Genetic association studies of leprosy cohorts across the world have identified numerous polymorphisms which alter susceptibility and outcome to infection with Mycobacterium leprae. As expected, many of the polymorphisms reside within genes that encode components of the innate and adaptive immune system. Despite the preponderance of these studies, our understanding of the mechanisms that underlie these genetic associations remains sparse. Toll-like receptors (TLRs) have emerged as an essential family of innate immune pattern recognition receptors which play a pivotal role in host defense against microbes, including pathogenic strains of mycobacteria. This paper will highlight studies which have uncovered the association of specific TLR gene polymorphisms with leprosy or tuberculosis: two important diseases resulting from mycobacterial infection. This analysis will focus on the potential influence these polymorphic variants have on TLR expression and function and how altered TLR recognition or signaling may contribute to successful antimycobacterial immunity. 1. Introduction Mycobacterium leprae is an evolutionarily ancient pathogen of historical and worldwide prevalence. Identified in 1873 by Gerhard Armauer Hansen as the causative agent of leprosy, these fastidious, intracellular bacilli have been studied extensively for their complex pathogenesis and host interactions. Cellular tropisms for M. leprae principally include tissue-resident macrophages, especially in the skin and upper respiratory tract, and Schwann cells of the peripheral nervous system. The intricate spectrum of clinical manifestations which exists for the disease is illustrated by two polar responses, tuberculoid or lepromatous leprosy, and various intermediate or borderline forms [1]. The tuberculoid manifestation is typically less severe and is characterized by lower leprosy burden and containment of bacilli by distinct granulomas. This form exhibits few hypopigmented skin lesions and scarce thickening of peripheral nerves, leading to loss of sensation in extremities and the skin. Lepromatous leprosy constitutes the opposite polar reaction to infection where high, diffuse bacterial load can cause extensive skin plaques, nodules and thickening, and numerous anesthetic zones due to pervasive peripheral nerve damage. Surprisingly little genotypic variation exists between strains of M. leprae, a fact inconsistent with the high degree of variability in virulence and disease penetrance between individuals. This suggests that success of infection and leprosy progression rests in large part
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