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Host innate immune mechanisms control temporal expression of flagellin by pathogenic Salmonella

Award Number: R01AI155685
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary Inflammasomes are multiprotein complexes that sense microbial infections and respond by inducing a caspase- 1-mediated form of inflammatory cell death called pyroptosis. Inflammasomes have been implicated in the detection and clearance of a variety of bacterial pathogens, but little is known about whether there is active cross-talk between the host sensing mechanism and the expression of stimulatory ligands by the pathogen. We have found that inflammasome activation regulates expression of the NLRC4 ligand, flagellin, by Salmonella. A host lipid stimulus released upon NLRC4-mediated macrophage pyroptosis increases expression of flagellin by extracellular bacteria that enhances pyroptosis upon internalization, establishing a positive feedback loop that potentiates Salmonella detection and clearance. As infection progresses, a natural type I interferon-dependent host negative feedback response shuts down expression of NLRC4 and the lysophospholipid biosynthetic enzyme iPLA2 to sub-baseline levels, switching Salmonella to a flagellin-low phenotype inside macrophages. Based on these findings we hypothesize that Salmonella has evolved to co-opt NLRC4 activation and lipid production to initially enhance production of extracellular flagellin that promotes systemic spread of the pathogen at the risk of NLRC4-mediated clearance, and later on take advantage of decreased NLRC4 and lipid production (a host strategy likely aimed at limiting excessive NLRC4-mediated immunopathology) to downregulate flagellin intracellularly within macrophages. In this proposal we will investigate the host cell-intrinsic innate regulatory circuit involving type I IFN signaling, NLRC4 and iPLA2 activity that regulates the temporal switch of Salmonella from a flagellin-high to a flagellin-low phenotype inside macrophages. We will conduct these investigations in the following specific aims: 1) To identify how macrophage pyroptosis promotes early increase in flagellin production by extracellular Salmonella; 2) To dissect the natural type I interferon-dependent host negative feedback response that establishes a NLRC4-low and iPLA2-low intracellular environment prompting Salmonella to switch to a flagellin-low phenotype inside macrophages. Our investigations will identify the temporal and biphasic regulation of a pathogen-derived inflammasome ligand by the very process of inflammasome activation as a novel mode of host-pathogen cross-talk and reveal a host mechanism that Salmonella takes advantage of for flagellin downregulation and immune escape within macrophages. These studies will also have broader implications for understanding how host innate immunity contributes to modulation of microbial effectors impacting the development and resolution of infections.


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: 2024 ( Subtotal = $490,327 )
2024	2024	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	4	5/7/2024	NON-COMPETING CONTINUATION	$490,327
														Subtotal = $490,327

Issue Date FY: 2023 ( Subtotal = $564,485 )
2023	2023	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	3	5/24/2023	NON-COMPETING CONTINUATION	$564,485
														Subtotal = $564,485

Issue Date FY: 2022 ( Subtotal = $543,982 )
2022	2022	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	2	6/3/2022	NON-COMPETING CONTINUATION	$543,982
														Subtotal = $543,982

Issue Date FY: 2021 ( Subtotal = $484,606 )
2021	2021	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	1	6/10/2021	NEW	$484,606
														Subtotal = $484,606

Grand Total All Awards = $2,083,400

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Host innate immune mechanisms control temporal expression of flagellin by pathogenic Salmonella

Award Number: R01AI155685

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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