Immunomodulatory metabolite production by commensal microbiome bacteria

Document Type

Article

Publication Date

Summer 2022

Keywords

JGM

JAX Location

In: Student Reports, Summer 2022, The Jackson Laboratory

Abstract

Immune checkpoint inhibitors (ICIs) are a relatively new method of cancer treatment utilizing natural mechanisms to block T-cell repressive receptors. However, their low efficacy leaves much to be desired and improved upon. It has been shown that the human microbiome has a significant impact on our immune system, and through that, our body’s response to cancer treatments such as ICIs. Through an investigation of the Staphylococcus aureus (S. aureus) genome, we hope to understand the immunomodulatory characteristics of its metabolites and uncover the gene encoding the protein responsible for their production. Through the creation of a fosmid library containing 40 kilobase segments of S. aureus DNA, bacterial metabolites were collected and introduced to human peripheral blood mononuclear cells (PBMCs), where their immunomodulatory capabilities were assessed through quantification of Interferon-g production by an enzyme-linked immune assay (ELISA). After sequencing the clones that showed promotion of IFN-g production, the DNA sequences were traced back to the S. aureus genome via BLAST. The overlap of sequences from various fosmid clones revealed areas of interest which may be responsible for the immunomodulatory potential of the S. aureus bacterium. Targeting these areas of interest with transposon insertions in this study allowed us to determine the genes responsible for these capabilities. In conjunction with this, an investigation into the mechanisms by which the metabolites influence the immune system in future studies will allow for the potential creation of therapeutic agents or adjunctive treatments in combination with ICIs and other cancer treatments.

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