family members at the beginning of vertebrate evolution. This premise is further supported by several functional analyses of non-mammalian TLRs. We have summarized several teleost TLRs with unique properties distinct from mammalian TLRs to outline their specific roles. According to Takifugu rubripes genome project, the puffer fish possesses fish-specific TLR21 and 22. Surprisingly, phylogenetic analyses indicate that TLR21 and 22 emerged during an early period of vertebrate evolution in parallel with other TLRs and that the mammalian ancestor lost TLR21 and 22 during evolution. Our laboratory recently revealed that TLR22 recognizes double-strand RNA and induces interferon production through the TICAM-1 adaptor, as in TLR3, but unlike TLR3, TLR22 localizes to the cell surface. Therefore, differential expression of TLR3 and TLR22, rather than simple redundancy of RNA sensors, may explain the effective protection of fish from RNA virus infection in the water. In this review, we summarize the similarities and differences of the TLR family in various vertebrates and introduce these unique TLRs for a possible application to the field of clinical practices for cancer or virus infection.

Cloning and characterization of the grass carp (Ctenopharyngodon idella) Toll-like receptor 22 gene, a fish-specific gene

“…Both, TLR3 and TLR22 serve as a dsRNA recognition receptor and recruit a common adaptor, TICAM-1. But, as shown by the phylogenetic analysis, TLR22 does not belong to the TLR3 family [16,21,40]. Why are there two TLRs that respond to dsRNA in teleosts?…”

“…200 AE 20 embryos of each group were sample at 0, 8,16,24,32,40,48,56, and 64 h post-fertilization, the expression profile of CiTLR22 and CiTLR3 mRNA in embryos was assessed using RT-PCR as described above and real-time quantitative reverse transcription PCR (qRT-PCR) as described in the following section. The relative expression ratio of the target gene versus the b-actin gene were calculated using the 6CT method.…”

Toll-like receptor responses in tuatara

“…This finding is the first description of TLR agonist-stimulated responses in tuatara, and suggests that, like those of most other multicellular organisms, tuatara immune cells express TLR homologues for TLR2, TLR3, TLR4 and TLR 7/8. Functional studies have shown that vertebrate orthologues of TLR have the same function and recognition as their human counterpart; for example, Takifugu rubripes (Japanese pufferfish) TLR3, like human TLR3 responds to poly I:C (Oshiumi et al 2008). Furthermore, this idea is supported by DNA sequence comparisons of TLR genes in reptiles, birds, Drosophila, and mammals, revealing genes that have remained highly conserved throughout vertebrate evolution (Kimbrell & Beutler 2001;Armant & Fenton 2002;Roach et al 2005).…”

Molecular evolution of vertebrate Toll-like receptors: Evolutionary rate difference between their leucine-rich repeats and their TIR domains

“…Phylogenetic analyses showed that the vertebrate TLRs evolved independently by gene duplication prior to the divergence of protostomes and deuterostomes (Hughes and Piontkivska, 2008;Roach et al, 2005). Gene loss and gene conversions were also suggested to have occurred (Huang et al, 2011;Kruithof et al, 2007;Oshiumi et al, 2008;Rebl et al, 2010;Temperley et al, 2008). Although vertebrate TLRs have been cited as an example of evolutionary conservation and strong functional constraint (Roach et al, 2005), recent studies suggested positive selection in some TLRs in extremely broad organisms including primates fishes or birds (Chen et al, 2008;Huang et al, 2011;Jann et al, 2008;Nakajima et al, 2008;Park et al, 2010;Tschirren et al, 2011;Wlasiuk et al, 2009).…”