Novel alternative transcripts of TLR8 and TLR9 reveal evolutionary pressure to conserve protein structure

TLR8 and TLR9 are innate immune receptors belonging to the TLR family that are essential for viral recognition and early immune activation. Their dysfunction is linked to increased susceptibility to infections. TLR8 detects viral single- and double-stranded RNA, while TLR9 recognizes viral DNA molecules with CpG motifs. Six TLR8 alternative transcripts (V1, V2, V5, V6, V7, and V8) and nine TLR9 (V1, A, B, C, D, E, V8, V9, and V10) have been previously described in humans. In the present study, we have performed a comprehensive analysis of TLR8 and TLR9 transcripts in a healthy population and two new TLR8 transcripts (V3 and V4) and four new TLR9 transcripts (V2, V5, V6, and V7) were found. The main mechanisms for the generation of different mRNA variants were the insertion of non-coding regions and the loss of whole or partial exons. These changes result in the loss or insertion of new amino acids but only modify the initial leucine-rich repeat (LRR) region and preserve the rest of the receptor's complete structure. From the results obtained, we can deduce that there seems to be a strong evolutionary drive to maintain TLR8 and TLR9 functionality, unlike other innate immune response receptors.