Wednesday, September 17, 2025 9/17/2025

Novel Role of Lactate in Sepsis Impaired Immune Function

Award Number: R01AI174020
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: 12/12/2023
PERIOD OF PERFORMANCE END DATE: 10/31/2028

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Novel Role of Lactate in Sepsis Impaired Immune Function - Sepsis represents a life-threatening disorder caused by a dysregulated host response. Sepsis survivors frequently have long-term immune dysfunction that contributes to high mortality from opportunistic infections. Clinical data shows that lactate levels strongly and positively correlate with severity, morbidity and mortality in sepsis5-8. It is unclear whether lactate contributes to sepsis impaired immune response and susceptibility to subsequent infection. To address this important question, we performed preliminary studies and observed that enhanced lactate levels markedly increased mortality. We also observed that lactate suppresses macrophage phagocytic function during sepsis. Our findings suggest that lactate exerts a previously unknown biological function contributing to the mortality of sepsis and re-infection of sepsis survivors. Cellular senescence is a fundamental mechanism of age-related organ dysfunction. Our RNA-seq and other preliminary data shows that lactate markedly induces macrophage senescence during sepsis. our preliminary data also shows that splenic macrophage senescence is significantly greater in macrophage specific YAP/TAZ deficient (mYAP/TAZ-/-) sham and septic mice than in WT controls. Our finding suggests that YAP is required for the protection against cellular senescence during sepsis. Interestingly, we found that lactate induces lactylation of YAP. We reported that lactate induces HMGB1 lactylation in macrophages25, suggesting that lactate could induce lactylation of non-histone proteins. Indeed, we made a novel observation in our preliminary studies that lactate induces Keap1 lactylation and increases Nrf2 activation. Keap1 is an important suppressor for activation of Nrf2 to upregulate the expression of genes related to suppressive Immune responses. Our findings indicate that lactate alters macrophage immune response during sepsis that may be mediated by promoting macrophage senescence and inducing lactylation of important transcription factors and co-effectors. Based on our novel findings, we hypothesize that lactate is a novel endogenous mediator which contributes to impaired macrophage immune function during sepsis via lactylation of transcription factors and effectors and promotion of cellular senescence. To critically evaluate this hypothesis, we propose three specific aims. Specific aim 1. Investigate the role of lactylation of YAP/TAZ in macrophage immune dysfunction during sepsis. Specific aim 2. Define the role of Keap1 lactylation and Nrf2 activation in macrophage immune dysfunction during sepsis. Specific aim 3. Investigate whether lactate promoted senescence of macrophages will contribute to impaired macrophage immune function during sepsis. Successful completion of the proposed studies will result in a wealth of new and novel data showing that lactate plays an important role in the regulation of immune responses during 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: 2025 ( Subtotal = $559,034 )
2025	2025	EAST TENNESSEE STATE UNIVERSITY	1276 GILBREATH DR	JOHNSON CITY	TN	37614	WASHINGTON	USA	Allergy and Infectious Diseases Research	000	2	11/6/2024	NON-COMPETING CONTINUATION	$559,034
														Subtotal = $559,034

Issue Date FY: 2024 ( Subtotal = $576,326 )
2024	2024	EAST TENNESSEE STATE UNIVERSITY	1276 GILBREATH DR	JOHNSON CITY	TN	37614	WASHINGTON	USA	Allergy and Infectious Diseases Research	001	1	9/5/2024	NEW	$57,632
2024	2024	EAST TENNESSEE STATE UNIVERSITY	1276 GILBREATH DR	JOHNSON CITY	TN	37614	WASHINGTON	USA	Allergy and Infectious Diseases Research	000	1	12/12/2023	NEW	$518,694
														Subtotal = $576,326

Grand Total All Awards = $1,135,360

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Novel Role of Lactate in Sepsis Impaired Immune Function

Award Number: R01AI174020

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: 12/12/2023

PERIOD OF PERFORMANCE END DATE: 10/31/2028

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