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Subversion of Keratinocyte Function by a Tick Salivary Protein

Award Number: R21AI178839
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: 02/16/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Subversion of Keratinocyte Function by a Tick Salivary Protein - Summary: Tick feeding affects skin inflammation and allows the transmission of microbes that cause human diseases. Although host immunity functions to impair tick feeding, salivary glands secrete immunosuppressive molecules that compromise skin defenses. Among the characterized tick salivary gland components is sialostatin L2, a multifunctional, versatile, and immunomodulatory molecule involved in cathepsin inhibition and suppression of a non-canonical NLRC4 inflammasome scaffold. In this R21 application, we show a novel function of sialostatin L2 whereby this molecule binds to the mammalian high mobility group 1 (HMGB1) protein, an alarmin highly expressed in keratinocytes. Keratinocytes are the most predominant cells in the skin epidermis and express HMGB1. Notably, HMGB1 serves as a damage-associated molecular pattern (DAMP) triggering inflammation via cell-surface pattern recognition receptors. Thus, we postulate that a tick bite leads to the release of HMGB1 from damaged keratinocytes, and the interaction between HMGB1 and sialostatin L2 blocks downstream immune signaling events, preventing skin inflammation, and enabling tick feeding. Our central hypothesis is that the sialostatin L2-HMGB1 axis in keratinocytes countermeasures skin immunity. Our preliminary data show that sialostatin L2 mitigates the HMGB1-triggered proinflammatory response, suggesting a pivotal role of sialostatin L2 in suppressing mammalian inflammation during ectoparasite feeding. How HMGB1 signal transduction in keratinocytes is affected by sialostatin L2 remains elusive. Accordingly, Aim#1 of this R21 grant proposal will investigate the immunosuppressive function of sialostatin L2 through inhibition of HMGB1 signaling in keratinocytes. Aim#2 of this proposal will examine tick feeding in the context of HMGB1 released by keratinocytes. Collectively, we will: (1) uncover a previously unidentified mechanism of epidermal immunosuppression by a tick salivary molecule; and (2) shed light on the immunological role of alarmins during ectoparasite feeding.


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 = $194,375 )
2025	2025	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	2	12/9/2024	NON-COMPETING CONTINUATION	$194,375
														Subtotal = $194,375

Issue Date FY: 2024 ( Subtotal = $233,250 )
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	1	2/15/2024	NEW	$209,925
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	001	1	6/11/2024	NEW	$23,325
														Subtotal = $233,250

Grand Total All Awards = $427,625

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Subversion of Keratinocyte Function by a Tick Salivary Protein

Award Number: R21AI178839

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: 02/16/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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