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Proteolytic regulation of the Streptococcus pyogenes cell surface

Award Number: R01AI153071
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/15/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Proteolytic regulation of the Streptococcus pyogenes cell surface - PROJECT SUMMARY/ABSTRACT Streptococcus pyogenes (Spy; group A Streptococcus) is the most prolific pathogen in the number of distinct diseases it is responsible for. Most commonly Spy is a cause of childhood acute pharyngitis (strep throat), but it is also a top-10-pathogen in mortality that results in more than half a million deaths annually through invasive infections and immune diseases that include necrotizing fasciitis, toxic shock syndrome, and acute rheumatic fever. Despite their public health importance, the pathogenesis of these severe diseases is poorly understood, and they remain challenging to treat. Our long-term goal seeks to determine how Spy virulence factors contribute to the development of these more severe forms of disease so that effective therapeutic countermeasures can be developed. Our previous studies show that the streptococcal protease SpeB acts directly on the host cytokine pro-IL-1β to induce inflammatory pathology during invasive infection. We hypothesize that additional proteins targeted by SpeB, from both host and microbe, contribute to the proinflammatory responses we see during infection. In our preliminary data, we have characterized the biochemical activity of SpeB and identified two of its substrates that cooperatively lead to fundamental shifts in pathogenesis. In our first aim, we examine how SpeB regulates the activities of M protein, a pleiotropic virulence factor with numerous host targets. By eliminating domains specific for the binding of some host molecules or anchoring of M protein to the Spy surface, SpeB directly contributes to pathological complications of infection like glomerulonephritis and toxic shock syndrome. In our second aim, we define the molecular determinates of how SpeB blocks signaling by the CovR/CovS two-component regulator by targeting its agonist, the host defense peptide LL-37. This mechanism results in a positive-feedback loop for SpeB production and repression of capsule and other cell surface factors that alter antimicrobial resistance, detection by the host, and promotes inflammation and disease complications. Both aims take advantage of new genetic and biochemical tools we developed for targeted control and specific detection of SpeB and its substrates. These innovations allow us for the first time to separate activities for these multifunctional proteins and examine in vivo dramatic switch in the virulence strategy of Spy regulated by SpeB. The expected contribution of the proposed research is an expanded understanding of how Spy pathogenesis is regulated that provides attractive therapeutic targets for the prevention and treatment of severe Spy disease and insights into orthologous systems of other pathogens highly relevant to the NIAID mission.


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: 2025 ( Subtotal = $368,853 )
2025	2025	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	5	12/10/2024	NON-COMPETING CONTINUATION	$368,853
														Subtotal = $368,853

Issue Date FY: 2024 ( Subtotal = $381,260 )
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	4	12/8/2023	NON-COMPETING CONTINUATION	$343,134
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	001	4	5/21/2024	NON-COMPETING CONTINUATION	$38,126
														Subtotal = $381,260

Issue Date FY: 2023 ( Subtotal = $382,168 )
2023	2023	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	3	12/8/2022	NON-COMPETING CONTINUATION	$382,168
														Subtotal = $382,168

Issue Date FY: 2022 ( Subtotal = $382,994 )
2022	2022	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	2	12/21/2021	NON-COMPETING CONTINUATION	$382,994
														Subtotal = $382,994

Issue Date FY: 2021 ( Subtotal = $382,955 )
2021	2021	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	1	1/15/2021	NEW	$382,955
														Subtotal = $382,955

Grand Total All Awards = $1,898,230

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Proteolytic regulation of the Streptococcus pyogenes cell surface

Award Number: R01AI153071

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/15/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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