Host-bacterial coevolution and the search for new drug targets

Abstract

Understanding the coevolution between humans and our microbial symbionts and pathogens requires complementary approaches, ranging from community analysis to in-depth analysis of individual genomes. Here we review the evidence for coevolution between symbionts and their hosts, the role of horizontal gene transfer in coevolution, and genomic and metagenomic approaches to identify drug targets. Recent studies have shown that our symbiotic microbes confer many metabolic capabilities that our mammalian genomes lack, and that targeting mechanisms of horizontal gene transfer is a promising new direction for drug discovery. Gnotobiotic ('germ-free') mice are an especially exciting new tool for unraveling the function of microbes, whether individually or in the context of complex communities.

Fig. 1. Understanding the microbial part of ourselves

A key part of understanding human metabolic capabilities is to understand our microbial symbionts, and the genomes of those symbionts.

Fig 2. Processes affecting host-microbe coevolution

Large gray tubes indicate relationships between host lineages, while thin colored lines indicate relationships between microbial lineages (top tree). Importantly, divergence between bacterial divisions (black lines) occurred over a much longer time-scale than divergence between metazoan host lineages such as, for example, humans, chimpanzees and bonobos (see scale). Processes depicted include co-divergence of host and microbial lineages (A), diversification of a microbial lineage while associated with a host (B), extinction (C), host-swapping (D) and association of a free-living microbial lineage with a host (E). Co-divergence, adaptation to a novel host, host-swapping or diversification within a lineage all produce splits on the microbial phylogenetic tree (bottom tree). Although great caution and deep sampling are required, studies of the distribution of microbial lineages among hosts (numbers at tips of bottom tree), and comparison of the microbial phylogeny to the host phylogeny, may help to resolve which evolutionary processes are responsible for observed divergence between host-associated microbial lineages.

Fig. 3. A comprehensive understanding of our microbial ecology requires integration of many data sources

Community profiles with 16S rRNA indicate which types of organisms are present, metagenomic profiling allows us to identify specific functional categories of genes that are critical for differences in function, and complete genomes act as scaffolds for understanding changes in gene content through loss, amplification, and HGT that allow microbes to adapt to functional roles in different environments.