Friday, October 31, 2025 10/31/2025

Ehrlichia Notch SLiM-activated oncoprotein inhibition of apoptosis

Award Number: R01AI158422
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: 11/01/2021
PERIOD OF PERFORMANCE END DATE: 10/31/2026

Group Awards By:

View Award Description

Ehrlichia Notch SLiM-activated oncoprotein inhibition of apoptosis - ABSTRACT Ehrlichia chaffeensis (E. ch.) is a gram-negative, obligately intracellular bacterium and the etiologic agent of human monocytotropic ehrlichiosis (HME), an emerging, life-threatening, tick-borne zoonosis. E. ch. preferentially infects mononuclear phagocytes and survives intracellularly by subverting innate immune defenses mediated in part by tandem repeat protein (TRP) effectors. Within the last decade, our laboratory has identified a multitude of molecular ehrlichial TRP-host interactions, many that are new to science, illuminating the breath and complexity of pathogen-host interaction dynamics that occur during infection. We have shown that E. ch. is dependent on activation of conserved eukaryotic signaling pathways including Notch and Wnt for infection. However, understanding the molecular basis of Notch activation events, whereby E. ch. repurposes Notch signaling for infection remains a major gap in our knowledge. Thus, the purpose of this investigation is to define the molecular and cellular mechanisms E. ch. has evolved to repurpose Notch signaling for infection. We propose that E. ch. TRP120 has distinct eukaryotic protein interaction modules known as short linear motifs (SLiMs) that mimic Notch ligand function and directly engage cognate receptors to exploit Notch signaling for infection. This investigation will address our limited understanding of the functionally diverse roles of protein interaction modules in the continuum of host-pathogen interactions and cellular reprogramming. The long-term goal of this research is to define the molecular basis of Ehrlichia host cell mimicry, and the mechanisms involved in infection and immune evasion. The objective of this proposal is to determine the molecular interactions involved and functional mechanisms whereby E. ch. TRP120 Notch ligand mimicry establishes and promotes infection by inhibiting host cell apoptosis. We hypothesize that E. ch. TRP120 has a Notch SLiM mimetic that activates Notch signaling to upregulate anti-apoptotic regulators (MCL1 and NICD), thereby inhibiting mitochondrial apoptotic signaling and caspase activation. Aim 1 will define the E. ch. TRP120 Notch SLiM mimetic and investigate receptor binding and signaling; Aim 2 will examine E. ch. TRP120 Notch-upregulated MCL1 inhibition of mitochondrial apoptosis; and Aim 3 will investigate the role of E. ch. Notch stabilization of XIAP and inhibition of caspase activation. This investigation will extend our knowledge of the molecular interactions by which E. ch. TRP120 surface protein exploits Notch signaling to inhibit apoptosis and promote host cell survival and infection. The significance of this research is defining the mechanistic strategies whereby intracellular pathogens with small genomes and a limited number of effector proteins, have evolved host mimicry modules to repurpose host cell signaling to manipulate downstream host defense mechanisms for infection. A molecular understanding of E. ch. pathobiology will also facilitate development of novel therapeutic approaches for Ehrlichia spp. and intracellular pathogens that utilize SLiM mimicry or exploit conserved cellular pathways for infection and immune evasion.


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 = $400,000 )
2025	2025	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	000	4	11/7/2024	NON-COMPETING CONTINUATION	$400,000
														Subtotal = $400,000

Issue Date FY: 2024 ( Subtotal = $400,000 )
2024	2024	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	001	3	5/15/2024	NON-COMPETING CONTINUATION	$40,000
2024	2024	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	000	3	11/3/2023	NON-COMPETING CONTINUATION	$360,000
														Subtotal = $400,000

Issue Date FY: 2023 ( Subtotal = $400,000 )
2023	2023	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	000	2	10/25/2022	NON-COMPETING CONTINUATION	$400,000
														Subtotal = $400,000

Issue Date FY: 2022 ( Subtotal = $400,000 )
2022	2022	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	000	1	10/22/2021	NEW	$400,000
														Subtotal = $400,000

Grand Total All Awards = $1,600,000

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Ehrlichia Notch SLiM-activated oncoprotein inhibition of apoptosis

Award Number: R01AI158422

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: 11/01/2021

PERIOD OF PERFORMANCE END DATE: 10/31/2026

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer