Sunday, November 24, 2024
11/24/2024
Abstract Saccharibacteria (also known as TM7) are ubiquitous members of the human oral microbiome whose relative abundance increases dramatically during mucosal inflammation (gingivitis and periodontitis), yet their biology and role in microbial ecology and pathogenesis have remained largely elusive. During the previous funding cycles, we successfully isolated TM7x, the first member of the uncultivated TM7 phylum from humans. we demonstrated that TM7x has ultrasmall cell size with a highly reduced genome, and it displays an obligate episymbiotic lifestyle where TM7x lives on the surface of its bacterial host Schaalia odontolytica XH001. Our studies have provided critical insights into the unique biology of these ultrasmall bacteria and their impact on the physiology and pathogenesis of host bacteria. The knowledge gained in our prior work not only allows a better understanding of the TM7 phylum, but also sheds light on the general biology of Candidate Phyla Radiation (CPR) organisms among which episymbiosis is predicted to be a preferred lifestyle. Nevertheless, due to the lack of effective genetic tools, the genetic determinants that govern TM7x and XH001 interaction and the molecular underpinnings of episymbiosis remain largely unexplored. In this ongoing project, we have found that TM7x/XH001 episymbiosis is a dynamic, reciprocal, multi-stage process that spans four main phases: initial binding, host killing, recovery and stable symbiosis. These biological processes are highly relevant to their prevalence and persistence in the human oral cavity. Our analyses suggest the presence of two forms of type IV pili (T4P) in TM7x which may carry out diverse functions. Specifically, in the initial binding phase, the recognition and binding, a critical step in establishing episymbiosis, is mediated through TM7x-encoded T4P and can be inhibited by exogenously added sugars, similar to a key cell surface carbohydrate component in the host bacterium XH001. Importantly, a recent significant breakthrough in TM7x genetics now enables significant advancements. Thus , the overall goal of the proposed study is to build upon intriguing new findings within the distinct phases during episymbiosis and leverage newly developed molecular tools to achieve a mechanistic level understanding of the detailed molecular processes required for bacterial episymbiosis in the human microbiome. The proposal comprises two parts. Part I is designed for focused investigation on the critical roles of multiple TM7x-encoded T4P in its symbiotic lifestyle; while Part II seeks to identify and validate the key molecular components in TM7x and its host governing the dynamic symbiotic process. The successful completion of these aims will provide a fundamental mechanistic understanding of the episymbiotic interaction between TM7 and their hosts, setting a solid foundation with key enabling toolsets and molecular level information to ultimately understand their observed in vivo persistence in disease, impact on the pathogenesis of oral bacteria and potential to modulate the microbial ecology within the human microbiome.
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