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Modulation of Herpes Simplex Virus Pathogenesis by Leucine Rich Repeat Kinase 2

Award Number: K08AI156021
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 06/11/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Modulation of Herpes Simplex Virus Pathogenesis by Leucine Rich Repeat Kinase 2 - PROJECT SUMMARY In the United States, herpes simplex virus type 1 (HSV-1) infects more than half the adult population and is the leading cause of viral encephalitis and infectious blindness. Yet, the host factors contributing to the most severe manifestations of HSV-1 remain unclear. Inflammasomes, a recently discovered antiviral innate immune defense, and the production of two inflammasome cytokines (interleukin (IL)-1β and IL-18) are critical in HSV-1 control and pathogenesis. However, how inflammasomes are regulated during HSV-1 infection is poorly understood. Recently, leucine-rich repeat kinase 2 (LRRK2) has emerged as a possible regulator of inflammasome signaling. LRRK2 has been studied extensively because specific alleles are associated with Parkinson’s disease, Crohn’s disease, cancer, and leprosy. Despite the disease associations, the precise function of LRRK2 and how it mediates disease are unknown. Evidence for a role in the immune response include that LRRK2 is highly expressed on immune cells, is upregulated in response to infection, and was recently shown to modulate the NLRC4 inflammasome in response to bacterial infection. We recently demonstrated that NLRP3 is critical in inflammasome activation by HSV-1, and our preliminary data indicate that LRRK2 enhances NLRP3 signaling. We found that the common LRRK2 mutation G2019S enhances HSV- 1 pathology in mice without altering viral replication. These results point to a novel role for LRRK2 in inflammasome signaling and HSV-1 pathogenesis. We hypothesize that LRRK2 modulates inflammasome signaling in response to HSV-1 infection and that the G2019S mutation further enhances inflammasome activation in vivo, leading to more severe eye, skin, and central nervous system (CNS) pathology after HSV-1 infection. LRRK2 has not been studied in human viral infection, and these represent the first studies to define its role in the pathogenesis of a common neurotropic human viral infection. In Aim 1, we will identify how LRRK2 associates with NLRP3, the critical inflammasome adapter in HSV-1 infection, and how mutations in LRRK2 alter inflammasome signaling in the context of HSV-1 infection. We will accomplish this by using targeted mutagenesis in a transfection model of inflammasome signaling and by studying inflammasome activation after HSV-1 infection of cell lines stably expressing LRRK2 mutants. For Aim 2, we will determine how LRRK2 alters the inflammasome response to HSV-1 using LRRK2 transgenic mice and mice with inflammasome gene disruptions. Additionally, the PI will gain critical skills and expertise necessary to study the innate immune response to HSV-1 and other herpesviruses. These learning objectives will be accomplished through formal coursework, scientific programing, and direct mentorship by experts in viral and murine immunology, herpesvirology, and biostatistics. The proposed career development plan and research aims will provide a pathway to a career as an independent investigator studying the interactions between herpesviruses and the innate immune system.


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: 2026 ( Subtotal = $0 )
2026	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	5	3/12/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $198,720 )
2025	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	001	5	8/5/2025	NON-COMPETING CONTINUATION	$0
2025	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	5	4/4/2025	NON-COMPETING CONTINUATION	$198,720
														Subtotal = $198,720

Issue Date FY: 2024 ( Subtotal = $198,720 )
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	4	3/29/2024	NON-COMPETING CONTINUATION	$198,720
														Subtotal = $198,720

Issue Date FY: 2023 ( Subtotal = $198,720 )
2023	2023	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	3	3/29/2023	NON-COMPETING CONTINUATION	$198,720
														Subtotal = $198,720

Issue Date FY: 2022 ( Subtotal = $198,720 )
2022	2022	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	2	4/11/2022	NON-COMPETING CONTINUATION	$198,720
														Subtotal = $198,720

Issue Date FY: 2021 ( Subtotal = $198,720 )
2021	2021	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	1	6/11/2021	NEW	$198,720
														Subtotal = $198,720

Grand Total All Awards = $993,600

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Modulation of Herpes Simplex Virus Pathogenesis by Leucine Rich Repeat Kinase 2

Award Number: K08AI156021

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 06/11/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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