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Principal Investigator: Eric P Skaar
Organization: VANDERBILT UNIVERSITY MEDICAL CENTER
Fiscal Year: 2024
Award: $498,638
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <Affect><Anthrax><Anthrax disease><Antimicrobial Resistance><B anthracis><B. anthracis><Bacillus anthracis><Bacteria><Basal Transcription Factor><Basal transcription factor genes><Binding><Biochemical><Biological Terrorism><Bioterror><Bioterrorism><Cardiolipins><Catalogs><Cell Communication and Signaling><Cell Signaling><Data><Detection><Development><Drug Metabolic Detoxication><Drug Metabolic Detoxification><Enabling Factors><Enterococcus><Environment><Enzyme Gene><Enzymes><Event><Family member><Ferroprotoporphyrin><Gene Expression><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Generalized Growth><Genes><Genetic><Genetic Transcription><Gram-Positive Bacteria><Growth><Heme><Host Factor><Host Factor Protein><Infection><Integration Host Factors><Intracellular Communication and Signaling><Kinetics><Life Cycle><Life Cycle Stages><Listeria Infections><Listeriosis><Location><Macrophage><Mediating><Membrane><Metabolic Drug Detoxications><Metabolism of Toxic Agents><Microbiology><Modeling><Molecular Interaction><Mφ><Names><National Security><Non-Polyadenylated RNA><Organism><Pathogenesis><Pathogenicity><Phagocytes><Phagocytic Cell><Phagocytosis><Process><Production><Proteins><Protoheme><Public Health><RNA><RNA Expression><RNA Gene Products><RNA Stability><RNA-Binding Proteins><Regulation><Regulatory Protein><Regulon><Resistance><Ribonucleic Acid><Role><S aureus><S. aureus><Series><Signal Transduction><Signal Transduction Systems><Signaling><Staph aureus><Staphylococcal Infections><Staphylococcus aureus><Staphylococcus infection><Stimulus><Streptococcus enterococcus group><Stress><System><Systemic infection><Testing><Tissue Growth><Toxic effect><Toxicities><Transcript><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Translating><Vertebrate Animals><Vertebrates><amebocyte><anthracis><anti-microbial><anti-microbial resistant><antimicrobial><bacteria pathogen><bacterial pathogen><biological adaptation to stress><biological signal transduction><catalog><cell envelope><coping><detoxification><developmental><experiment><experimental research><experimental study><experiments><ferroheme><genetic regulatory protein><genetic selection><human pathogen><infectious disease treatment><innovate><innovation><innovative><insight><life course><living system><mRNA Degradation><mRNA Stability><mRNA Transcript Degradation><member><membrane structure><microbe pathogen><microbial><microbial pathogen><name><named><naming><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><ontogeny><pathogen><pathogenic bacteria><pathogenic microbe><posttranscriptional><reaction; crisis><regulatory gene product><resistance strain><resistance to anti-microbial><resistant><resistant strain><resistant to antimicrobial><response><social role><staph infections><stress response><stress; reaction><stressor><transcription factor><vertebrata>