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Impact of inflammatory lipids on Yersinia pestis infection

Award Number: R01AI178106
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: 07/14/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Impact of inflammatory lipids on Yersinia pestis infection - ABSTRACT Yersinia pestis causes the acute human disease commonly referred to as plague. A hallmark manifestation of this disease is delayed inflammation despite active bacterial replication. Y. pestis modulates inflammation by actively inhibiting the expression of pro-inflammatory cytokines via the action of a group of proteins called Yop effectors that are directly injected into host cells by a bacterial type three secretion system (T3SS). Because establishment of this non-inflammatory environment is key for Y. pestis to colonize the host, understanding how Y. pestis modulates the host inflammatory response during early stages of infection will provide crucial insights into both the pathogenesis of the bacterium and potential strategies to improve therapy. Lipid mediators, such as members of the eicosanoid family, are essential to initiate the cascade of signaling events that regulates inflammation. Therefore, disruption of the synthesis of pro-inflammatory eicosanoids can effectively stifle a rapid immune response. Despite their importance in initiating inflammation, the role of lipid mediators in the context of plague has not been previously investigated. Recently, we discovered a dysregulation in eicosanoid synthesis during pneumonic plague, highlighted by the inhibition in the synthesis of the pro-inflammatory lipid leukotriene B4 (LTB4). Furthermore, using Y. pestis mutants we uncovered a novel mechanism for the recognition of the T3SS by neutrophils that triggers LTB4 synthesis, which is normally inhibited by the Yop effectors. Together, these discoveries support a conceptually innovative hypothesis that Y. pestis actively manipulates the synthesis of lipid mediators to disrupt the proper inflammatory cascade that would normally recruit circulating leukocytes to control infection. In Aim 1, we will test this hypothesis using animal models to define the contribution of eicosanoids to the host response during plague and determine how disruption of LTB4 synthesis benefits Y. pestis. In Aim 2, we will use Y. pestis as a tool to define the molecular mechanisms responsible for T3SS- dependent LTB4 synthesis by neutrophils. Because lipid mediators of inflammation have been overlooked in the context of Y. pestis immune evasion, completion of these studies will significantly transform our conceptual understanding of the early immune events during pneumonic plague.


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 = $723,955 )
2025	2025	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	3	6/26/2025	NON-COMPETING CONTINUATION	$723,955
														Subtotal = $723,955

Issue Date FY: 2024 ( Subtotal = $723,955 )
2024	2024	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	2	6/6/2024	NON-COMPETING CONTINUATION	$723,955
														Subtotal = $723,955

Issue Date FY: 2023 ( Subtotal = $723,496 )
2023	2023	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	1	7/14/2023	NEW	$723,496
														Subtotal = $723,496

Grand Total All Awards = $2,171,406

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Impact of inflammatory lipids on Yersinia pestis infection

Award Number: R01AI178106

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: 07/14/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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