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Post-translational regulation of alpha PSM production in Staphylococcus aureus by the small RNA Teg41

Award Number: R01AI143743
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY/ABSTRACT Staphylococcus aureus is both a commensal of humans and a highly dangerous bacterial pathogen. S. aureus pathogenesis is mediated by a large repertoire of secreted and cell wall-associated virulence factors, including a number of potent cytolytic peptides called phenol soluble modulins (PSMs). PSMs are amphipathic, alpha helical peptides that vary in size depending on their classification. The a type PSMs are ~22 amino acids in size and have been the focus of intense study in recent years. They have been implicated in contributing to the high virulence potential of community-acquired methicillin resistant S. aureus (CA-MRSA) strains, in particular those of the USA300 lineage. While the role of aPSMs in S. aureus infection has been extensively investigated, significant gaps still exist in our understanding of how they are produced in the bacterial cell. There are five aPSM peptides produced by most S. aureus strains (PSMa1-4 and the d-toxin). PSMa1-4 are encoded within the same polycistronic transcript (the aPSM transcript), yet studies have shown that the relative levels of the four peptides vary considerably. PSMa4 (located at the 3' end of the transcript) is commonly the most abundant, while PSMa3 (the most potent of the four peptides) is typically the least abundant. This variation in aPSM abundance is suggestive of post-transcriptional regulation. The long-term objective of this project is to understand the molecular mechanism(s) that contribute to aPSM production in S. aureus. In this proposal, we will specifically investigate the contribution of the small RNA Teg41 to aPSM production and virulence. Preliminary studies show that Teg41 positively influences aPSM production at the post-transcription level. We will investigate (i) which of the PSMa1-4 peptides is/are regulated by Teg41, (ii) if Teg41-mediated regulation is facilitated by direct base pairing with the aPSM transcript, and (iii) at what stage in aPSM production, and how, Teg41 exerts its influence. To investigate these three aims, we will use a combination of in vitro, in vivo, genetic, biochemical, and molecular biology approaches. We will also utilize a number of cutting edge techniques based on high throughput DNA sequencing (SHAPE-seq, miR-CATCH, and Ribo-seq). The results from this study could have direct implications for human health. Disrupting Teg41-mediated aPSM-production could dramatically lower the virulence potential of S. aureus and therefore may represent a novel target for therapeutic intervention.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $410,424 )
2023	2023	OHIO UNIVERSITY	1 OHIO UNIVERSITY	ATHENS	OH	45701	ATHENS	USA	Allergy and Infectious Diseases Research	000	5	7/14/2023	NON-COMPETING CONTINUATION	$410,424
														Subtotal = $410,424

Issue Date FY: 2022 ( Subtotal = $410,424 )
2022	2022	OHIO UNIVERSITY	1 OHIO UNIVERSITY	ATHENS	OH	45701	ATHENS	USA	Allergy and Infectious Diseases Research	000	4	8/15/2022	NON-COMPETING CONTINUATION	$410,424
														Subtotal = $410,424

Issue Date FY: 2021 ( Subtotal = $410,424 )
2021	2021	OHIO UNIVERSITY	1 OHIO UNIVERSITY	ATHENS	OH	45701	ATHENS	USA	Allergy and Infectious Diseases Research	000	3	8/4/2021	NON-COMPETING CONTINUATION	$410,424
														Subtotal = $410,424

Issue Date FY: 2020 ( Subtotal = $428,661 )
2020	2020	OHIO UNIVERSITY	1 OHIO UNIVERSITY	ATHENS	OH	45701	ATHENS	USA	Allergy and Infectious Diseases Research	001	2	8/17/2020	NON-COMPETING CONTINUATION	$428,661
2020	2019	OHIO UNIVERSITY	1 OHIO UNIVERSITY	ATHENS	OH	45701	ATHENS	USA	Allergy and Infectious Diseases Research	000	1	8/14/2020	NEW	$0
														Subtotal = $428,661

Issue Date FY: 2019 ( Subtotal = $453,011 )
2019	2019	OHIO UNIVERSITY	1 OHIO UNIVERSITY	ATHENS	OH	45701	ATHENS	USA	Allergy and Infectious Diseases Research	000	1	8/27/2019	NEW	$453,011
														Subtotal = $453,011

Grand Total All Awards = $2,112,944

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Post-translational regulation of alpha PSM production in Staphylococcus aureus by the small RNA Teg41

Award Number: R01AI143743

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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