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Host Ca2+, actin, and ATP production in rickettsia-endothelial cell dysfunction

Award Number: R21AI171791
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: 07/05/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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Host Ca2+, actin, and ATP production in rickettsia-endothelial cell dysfunction - Project Summary/Abstract Spotted fever group rickettsioses (SFGR) are in aggregate the second most common tick-borne infections in the U.S. and account for considerable severe disease and death, with case fatality rates over 10% in many regions of the world. Rocky Mountain spotted fever is the prototypical disease in this group for which the major pathophysiologic adverse consequence is increased vascular permeability, leading to hypotension, hypoperfusion, and ischemic injury to the lungs, brain and other organs. SFG rickettsiae infect endothelial cells and parasitize host ATP for growth and spread. Our preliminary studies showed that regulation of calcium flux in infected endothelial cell barriers using calcium chelators or specific calcium channel blockers abrogates vascular permeability. We propose that spotted fever rickettsiae utilize a nutritional virulence strategy to subvert host calcium handling – through an acquired “channelopathy” - that drives increases in access to cellular metabolic substrates, but that in turn damages key functions of endothelial cells. Our hypothesis is that increasing competition for cellular ATP by rickettsiae impairs ATP-dependent Ca2+ pumps, which in turn leads to increased intracellular calcium concentrations, activation of Ca2+ channels, Ca2+-dependent kinases, signaling pathways and transcriptional regulation that increase cellular content of key nutrients for rickettsial growth. The consequences of improved rickettsial fitness ultimately leads to reorganization of cellular cytoskeleton, disassembly of inter-endothelial junctions, and inevitably, increased vascular permeability. The proposal will measure intracellular calcium and ATP concentrations in the presence or absence of calcium channel-blocking agent, while monitoring for endothelial barrier dysfunction in both early and late stages of Rickettsia parkeri infection. Evidence of a role for calcium flux in rickettsial vascular permeability includes localized calcium “puffs” with transient focal cytosolic ATP depletion and local cytoskeletal restructuring as early post-invasion events. This is predicted to be followed by global increases in intracellular calcium, ATP depletion, cytoskeleton restructuring, and inter-endothelial junction disassembly with massive rickettsial proliferation, sensitive to buffering cytosolic calcium concentrations through chelation or blocking or silencing of key calcium channels. Rickettsial load will also be determined to understand the effect of these manipulations on microbial fitness. This work will identify key mechanisms that permit changes in vascular permeability with spotted fever rickettsia infection, perhaps driven by rickettsial effector proteins, and potential targets for host-based pharmacologic intervention to prevent severe and fatal outcomes of SFGR and potentially other infectious diseases.


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 = $0 )
2025	2023	THE HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC.	6720A ROCKLEDGE DR	BETHESDA	MD	20817	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	2	1/30/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $189,828 )
2023	2023	THE HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC.	6720A ROCKLEDGE DR	BETHESDA	MD	20817	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	2	6/7/2023	NON-COMPETING CONTINUATION	$189,828
														Subtotal = $189,828

Issue Date FY: 2022 ( Subtotal = $227,793 )
2022	2022	HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC., THE	6720-A ROCKLEDGE DR STE 100	BETHESDA	MD	20817	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	1	7/5/2022	NEW	$227,793
														Subtotal = $227,793

Grand Total All Awards = $417,621

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Host Ca2+, actin, and ATP production in rickettsia-endothelial cell dysfunction

Award Number: R21AI171791

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: 07/05/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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