Genetic analysis of the innate immune responses in wild‐derived inbred strains of mice

Abstract

The vertebrate immune system has evolved to recognize nucleic acids of bacterial and viral origin. Microbial DNA, as well as synthetic oligonucleotides based on these motifs, activates innate immune pathways mediated by the family of Toll‐like receptors (TLR) initiating a cascade of signals in immune cells necessary for responses to pathogens. However, not all of the proteins that participate in TLR‐mediated responses have been identified. In studies described herein, we observed significant variation in innate immune responses among selected wild‐derived strains of mice. Specifically, we show that mice of MOLF/Ei, Czech/Ei, and MSM/Ms strains are hypo‐responsive to polyinosinic‐polycytidylic acid (poly(I:C)) because of a mutation in Tlr3. In addition, we discovered a hypo‐response to cytosine guanine dinuleotide in MOLF/Ei mice and established that it is not linked to Tlr9, but to another locus. Further inquiry revealed that this hypo‐response is transmitted as a monogenic dominant trait that can be mapped and cloned through positional cloning methods. These results suggest the existence of a novel molecule that can alter pro‐inflammatory signals or activate additional signal transduction pathways. In addition, they support the wild‐derived mouse strain as a forward genetic tool for the identification of novel immunological phenotypes.

A Hemidominant Naip5 Allele in Mouse Strain MOLF/Ei-Derived Macrophages Restricts Legionella pneumophila Intracellular Growth

“…In contrast, wild-derived mice originated mainly from M. m. musculus and M. m. castaneus subspecies are genetically diverse compared to the classical inbred strains. Compared to one another, the genomes of the wild-derived and classical inbred strains show a polymorphism in every 100 to 200 bp (34), suggesting that screening wild-derived mice may uncover other host factors or novel alleles of previously characterized genes that influence L. pneumophila intracellular growth.…”

Variation matters: TLR structure and species-specific pathogen recognition

“…(iii) Third, the same TLR from different strains of the same species might differ in single amino acids, which are essential for the recognition of certain ligands. Indeed, monogenic dominant traits in TLR genes have recently been identified in wild-derived mice strains [50], indicating that studying inbred laboratory strains might fail to capture all the polymorphisms that exist in the mouse species. Such analyses could help to assess genetic predisposition to certain infectious diseases in humans and livestock, and could be used to improve breeding strategies for genetic disease resistance in livestock.…”

645 Imiquimod has strain-dependent effects in mice and does not uniquely model human psoriasis

“…It was of interest to evaluate IMQ dermatitis in MOLF mice, since previous studies have identified MOLF genetic variants impacting Toll-like receptor (TLR) signaling, including alleles associated with Tlr5 [57], Irak1bp1 [56], Irak2 [70], Irak2c [71], and Cyld [72]. These variants appear to alter immune responses of MOLF mice to several stimuli, such as lipoteichoic acid, poly(I:C), lipopolysaccharide, and schistosome infection [18,56,70]. IMQ is a TLR7 agonist and previous work has identified TLR7 expression in a subpopulation of mouse interfollicular epidermal keratinocytes [73].…”

“…Previous work has shown that MOLF mice exhibit unique responses to TLR agonists, such as lipoteichoic acid, poly(I:C), lipopolysaccharides, cytosine guanine dinucleotide (CpG), and resiquimod [18,56,57]. A set of 101 TLR-associated genes compiled by the Kyoto Encyclopedia of Genes and Genomes (KEGG) [58] was disproportionately elevated by IMQ in all strains, including MOLF males and females (Additional file 12; KEGG pathway mmu04620).…”

“…At the same time, those responses that are strain-dependent may point towards allelic variants that shape innate immune responses, suggesting new avenues for studies of gene function [18]. Ultimately, such investigation should help refine the IMQ model by clarifying its strengths and limitations relative to human psoriasis, which should improve the chance that new findings are successfully translated to clinical studies with patients [12].…”