Thursday, April 25, 2024
4/25/2024
SUMMARY Staphylococcus aureus and Bacillus anthracis are pathogenic members of the order Bacillales that each represent a considerable threat to global public health. The rise of S. aureus strains resistant to all known antimicrobials has the potential to eliminate available treatment options whereas the successful use of B. anthracis as an agent of bioterror threatens national security. Identifying novel therapeutic targets against these organisms is critical to our continued ability to protect against these infections. Promising antimicrobial targets include bacterial stress sensing and detoxification systems as both processes are required for infection. Alterations in gene expression in response to stress can be orchestrated by signal transduction proteins known as two-component regulatory systems (TCSs). Bacteria typically encode many TCSs that are responsible for recognizing and responding to distinct signals, enabling adaptation to diverse environments. We have identified and functionally characterized two TCSs named EdsRS and HitRS that trigger the response to cell envelope damage as a strategy to defend against phagocyte-dependent killing. EdsRS is conserved in both S. aureus and B. anthracis whereas HitRS is only present in B. anthracis, suggesting that HitRS may have evolved to enable the intracellular lifecycle of this organism. In this proposal, we describe the discovery of additional regulatory factors that govern signal transduction through EdsRS and HitRS, including known enzymes as well as previously unstudied factors involved in RNA expression and stability. The combined activities of these regulatory factors enable transcriptional, post-transcriptional, and post-translational control of TCS signaling. Based on these discoveries, we propose a model whereby HitRS and EdsRS signal transduction is controlled by accessory proteins that enable a coordinated and tightly controlled response to host-mediated barrier damage. We propose that tight regulation of EdsRS and HitRS is required for survival within macrophages and subsequent pathogenesis. This model uncovers new regulatory proteins that control TCS signal transduction, expanding the small but rapidly growing catalogue of known TCS accessory proteins. We will test this model through a series of interconnected specific aims that define the mechanism of control of HitRS and EdsRS signal transduction, elucidate the cascade of events leading to HitRS and EdsRS activation during infection, and uncover host factors that target the cell envelope of Gram positive bacteria and trigger HitRS and EdsRS signaling. Due to the fundamental requirement for TCS in bacterial stress sensing, these studies will be universally relevant to the field of microbial signal transduction.
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