GENETIC ANALYSIS OF HOST RESISTANCE: Toll-Like Receptor Signaling and Immunity at Large

Abstract

Classical genetic methods, driven by phenotype rather than hypotheses, generally permit the identification of all proteins that serve nonredundant functions in a defined biological process. Long before this goal is achieved, and sometimes at the very outset, genetics may cut to the heart of a biological puzzle. So it was in the field of mammalian innate immunity. The positional cloning of a spontaneous mutation that caused lipopolysaccharide resistance and susceptibility to Gram-negative infection led directly to the understanding that Toll-like receptors (TLRs) are essential sensors of microbial infection. Other mutations, induced by the random germ line mutagen ENU (N-ethyl-N-nitrosourea), have disclosed key molecules in the TLR signaling pathways and helped us to construct a reasonably sophisticated portrait of the afferent innate immune response. A still broader genetic screen--one that detects all mutations that compromise survival during infection--is permitting fresh insight into the number and types of proteins that mammals use to defend themselves against microbes.

Small hyaluronan oligosaccharides induce inflammation by engaging both toll-like-4 and CD44 receptors in human chondrocytes

“…They recognize structurally conserved molecules derived from microbes. Once these microbes cross physical barriers such as the skin or intestinal tract mucosa, they are recognized by TLRs which activates the innate immune response [1]. Although each TLR recognizes specific ligands, they may trigger other different molecules.…”

A Role of Toll-IL-1 Receptor Domain-Containing Adaptor-Inducing IFN-β in the Host Response to Pseudomonas aeruginosa Lung Infection in Mice

“…TLRs mediate distinct immune responses depending upon their usage of specific adaptor molecules, which transduce signals from TLRs to transcription factors. Increasing evidence suggests that the adaptor proteins MyD88 and Toll-IL-1R domain-containing adaptor-inducing IFN-␤ (TRIF), 3 also known as TICAM-1, mediate two distinct TLR signaling pathways (12,13). MyD88 mediates NF-B activation and subsequent expression of NF-B-regulated genes, such as TNF and IL-1.…”

Tuberculosis infection: Insight from immunogenomics

“…The TLRs are a family of transmembrane proteins that are known as pattern recognition receptors (PRRs). Through recognition of specific microbial ligands, TLRs activate inflammatory signaling pathways [8][9][10]. There are a number of components of the mycobacterial cell wall that stimulate TLRs, including lipoproteins, the MTb cell wall core structure mucolylarabinogalactan-peptidoglycan complex (mAGP), lipids, and LAM [11,12].…”

“…Rather than providing a comprehensive review, we will highlight factors that may influence partial immunity to MTb and how modulation of the innate immune response may be incorporated into future MTb vaccines and therapeutic strategies. In-depth review of subtopics within this manuscript include work on the immune response to Tb [2,3], genetic influences on Tb susceptibility [4][5][6][7], and the innate immune response [8][9][10].…”