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Characterization of a Type VII Secretion System in Group B Streptococcus and its Role in Virulence and Immune Response

Award Number: K22AI170795
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/01/2024
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Characterization of a Type VII Secretion System in Group B Streptococcus and its Role in Virulence and Immune Response - PROJECT SUMMARY Group B Streptococcus (GBS) remains the leading etiologic agent of neonatal bacterial meningitis and a major opportunistic pathogen in certain adult populations, including pregnant women. During pregnancy, GBS asymptomatically colonizes the vaginal tract of 20-30% of healthy women but can be transmitted to the neonate in utero or during birth resulting in neonatal meningitis upon GBS disruption of the blood-brain barrier (BBB) and 10-15% mortality, regardless of antibiotic treatment. Despite this major public health concern, the mechanisms specific by which Group B streptococcal effectors mediate toxicity and drive inflammatory responses during colonization and development of meningitis are still being elucidated. Type VII secretion systems (T7SS) have been identified in Actinobacteria and Firmicutes and shown to secrete functions GBS lacking highly immunogenic effector proteins with in virulence, host toxicity, or interbacterial killing; however, a T7SS had never been characterized in and our analysis suggests that GBS encodes unique T7SS effectors. My recent work shows that GBS the ATPase EssC (which drives T7SS) or the secreted T7 effector EsxA areattenuated in murine models of meningitis and reproductive tract ascending infection and exhibit decreased cytotoxicity in brain endothelium. We have further shown that EsxA is a pore-forming protein, possibly mediating T7SS-dependent cytotoxicity. Finally, my recent work suggests that IL-17 is important for clearance of GBS during vaginal colonization and may be dampened by the T7SS resulting in GBS immune evasion. Based on these data, this K22 proposal seeks to identify GBS T7-secreted effectors and elucidate the mechanism by which they mediate promote host toxicity and elicit immune responses during GBS disease progression and colonization. These questions will be addressed with both in vitro and in vivo models of GBS vaginal colonization and BBB penetration in the following specific aims: AIM 1: Elucidate the mechanism of GBS EsxA pore-formation and host cytotoxicity. AIM 2: Identify and characterize the GBS T7SS secretome. AIM 3: Evaluate the T7SS-dependent IL-17 responses to GBS in the female reproductive tract This proposal is the first to characterize GBS T7SS effectors and their role in both GBS colonization and pathogenesis and may afford novel targets and alternative therapeutic strategies to treat and prevent GBS disease.


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 = $105,840 )
2025	2025	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	000	2	9/4/2025	NON-COMPETING CONTINUATION	$105,840
														Subtotal = $105,840

Issue Date FY: 2024 ( Subtotal = $162,000 )
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	000	1	8/29/2024	NEW	$162,000
														Subtotal = $162,000

Grand Total All Awards = $267,840

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Characterization of a Type VII Secretion System in Group B Streptococcus and its Role in Virulence and Immune Response

Award Number: K22AI170795

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/01/2024

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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