Elucidating novel mechanisms of phosphate liberation in staphylococcus aureus and how phosphate-limitation impacts the host-pathogen interface
Active Project Grant Awarded Last action
- Award ID
- F31AI197476
- Recipient
-
The University Of Iowa UEI Z1H9VJS8NG16
- Awarding agency
-
National Institute of Allergy and Infectious Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $84,358
Award facts
- Assistance listing
- 93.855 Allergy and Infectious Diseases Research
- Completion date 2% complete
- Originally
- Place of performance
- Iowa City, IA 52242, USA
Award details come from USAspending.gov.
Description
- Abstract
- Phosphorous in the form of phosphate, with numerous critical roles, is essential for life. Inorganic phosphate (PI) is the main assimilable form of phosphorus. Despite possessing dedicated PI uptake systems, staphylococcus aureus and other pathogens experience PI starvation. In addition to PI uptake systems based on studies primarily using non-pathogenic model systems, bacteria must possess additional strategies for overcoming PI starvation including metabolic adaptations and scavenging of PI from organophosphates. S. Aureus lacks the established metabolic adaptation, thus, to overcome PI limitation S. Aureus obtains PI from organophosphates. This is accomplished by cleaving the PI moiety from organophosphates and importing IT using the PI-transporters. Alkaline phosphatase (PHOB) can liberate PI from many organophosphates. However, prior work revealed that S. Aureus consumes numerous organophosphates including those that are highly abundant within the host such as nucleotides, in a PHOB-independent and PI-transporter-dependent manner. IT is also clear that S. Aureus must utilize more than PI transporters to overcome PI limitation during infection, as the δphopr mutant has a more severe virulence defect than the PI-transporter double mutant δpstsδnpta. To better understand how S. Aureus overcomes PI limitation during infection, the staphylococcal genes induced by PI limitation and phopr were determined. This analysis identified adsa (adenosine synthase), which catalyzes the conversion of extracellular adenosine mono-, DI- and triphosphates into adenosine and free PI. Adsa can also catalyze a similar reaction with other nucleotides. Further work confirmed that adsa is expressed in a phopr-dependent manner in response to PI limitation and that IT enables S. Aureus to use adenosine mono- and diphosphates as PI sources. PHOB can catalyze the same reaction as adsa and further investigation revealed that the relative contribution of these two enzymes to using nucleotides as a PI source is environment dependent. Extracellular adenosine suppresses the immune response and deoxyadenosine triggers macrophage death, with previous work revealing that loss of adsa reduces S. Aureus virulence and increases the inflammatory response. Combined, these observations lead to the hypothesis that PI limitation increases the expression of adsa and PHOB, which contribute to both suppression of the immune response and acquisition of PI during infection. The aims of this this proposal will test this hypothesis: aim 1: establish if PI limitation enhances immunomodulation by adsa and PHOB. Aim 2: determine if environment modulates the contribution of adsa and PHOB to phosphate uptake. Aim 3: elucidate the in vivo impact of adsa and PHOB on PI uptake and immunomodulation during infection. The support of this fellowship will facilitate my doctoral training in the department of microbiology and immunology at the university of iowa (UI). All my time will be dedicated to research, obtaining an MS in science education, presentation of my work, and professional development.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $42,179 | |
| Amendment | $42,179 | |
| Original award | $0 |
Quick answers
Who received award F31AI197476?
F31AI197476 was awarded to The University Of Iowa by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on October 9, 2026.
How much is award F31AI197476 worth?
$84,358 has been obligated on F31AI197476.
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