Molecular Mimicry: a Paradigm of Host-Microbe Coevolution Illustrated by Legionella

Abstract

Through coevolution with host cells, microorganisms have acquired mechanisms to avoid the detection by the host surveillance system and to use the cell's supplies to establish themselves. Indeed, certain pathogens have evolved proteins that imitate specific eukaryotic cell proteins, allowing them to manipulate host pathways, a phenomenon termed molecular mimicry. Bacterial "eukaryotic-like proteins" are a remarkable example of molecular mimicry. They are defined as proteins that strongly resemble eukaryotic proteins or that carry domains that are predominantly present in eukaryotes and that are generally absent from prokaryotes. The widest diversity of eukaryotic-like proteins known to date can be found in members of the bacterial genus Legionella, some of which cause a severe pneumonia in humans. The characterization of a number of these proteins shed light on their importance during infection. The subsequent identification of eukaryotic-like genes in the genomes of other amoeba-associated bacteria and bacterial symbionts suggested that eukaryotic-like proteins are a common means of bacterial evasion and communication, shaped by the continuous interactions between bacteria and their protozoan hosts. In this review, we discuss the concept of molecular mimicry using Legionella as an example and show that eukaryotic-like proteins effectively manipulate host cell pathways. The study of the function and evolution of such proteins is an exciting field of research that is leading us toward a better understanding of the complex world of bacterium-host interactions. Ultimately, this knowledge will teach us how host pathways are manipulated and how infections may possibly be tackled.

Keywords: Legionella; Legionella pneumophila; amoeba-resistant bacteria; eukaryotic-like proteins; host-pathogen interactions; molecular mimicry.

FIG 1

Selected Legionella eukaryotic-like T4SS-dependent effectors as discussed herein. Legionella spp. translocate eukaryotic-like proteins to manipulate specific host cell processes, like membrane trafficking (A), gene expression (B), signaling pathways (C), and host metabolism (D). While many of these translocated effectors harbor eukaryotic-like domains, others resemble eukaryotic proteins themselves. The functions of the different Legionella effectors implicated in the depicted processes are further discussed in the text. Orange box, Legionella effector; pink oval, host target protein/molecule; orange oval, Legionella target protein; Me, methylation; U, ubiquitination; P, phosphorylation; G, glutamylation, CaM, calmodulin; IP6, inositol hexakisphosphate; ER, endoplasmic reticulum.

FIG 2

Eukaryotic-like proteins as mediators of pathogenesis and symbiosis. Microorganisms use eukaryotic-like proteins (ELPs) to communicate with their hosts. (A) Legionella spp. translocate eukaryotic-like proteins to multiply within protozoa, and this capacity enabled the bacterial transition to humans (arrow 1). The simultaneous occurrence of Legionella with other bacteria and giant viruses inside amoebae allows for the genetic interchange between these microorganisms and the host (arrow 2) and the acquisition of diverse functions which might confer an advantage during human infection (arrow 3). (B, C) Despite their role in pathogenicity, eukaryotic-like proteins are also used by cooperative bacterial communities to interact with their hosts. Eukaryotic-like proteins are used by prokaryotes to establish a symbiosis with marine sponges (B) and by rhizobia to form nitrogen-fixing symbioses with legumes (C). N, nucleus; ER, endoplasmic reticulum.