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Understanding IL-27 as a negative regulator of protective immunity during neonatal sepsis

Award Number: R01AI163333
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: 06/01/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Understanding IL-27 as a negative regulator of protective immunity during neonatal sepsis - PROJECT SUMMARY Microbial infections are a major cause of infant mortality worldwide. For particularly vulnerable populations such as pre-term and low birthweight babies, the risk of invasive infections further escalates. The neonatal period is defined by a distinct, often described as immature, immune system. Many features of a protective host response to infection are deficient as compared with older children and adults. Our laboratory has identified that expression of the immune suppressive cytokine interleukin (IL)-27 is elevated in human and murine neonates. Other recent studies have shown IL-27 to be a biomarker for early onset neonatal sepsis. This suggests that elevated IL-27 may represent a risk factor and when further increased during bacterial challenge, compromise the host immune response. The overall premise of the current proposal is that IL-27 is a host molecule that represents a target for immune intervention to improve the host response and reduce susceptibility to bacterial infection early in life. We present strong evidence in a mouse model that the absence of IL-27 signaling translates to increased survival, improved weight gain, and enhanced clearance of bacteria during neonatal sepsis. To advance our knowledge of how IL-27 regulates the immune response during neonatal sepsis, we need to identify the complete repertoire of cell types responsible for IL-27 production, understand how these population may change over the course of infection, and further define their functionality. We will address this gap in understanding using an IL-27 reporter mouse that expresses a fluorescent protein under control of the IL-27p28 promoter. Using whole-animal imaging of the reporter mouse coupled with luminescent bacteria, this will allow us to identify IL-27 producers, sort them for further functional analysis, and correlate their presence in infected tissues with the bacterial burden. We also seek to understand cellular signaling pathways required for IL-27-mediated suppressive activity and compromised control of the bacterial burden. We hypothesize that signal transducer and activator of transcription (Stat)-3 signals downstream of IL-27 receptor binding to interfere with lysosomal trafficking and acidification. The net result is compromised bacterial clearance. Lastly, a primary objective is to investigate the outcomes of antagonizing IL- 27 during neonatal sepsis with the aim of establishing an immunotherapeutic approach for an infectious disease for which we can currently only offer antibiotics and supportive care. Antibiotic resistance confounds our reliance on this approach. Administration of a neutralizing antibody conjugated to a fluorescent tag will allow for visualization of tissue penetration in real time and directly correlate the presence of the antagonist with control of bacterial growth. At the completion of this project, we expect to have performed preclinical validation of a promising immunotherapeutic approach to improve immunological responses and susceptibility to infection disease in newborns, as well as provided an enhanced understanding of how IL-27 regulates host immunity and interactions with bacterial pathogens during neonatal sepsis.


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	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	886 CHESTNUT RIDGE ROAD	MORGANTOWN	WV	26505	MONONGALIA	USA	Allergy and Infectious Diseases Research	000	5	3/30/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $456,427 )
2025	2025	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	886 CHESTNUT RIDGE ROAD	MORGANTOWN	WV	26505	MONONGALIA	USA	Allergy and Infectious Diseases Research	000	5	6/6/2025	NON-COMPETING CONTINUATION	$456,427
														Subtotal = $456,427

Issue Date FY: 2024 ( Subtotal = $456,427 )
2024	2024	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	886 CHESTNUT RIDGE ROAD	MORGANTOWN	WV	26505	MONONGALIA	USA	Allergy and Infectious Diseases Research	000	4	5/30/2024	NON-COMPETING CONTINUATION	$456,427
														Subtotal = $456,427

Issue Date FY: 2023 ( Subtotal = $464,027 )
2023	2023	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	886 CHESTNUT RIDGE ROAD	MORGANTOWN	WV	26505	MONONGALIA	USA	Allergy and Infectious Diseases Research	000	3	5/11/2023	NON-COMPETING CONTINUATION	$464,027
														Subtotal = $464,027

Issue Date FY: 2022 ( Subtotal = $494,427 )
2022	2022	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	886 CHESTNUT RIDGE	MORGANTOWN	WV	26506	MONONGALIA	USA	Allergy and Infectious Diseases Research	000	2	5/18/2022	NON-COMPETING CONTINUATION	$494,427
														Subtotal = $494,427

Issue Date FY: 2021 ( Subtotal = $509,627 )
2021	2021	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	886 CHESTNUT RIDGE	MORGANTOWN	WV	26506	MONONGALIA	USA	Allergy and Infectious Diseases Research	000	1	5/31/2021	NEW	$509,627
														Subtotal = $509,627

Grand Total All Awards = $2,380,935

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Understanding IL-27 as a negative regulator of protective immunity during neonatal sepsis

Award Number: R01AI163333

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: 06/01/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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