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Redefining the Interaction Between Extracellular Immune Mechanisms and Intracellular Rickettsia Infections

Award Number: R21AI156069
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 Bacteria of the genus Rickettsia are obligate intracellular endosymbionts and the causative agents of many significant human and animal infections. These bacteria are transmitted to humans by hematophagous arthropods. Pathogenic Rickettsia species parasitize endothelial cells of the circulatory system, causing vascular leakage with significant morbidity and mortality. Rickettsia species are amongst the most important pathogens in history, with millions of human fatalities associated with these infections. The complement system is a well-known potion of the mammalian immune system that has classically been considered a secreted patroller of the extracellular spaces of the vasculature. Until recently it was considered unlikely that extracellular immune components like the complement system would encounter intracellular pathogens like Rickettsia; let alone that evolution would drive these systems into an adversarial relationship. Consequently, we are only beginning to appreciate how complement can control intracellular bacterial infections. Emerging data from Rickettsia and other organisms has begun to identify some of the molecular and cellular mechanisms of complement efficacy against intracellular pathogens. As the newly-emerging concept of “intracellular complement” is rapidly gaining traction, the experiments outlined in this proposal will be central to redefining an innate immune component that was discovered over a century ago. Based on both clinical and experimental evidence, we have hypothesized that complement activation is essential for the effective immune response to obligate intracellular Rickettsia infections. However, experimental data suggests that complement efficacy does not result directly from the antibacterial components of complement. Instead, complement efficacy against Rickettsia is derived from secondary interaction with other portions of the immune system. We therefore aim to 1) assess the contribution of the proinflammatory components of complement to the anti-Rickettsia immune response, and 2) define complement-induced components of the immune system that specifically target intracellular pathogens. By studying the interaction between complement and clinically relevant pathogens, the achieved results will advance our collective understanding of basic complement biology, further define the specific immune response to Rickettsia infection, directly influence the design of anti-Rickettsia vaccines, and provide the premise for future studies to analyze complement manipulation as a preventative or therapeutic intervention for intracellular bacterial pathogens.


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	2022	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	2	11/22/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $231,750 )
2022	2022	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	2	4/13/2022	NON-COMPETING CONTINUATION	$231,750
														Subtotal = $231,750

Issue Date FY: 2021 ( Subtotal = $193,125 )
2021	2021	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	1	5/25/2021	NEW	$193,125
														Subtotal = $193,125

Grand Total All Awards = $424,875

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Redefining the Interaction Between Extracellular Immune Mechanisms and Intracellular Rickettsia Infections

Award Number: R21AI156069

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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