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Mechanisms of Resilience to Cytokinopathy Flares

Award Number: F30AI197670
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 05/01/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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Mechanisms of Resilience to Cytokinopathy Flares - PROJECT SUMMARY/ABSTRACT Intricate cytokine networks mediate effective immune responses and their subsequent return to homeostasis. Inflammatory stimuli trigger orchestrated responses to potential threats, and failure to return to homeostasis results in a pathogenic cytokine environment that can manifest as an inflammatory flare. Recurrent flares impart significant physical and psychological burden in patients of lifelong autoimmune and autoinflammatory diseases. Previously, we discovered mutation in the X-linked ETS transcription factor E74-like factor-4 (ELF4) to be causal of a cytokinopathy with a Behçet’s- and inflammatory bowel disease-like autoinflammatory syndrome in males, termed ‘Deficiency in ELF4, X-linked’ (DEX). We have previously established that ELF4 restrains hyper-cytokine secretion of IL-17, IFNγ and IL-1β upon activation in vitro and restrains systemic hypercytokinemia upon lipopolysaccharide (LPS) challenge in vivo. Through a bone marrow chimera system, I have demonstrated that ELF4 is not necessary for the development, or suppressive capacity of regulatory T cells at homeostasis, implicating alternative control mechanisms. ELF4 heterozygotes are somatic mosaics of ELF4-expressing and ELF4-deficient cells, that, interestingly are predominantly asymptomatic. Yet, recent evidence highlights that skewed X-inactivation may be responsible for newly discovered symptomatic ELF4 heterozygous variants, suggesting a critical threshold of wild-type cells may be necessary to restrain hypercytokinemia in the setting of DEX. Leveraging these insights and generating experimental cytokine flares in vivo, this proposal seeks to decode the cytokine machinery necessary to restore homeostasis after flares. We hypothesize that ELF4 functions as a key mediator of negative regulatory circuits supporting recovery after inflammatory insults, thereby resolving hypercytokinemia and preserving homeostasis. In Aim 1, I seek to determine the cell-intrinsic roles of ELF4 in tuning responses to anti-CD3/LPS induced cytokine flares, delineating the magnitude and dynamics of the cytokine codes during the perturbation and restoration of cytokine homeostasis. In Aim 2, I aim to examine the contribution of STAT1- and STAT3- inducing cytokines to feedback circuits during experimental cytokinopathy flares, to unravel the mechanisms by which ELF4-expressing cells functionally mitigate cytokinopathy resilience in the setting of ELF4- heterozygosity. The results of these investigations will not only guide our clinical approach to DEX patients but also broaden our fundamental understanding of the mechanisms of resilience to cytokinopathy.


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 = $35,134 )
2026	2026	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Allergy and Infectious Diseases Research	002	1	4/2/2026	NEW	$0
2026	2026	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Allergy and Infectious Diseases Research	001	1	4/2/2026	NEW	$576
2026	2026	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Allergy and Infectious Diseases Research	000	1	3/27/2026	NEW	$34,558
														Subtotal = $35,134

Grand Total All Awards = $35,134

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Mechanisms of Resilience to Cytokinopathy Flares

Award Number: F30AI197670

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 05/01/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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