The bacteria that make up the microbiome of the human intestines play many different roles. In healthy individuals we can find commensal and pathobiont strains of bacteria. Commensal bacteria are bacterial strains that help shape immune function, provide scarce nutrients, aid in digestion, and maintain balance (homeostasis) in the gut. Pathobionts are bacterial strains that benefit the host like commensals or have no effect on the host under homeostatic conditions. When the gut microbiome is unbalanced (dysbiosis), these pathobionts can behave like pathogenic bacteria. Dysbiosis occurs when the host becomes immunocompromised, there is a loss of commensal diversity, an overgrowth of pathobionts, or colonization by pathogenic bacteria. Our project aims to better understand how changes in the gut microbiome enable pathogenic bacteria to take over niches previously occupied by commensals or utilize new niches and cause disease. The genetic factors that are required for these bacteria to bind to the host mucosal surface could be used as novel vaccine targets. If we were to identify variants of adherence factors associated with bacteria that can translocate into the bloodstream, we could potentially use that factors to design a vaccine that specifically targets bacteria that cause bacteremia and sepsis.
Enterobacteriaceae and Enterococcaceae are the most prominent bacterial superfamilies that cause bacteremia and sepsis. The Enterobacteriaceae family is made up of Gram-negative bacteria, and the species of most concern are Escherichia coli and Klebsiella pneumoniae. The Enterococcaceae family is made up of Gram-positive bacteria, and the species of most concern are Enterococcus faecalis and Enterococcus faecium. These species are also ESKAPE pathogens. ESKAPE pathogens are a group of bacteria that are multidrug resistant (MDR), responsible for the majority of hospital acquired infections, and are associated with the highest risk of mortality. This makes treating these infections difficult and expensive. These MDR bacteria are called ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species and Escherichia coli) pathogens as they can ‘escape’ the biocidal action of antimicrobial agents. There are no vaccines for any of these species.
The foundation project that our other bacterial GCID projects rely on is the creation of a fully annotated and searchable reference library of pathogenic and drug-resistance pathobionts that colonize the human intestines. This library is continually growing and currently contains clinical strains of Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus. Alongside these clinical libraries we have also curated libraries of publicly available genomes for these species. Additionally, we have curated virulence databases for each of these species that we use to annotate the libraries. So far, these libraries and databases have been used to identify virulence factors that were used to create a vaccine that has been shown to be protective against ExPEC (Extraintestinal Pathogenic E. coli) colonization in a mouse model. It also enabled us to identify a new commensal-like strain that outcompetes ExPEC in mixed infections on colonoids, which we can track in a mixed population without adding barcodes using SUMMIT (Sequence Ushered Microbial Monolayer Infection Tournament), which is a new tool we designed using the reference library. Lastly, we found a potential novel function for an adhesin that pertains to bacterial-bacterial interactions and not adherence to host.
We aim to expand our libraries so that we will have libraries for each the different ESKAPE pathogen. We will also continue to use these libraries and the SUMMIT system to find virulence factors that can be used as novel vaccine targets. At the completion of the project, there will be numerous bacterial, host, and commensal targets for new drug development.
Team Bacteria