Ecology and evolution of a dominant skin commensal and its phage

Abstract

Poor predictability of stable microbial colonization undermines our ability to harness microbes in biotechnological and human health applications. How microbes colonize and evolve within ecosystems to create microbiomes with unique compositions, in which genetic variation occurs both within and across species boundaries is unclear. Bacteriophages are a likely determinant of colonization, as bacteria-phage dynamics are hypothesized to promote intraspecies diversity in microbiomes by generating strain-level population fluctuations. Human sebaceous skin offers a tractable model system to take a reductionist approach that combines metagenomics and culture-based whole genomics to extensively study the role of phage in microbial community colonization and intraspecies diversity in a natural ecosystem. This thesis studies the ecology and evolution of the highly abundant and ubiquitous skin commensal Cutibacterium acnes and its phage. The first chapter examines the role of phage-mediated selection in the assembly and structure of on-person C. acnes populations. We report findings that phage resistance is not a major determinant of C. acnes intraspecies diversity. As evidenced by widespread susceptibility to phage, resulting from weak selective pressure to maintain or diversify the limited pan-immune repertoire of C. acnes. Furthermore, despite the high prevalence of C. acnes phage in global facial skin metagenomes, the virus-to-microbe ratio is low, and phage-sensitive strains are the most prevalent and abundant members of on-person C. acnes populations. We therefore propose that the physiology and spatial structure of human skin buffers against strong phage-mediated selection and thus minimize the ecological relevance of encoding phage resistance. The second chapter examines the population structure and ecoevolutionary dynamics of C. acnes phage on human skin. We find strong evidence of one or more distinct phage lineages coexisting on individuals’ skin with person-specific genetic signatures that likely arose from independent colonization events. Within these lineages, closely related phage sublineages can coexist and diversify within the same individual, indicating stable phage engraftment and subsequent on-person evolution rather than transient colonization. Overall, this work enhances understanding of phage-mediated ecological and phylogenetic determinants of microbial colonization in human ecosystems, highlights the potential of viruses to colonize and adapt in individual microbiomes, and contributes to better design of microbial-based products with higher potential for durable colonization.