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Myeloid-derived suppressor cells modulate disease severity in children with viral lower respiratory tract infections

Award Number: K23HL171862
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/01/2024
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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Myeloid-derived suppressor cells modulate disease severity in children with viral lower respiratory tract infections - Project Summary Severe lower respiratory tract infection (LRTI) due to viral pathogens remains one of the most common causes of death for young children worldwide. Current management of patients with viral-induced LRTI focuses on supportive care, but outcomes may be improved by augmenting the host immune response to fight the virus and regain immune homeostasis. A growing body of literature suggests that children with severe viral LRTI have an impaired adaptive immune response, specifically decreased T cell proliferation and cytokine production. Myeloid- derived suppressor cells (MDSC) are a heterogeneous cell population that expand during inflammatory conditions and potently inhibit T cell proliferation and function. MDSC have been extensively studied in adult oncologic populations where clinical trials show promising results of improved outcomes by inhibiting MDSC as part of chemotherapy and anti-tumor vaccine treatment regimens. Our group has identified significant increases in the frequency of MDSC populations in children with septic shock and COVID-19 and demonstrated associations between increased percentages of MDSC and worse clinical outcomes. However, it is unknown what role MDSC play in children with viral-induced severe LRTI. The overall goal of this proposal is to identify MDSC as contributors to the immune response in children with viral LRTI and identify mechanistic pathways as potential therapeutic targets for future investigations. Our central hypothesis is that increased frequency of MDSC will be associated with worse clinical outcomes and decreased numbers of CD4+ and CD8+ T cells in children with viral LRTI, and that pediatric MDSC-induced T cell suppression is reversible through inhibition of the PD-1 pathway. The proposed experiments will involve blood sampling of children with PCR-confirmed viral LRTI to characterize the dynamics of MDSC and lymphocyte populations during hospitalization. We will also use our in vitro model of MDSC induced from pediatric peripheral blood mononuclear cells and select patient samples to establish the PD-1 pathway as an important mechanism of MDSC-mediated inhibition of T cell proliferation and cytokine production in children. This career development award will generate the necessary data to inform the design of future studies of the pediatric immune response in severe lower respiratory tract infections and will equip me with the necessary tools to achieve independence as a patient- oriented clinician-scientist.


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 = $180,199 )
2026	2026	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Lung Diseases Research	000	3	8/25/2026	NON-COMPETING CONTINUATION	$180,199
														Subtotal = $180,199

Issue Date FY: 2025 ( Subtotal = $180,199 )
2025	2025	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Lung Diseases Research	000	2	8/27/2025	NON-COMPETING CONTINUATION	$180,199
														Subtotal = $180,199

Issue Date FY: 2024 ( Subtotal = $180,199 )
2024	2024	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Lung Diseases Research	000	1	8/6/2024	NEW	$180,199
														Subtotal = $180,199

Grand Total All Awards = $540,597

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Myeloid-derived suppressor cells modulate disease severity in children with viral lower respiratory tract infections

Award Number: K23HL171862

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/01/2024

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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