Innate immunity against molecular mimicry: Examining galectin-mediated antimicrobial activity

Abstract

Adaptive immunity provides the unique ability to respond to a nearly infinite range of antigenic determinants. Given the inherent plasticity of the adaptive immune system, a series of tolerance mechanisms exist to reduce reactivity toward self. While this reduces the probability of autoimmunity, it also creates an important gap in adaptive immunity: the ability to recognize microbes that look like self. As a variety of microbes decorate themselves in self-like carbohydrate antigens and tolerance reduces the ability of adaptive immunity to react with self-like structures, protection against molecular mimicry likely resides within the innate arm of immunity. In this review, we will explore the potential consequences of microbial molecular mimicry, including factors within innate immunity that appear to specifically target microbes expressing self-like antigens, and therefore provide protection against molecular mimicry.

Keywords: adaptive immunity; carbohydrates; galectins; innate immunity; lectins; microbes.

Figure 1:

Microbial carbohydrate molecular mimicry. While many constituents at or near the membrane are very unique to microbes, outer carbohydrate structures can closely mimic those found on the surface of mammalian cells. As these structures can completely envelope a microbe and host adaptive immunity is tolerized to these structures, microbes that decorate themselves in host-like glycans can become undetectable to most host immune factors (molecular mimicry, on the right). In contrast, many microbes decorate themselves in antigen motifs that are quite distinct from the host (nonself antigens). As a result, these structures can readily become the target of host immunity (left side).

Figure 2:

The galectin family. Human galectins have been classified into three primary classes: prototypical, chimeric, and tandem repeat. Each of these galectins possesses at least one unique carbohydrate recognition domain (CRD) that displays unique and overlapping binding specificity with other family members. Tandem repeat galectins possess two distinct carbohydrate recognition domains, each of which can exhibit very distinct binding preferences.

Figure 3:

Galectins provide innate immunity against blood group molecular mimicry. Blood group expression in blood group positive individuals results in the deletion of potentially blood group reactive B cells. While this reduces the probability of autoimmunity, it also creates an important gap in adaptive immunity against blood group positive microbes. Innate immune galectins secreted by host cells, such as epithelial cells, engage and kill blood group positive microbes. In this way, galectins possess the unique ability to fill an important gap in adaptive immunity by providing innate immunity against blood group molecular mimicry.

Figure 4:

Galectins recognize the same antigenic determinant expressed on host cells and microbes but only kill microbes. The very nature of immunological protection against molecular mimicry requires immune factor recognition of very similar features on host cells and microbes. However, as most immune factors direct their activity specifically toward a microbe through engagement of molecular motifs that are unique to microbes, the ability of galectins to recognize the same antigenic determinant on a microbe and host cell, but only kill the microbe, represents a new paradigm in immunological recognition and killing.

Figure 5:

Galectin family members possess the ability to recognize many microbes with various outcomes. Galectins represent one of the most ancient mammalian lectin families described. As these proteins are present in all metazoans, it is likely that their recognition and response to invading pathogens represents one of their earliest evolutionary functions. However, microbial diversification of carbohydrate cloaks likely outstripped galectin and other innate immune factor recognition, setting the stage for the evolution of adaptive immunity. While adaptive immunity provides the ability to respond to a nearly infinite range of microbial glycans, tolerance reduces reactivity toward self. As a result, it appears that galectins maintained the ability to recognize microbes that utilize molecular mimicry, in addition to other microbes, to fill this gap in adaptive immunity and thereby protect individuals against molecular mimicry. Red arrows indicate an activity that the respective galectin increases, while blue arrows signify galectin-induced decreases in the accompanying activity.