Evolution of the Bovine TLR Gene Family and Member Associations with Mycobacterium avium Subspecies paratuberculosis Infection

Fisher, Colleen A.; Bhattarai, Eric K.; Osterstock, Jason B.; Dowd, Scot E.; Seabury, Paul M.; Vikram, Meenu; Whitlock, Robert H.; Schukken, Ynte H.; Schnabel, Robert D.; Taylor, Jeremy F.; Womack, James E.; Seabury, Christopher M.

Relevant to the suppression of infectious diseases, the mammalian innate immune system provides host defense against a variety of pathogens without requiring prior exposure [5, 6] . Consequently, genes that modulate innate immunity have often been considered as candidate loci for improving host resistance to disease in agricultural species [7] [8] [9] [10] . Among mammals, the Tolllike receptor genes (TLRs) facilitate host recognition of pathogenassociated molecular patterns (PAMPs), thereafter eliciting host innate immune responses [5, 6] aimed at suppressing invading bacteria, viruses, protozoa, and fungi. Essential to their role in host defense, the mammalian TLRs encode type I transmembrane proteins of the Interleukin-1 receptor (IL-1R) family with Nterminal leucine-rich repeats (LRR) involved in ligand recognition, a transmembrane domain, and a C-terminal intracellular Toll/IL-1 receptor homologous (TIR/IL-1R) domain for signal transduction [5, 6, 11] . The mammalian TLR genes are primarily expressed by antigen-presenting cells (i.e., macrophages or dendritic cells), and most of the TLR ligand specificities have been experimentally elucidated, with six gene family members (TLR1, TLR2, TLR4, TLR5, TLR6, TLR9) known to recognize microbial (bacteria, fungi, protozoa) and/or synthetic ligands, and five (TLR3, TLR4, TLR7-TLR9) known to recognize viral components [11, 12] . Presently, TLR10 remains the only functional human TLR gene family member for which natural and/or synthetic ligands have not been fully elucidated [13] . However, given evidence for functional mammalian TLR protein heterodimers (TLR10/ TLR1; TLR2/TLR10) [13] , the host protein encoded by TLR10 may collaboratively enable recognition of a diverse array of microbial PAMPs, including those recognized by TLR2 [13] [14] [15] [16] .