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The Function of Host-derived Extracellular Vesicles in Trafficking of Bacterial Antigens to Stimulate the Antibacterial Immune Response

Award Number: R01AI158749
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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The Function of Host-derived Extracellular Vesicles in Trafficking of Bacterial Antigens to Stimulate the Antibacterial Immune Response - There is no licensed vaccine for humans against potentially life-threatening paratyphoid and nontyphoidal septicemia caused by the Salmonella enterica. This intracellular pathogen evades sophisticated host immune defenses. The host immune system is controlled by regulatory mechanisms, such as intercellular communication between infected and uninfected cells, which can also be accomplished via small extracellular vesicles (EVs), exosomes. Exosomes are vesicles that originate in the endosomal pathway and transport cargo to other cells. We found that exosomes carry bacterial antigens (Ags) from S. Typhimurium-infected macrophages ( MΦ s) and stimulate naïve antigen-presenting cells involved in T cell recruitment, and an intranasal administration of these exosomes leads to the production of anti-S. Typhimurium antibodies (Abs) and stimulation of Th 1 response critical for engulfing and killing intracellular bacteria. These adaptive responses are Ags-dependent, but the Ags responsible for this humoral response or the mechanisms responsible for Ag trafficking to EVs are unknown. We will address the contribution of exosomes to adaptive immune responses against intracellular pathogens as there is a critical need to determine new mechanisms of protective immune responses, such as exosome-modulated immunity. Our long-term goal is to advance the development of mechanism-based preventative measures for bacterial infections. Our overall objective is to elucidate the mechanisms whereby bacterial Ags are trafficked to exosomes and identify the capability of exosomes to generate protective cellular and humoral immunity against intracellular Salmonella. Our central hypothesis is that Salmonella Ags are trafficked to endosomal compartments of infected MΦs and released via exosomes to stimulate innate responses and Ag-specific Th1 cell responses . The rationale is that determining the mechanisms via which Salmonella Ags are trafficked to exosomes and generate adaptive immunity against Salmonella, we will assign a novel role of EVs in host defense, important for the design of preventative approaches. In Aim 1, we will identify mechanisms whereby Salmonella Ags are trafficked into EVs. In Aim 2, we will determine the mechanisms by which EVs produced by Salmonella-infected determine how EVs MΦ s regulate the activation and function of DCs in mucosal tissues. In Aim 3, we will derived from Salmonella-infected MΦ s drive adaptive immunity. The expected outcomes are that we will have established a mechanism responsible for the trafficking of Ags into EVs, and characterize novel roles of EVs in innate immunity and Th1 adaptive immunity. This study will have a positive impact as it will provide a conceptual framework for the future development of targets for vaccine design and significantly advance knowledge of how Salmonella disrupts host immunity, which is vital for the development of preventative and therapeutic approaches against this pathogen. The innovation lies in addressing the function of EVs produced by host cells in rendering protection against salmonellosis. This study is significant since we will advance knowledge on the function of host exosomes in altering the immune response to Salmonella infection.


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 = $473,541 )
2025	2025	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	4	3/27/2025	NON-COMPETING CONTINUATION	$473,541
														Subtotal = $473,541

Issue Date FY: 2024 ( Subtotal = $250,257 )
2024	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	3	4/10/2024	NON-COMPETING CONTINUATION	$250,257
														Subtotal = $250,257

Issue Date FY: 2023 ( Subtotal = $451,762 )
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	2	3/15/2023	NON-COMPETING CONTINUATION	$451,762
														Subtotal = $451,762

Issue Date FY: 2022 ( Subtotal = $543,320 )
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	1	4/12/2022	NEW	$543,320
														Subtotal = $543,320

Grand Total All Awards = $1,718,880

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The Function of Host-derived Extracellular Vesicles in Trafficking of Bacterial Antigens to Stimulate the Antibacterial Immune Response

Award Number: R01AI158749

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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