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The Functional Role of the Tetraspanin CD82/Kai1 in Fungal Innate Immunity

Award Number: R01AI136529
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: 01/11/2018
PERIOD OF PERFORMANCE END DATE: 12/31/2023

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The Functional Role of the Tetraspanin CD82/Kai1 in Fungal Innate Immunity - Project Summary: Invasive fungal infections (IFIs) represent a major threat to critically ill and immunocompromised patients and are associated with significant morbidity and mortality. Aspergillus and Candida are opportunistic fungi that cause the majority of these life-threatening infections. In order to exert their deleterious effects, pathogens including viruses, bacteria, parasites, and fungi can hijack tetraspanins for cell invasion or intracellular trafficking. Tetraspanins comprise a family of proteins that are expressed on the plasma membrane, intracellular membranes, and exosomes from nearly all cell types. As their name implies, tetraspanins span the membrane four times and have short intracellular amino and carboxyl-termini and two extracellular loops. Tetraspanins regulate diverse biological processes including cell migration, adhesion, and signaling events by serving as organizers of multimolecular complexes; they form promiscuous associations with one another and other membrane proteins and lipids to generate tetraspanin-enriched microdomains. Elucidating the precise function of tetraspanins has been difficult due to molecular redundancy, a lack of catalytic activity, and insufficient specific antibodies. Despite these challenges, several tetraspanins have been implicated as key regulators of cancer progression and immunity. In particular, CD82 acts as a potent suppressor of tumor metastasis. Tetraspanins including CD82 are also widely expressed in immune cells, but their exact role in undefined. We have made several key observations that begin to define the role of CD82 in fungal immunity. Following phagocytosis by macrophages, CD82 is specifically recruited to phagosomes containing fungal pathogens prior to lysosomal fusion. Remarkably, LysM-Cre CD82 knockout mice infected with Candida albicans have significantly reduced survival compared to wild-type controls, indicating that CD82 plays an important functional role in myeloid cells in response to systemic fungal infection. We developed fungal-like particles to probe directly the immune response to carbohydrates expressed on the fungal cell wall, such as β- 1,3 glucan which is recognized by the pathogen recognition receptor, Dectin-1. We demonstrated that Dectin-1 is critical for phagolysosomal maturation and controls recruitment of the autophagy-related protein, LC3, to fungal containing phagosomes through Syk activation. We also found that CD82 associates with Dectin-1 in macrophages and is important for downstream signaling events in response to fungal infection including Syk activation and ROS generation. To determine the molecular mechanism of CD82 in fungal innate immunity in macrophages, we propose the following two specific aims: (1) Determine the role of CD82 in Dectin-1 signaling by macrophages stimulated with β-1,3 glucan, and (2) Define the role of CD82 in LC3 associated phagocytosis in macrophages challenged by C. albicans.


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 = -$10,129 )
2024	2022	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	5	8/6/2024	NON-COMPETING CONTINUATION	-$10,129
														Subtotal = -$10,129

Issue Date FY: 2022 ( Subtotal = $529,433 )
2022	2022	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	5	12/23/2021	NON-COMPETING CONTINUATION	$529,433
														Subtotal = $529,433

Issue Date FY: 2021 ( Subtotal = $529,433 )
2021	2021	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	4	12/28/2020	NON-COMPETING CONTINUATION	$529,433
														Subtotal = $529,433

Issue Date FY: 2020 ( Subtotal = $582,212 )
2020	2020	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	3	1/28/2020	NON-COMPETING CONTINUATION	$582,212
														Subtotal = $582,212

Issue Date FY: 2019 ( Subtotal = $560,479 )
2019	2019	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	2	12/14/2018	NON-COMPETING CONTINUATION	$529,433
2019	2019	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	2	9/10/2019	SUPPLEMENT FOR EXPANSION	$31,046
														Subtotal = $560,479

Issue Date FY: 2018 ( Subtotal = $529,433 )
2018	2018	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	1	1/10/2018	NEW	$529,433
														Subtotal = $529,433

Grand Total All Awards = $2,720,861

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The Functional Role of the Tetraspanin CD82/Kai1 in Fungal Innate Immunity

Award Number: R01AI136529

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: 01/11/2018

PERIOD OF PERFORMANCE END DATE: 12/31/2023

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