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The Germinal Center and T cell help in Three Phases of Clearance of Plasmodium

Award Number: R01AI135061
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: 11/01/2017
PERIOD OF PERFORMANCE END DATE: 10/31/2024

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The Germinal Center and T cell help in Three Phases of Clearance of Plasmodium - ABSTRACT Despite improvements in infection control, one child dies every minute from malaria, which is caused by infection by Plasmodium parasites. Children develop immunity to malaria slowly after multiple exposures, and lose immunity in the absence of continuous exposure. A lack of critical knowledge about the antibody response that controls this infection hinders vaccine development. Early IFN-γ from Th1 cells limits early parasite growth and correlates with protection. CD4 T helper cells (Th) also promote parasite-specific antibody, which we have proposed is primarily required for full parasite clearance, which takes over a month. IL-21 promotes B cell responses and is also required for clearance of Plasmodium. Splenic germinal centers optimize B:T cell interactions that promote isotype switching and affinity maturation of antibodies, and long-lived plasma cell generation. However, the appearance of GCs is delayed until late in infection by the Th1 response. This slow response may explain the delay of development of immunity observed in the field. However, there is a significant extrafollicular antibody response that is faster, and actually corresponds with dramatic control of the parasite. In addition, our preliminary data showing that knockout mice lacking germinal centers (GC) control infection, led us to develop a working model of protection consisting of three phases. First, Th1 cytokines limit parasite growth; next, GC-independent factors control the parasite to low, but chronic levels without pathology; when finally, GCs play a role in complete clearance. Yet, the types of Th cells required, and the dominant mechanisms of antibody-mediated parasite killing are not yet clear, especially in the control phase. The role of IL-21 in an extrafollicular response has not been sufficiently studied to understand the mechanisms or importance. Therefore, we hypothesize that GC-independent mechanisms driven by IL-21 make a significant contribution to the control of Plasmodium infection. To test this, in Aim 1, we will compare the contribution of GCs and IL-21 for control of parasite. We will determine the importance of GC-driven antibody changes by using novel mouse models separately deficient in isotype switching and affinity maturation. There are also important unanswered questions about the type of Th cells that help B cells make antibody in malaria infection. We and others have recently discovered that the effector T helper cell response to mouse and human malaria is composed largely of a hybrid IFN-γ+ IL-21+ Th1/Tfh cell type that has all the hallmarks of both Th1 and Tfh. While IFN-γ was recently shown to inhibit GC formation, the role of hybrid IFN-γ+/IL-21+ T cells' contribution to antibody production in vivo, and their role in protection from parasitemia and pathology in malaria, have not been tested. Therefore, In Aim 2 we will evaluate the efficacy of hybrid IFN-γ+/IL-21+ Th1/Tfh in protection, by sorting them using cytokine reporter mice, and determine the phases of infection where IL-21 is critical. Understanding the mechanisms of both the control phase and final clearance is critical because control of parasite corresponds with termination of malaria pathology and may suggest novel vaccine strategies.


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 TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	000	5	1/21/2025	NON-COMPETING CONTINUATION	-$51,334
2025	2022	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Allergy and Infectious Diseases Research	001	6	1/21/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$51,334
2025	2022	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Allergy and Infectious Diseases Research	002	6	6/9/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Allergy and Infectious Diseases Research	000	6	12/21/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Allergy and Infectious Diseases Research	001	6	10/27/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$223,086
2023	2022	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	000	5	10/27/2022	NON-COMPETING CONTINUATION	-$223,086
2023	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Allergy and Infectious Diseases Research	002	6	12/8/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $393,556 )
2022	2022	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	000	5	10/18/2021	NON-COMPETING CONTINUATION	$393,556
														Subtotal = $393,556

Issue Date FY: 2021 ( Subtotal = $393,584 )
2021	2021	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	000	4	10/23/2020	NON-COMPETING CONTINUATION	$393,584
														Subtotal = $393,584

Issue Date FY: 2020 ( Subtotal = $393,612 )
2020	2020	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	000	3	11/6/2019	NON-COMPETING CONTINUATION	$393,612
														Subtotal = $393,612

Issue Date FY: 2019 ( Subtotal = $393,639 )
2019	2019	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	000	2	10/24/2018	NON-COMPETING CONTINUATION	$393,639
														Subtotal = $393,639

Issue Date FY: 2018 ( Subtotal = $388,058 )
2018	2018	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	000	1	11/1/2017	NEW	$388,058
														Subtotal = $388,058

Grand Total All Awards = $1,962,449

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The Germinal Center and T cell help in Three Phases of Clearance of Plasmodium

Award Number: R01AI135061

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: 11/01/2017

PERIOD OF PERFORMANCE END DATE: 10/31/2024

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