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Antibodies, B cells and resistance to human cryptococcosis

Award Number: R01AI143453
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: 07/25/2019
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Antibodies, B cells and resistance to human cryptococcosis - HIV-associated immunosuppression portends high risk for cryptococcal meningitis (CM). Despite progress that has increased HIV testing and anti-retroviral therapy (ART) availability in resource-limited settings, the incidence and mortality of CM remain very high. In addition, ART can elicit immune reconstitution inflammatory syndrome (C-IRIS), and CM also occurs in HIV- persons, including recipients of solid organ transplants and biologics. There are no host biomarkers to predict which HIV-infected (HIV+) patients will develop CM or C- IRIS. We are interested in the role antibody (Ab) immunity may play in resistance to CM, which is rare in people with intact immunity. We have contributed significant knowledge in this area, including recent data showing lower natural Laminarin (a β-glucan)-binding Ab levels in HIV+ patients with C-IRIS and positive serum cryptococcal antigen tests. Studies of HIV+ and HIV- patients revealed perturbations in Ab repertoires of patients with CM and C-IRIS, and lower IgM memory B cell levels in patients with CM. In mice, IgM memory homologs, B-1 cells and/or naïve IgM enhanced resistance to CM. These cells make Abs that bind microbial carbohydrates, e.g. the β-glucans on the Cn cell wall. The goal of this project is to probe the link between natural Ab and B cell responses to Cn and resistance to CM. We hypothesize CM risk will associate with deficiency of specific Cn- and/or β-glucan-binding Abs, stemming from B cell repertoire pertubations. Our aims are 1] To characterize Cn- and β-glucan-binding Abs of patients with and at risk for CM and C-IRIS, isolate monoclonal antibodies (huMabs) from normal persons and test their efficacy in mouse models. 2] To determine the ability of huMabs and GXM- and β-glucan-binding Abs to 1] exert direct effects on Cn viability and biology, and/or 2] mediate human effector cell Cn phagocytosis and/or killing. 3] To analyze B cell subsets, VH/VL repertoires, and transcriptional pathways of patients with and at risk for CM and C-IRIS, and controls, and use statistical modeling to identify signatures of CM risk. Knowledge gained from this project will inform tools to predict CM and C-IRIS risk, overcome roadblocks to diagnosis and therapy, provide new insight into the pathogenesis of CM, and inform development of immunotherapy and vaccines.


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: 2026 ( Subtotal = -$2,611 )
2026	2024	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	6	12/19/2025	NON-COMPETING CONTINUATION	-$2,611
														Subtotal = -$2,611

Issue Date FY: 2024 ( Subtotal = $532,469 )
2024	2024	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	6	6/18/2024	NON-COMPETING CONTINUATION	$532,469
														Subtotal = $532,469

Issue Date FY: 2023 ( Subtotal = $547,115 )
2023	2023	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	5	7/10/2023	NON-COMPETING CONTINUATION	$547,115
														Subtotal = $547,115

Issue Date FY: 2022 ( Subtotal = $177,490 )
2022	2022	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	4	6/30/2022	NON-COMPETING CONTINUATION	$177,490
														Subtotal = $177,490

Issue Date FY: 2021 ( Subtotal = $709,959 )
2021	2021	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	3	6/29/2021	NON-COMPETING CONTINUATION	$709,959
														Subtotal = $709,959

Issue Date FY: 2020 ( Subtotal = $667,846 )
2020	2020	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	2	6/11/2020	NON-COMPETING CONTINUATION	$667,846
														Subtotal = $667,846

Issue Date FY: 2019 ( Subtotal = $522,712 )
2019	2019	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	1	7/24/2019	NEW	$522,712
														Subtotal = $522,712

Grand Total All Awards = $3,154,980

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Antibodies, B cells and resistance to human cryptococcosis

Award Number: R01AI143453

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: 07/25/2019

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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