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Dysregulation of humoral immunity following Plasmodium infection

Award Number: R01AI197249
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: 02/10/2026
PERIOD OF PERFORMANCE END DATE: 01/31/2031

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Dysregulation of humoral immunity following Plasmodium infection - ABSTRACT Immune-mediated protection against malaria, termed clinical immunity, develops over many years of repeated exposure to Plasmodium, requires continuous exposure to Plasmodium, and correlates with circulating titers of Plasmodium-specific antibodies. Why Plasmodium infections fail to induce long-lasting protection following one or few infections, thereby contributing to the chronic pathogenesis of malaria, remains unknown. The objective of this proposal is to determine the effect of Plasmodium infections on germinal center (GC) B cells and bone marrow (BM) homeostasis towards inefficient generation of long-lived plasma cells (LLPCs). Many infections and vaccines elicit long-lasting antibody titers after one or just a few exposures. The half-lives of circulating antibody titers for viral antigens following infection or vaccination have been shown to range from 10 years to >300 years. In contrast, half-lives of circulating Plasmodium-specific antibody titers are reported to be in the range of several days. Long-term maintenance of circulating antibody titers comes from GC-derived plasma cells (PCs) that migrate to the BM where they receive survival signals and become LLPCs. To investigate why Plasmodium infection induces short antibody half-lives, we compared spleen GC responses and development of BM LLPCs in mice following infection with Plasmodium yoelii 17XNL (Py) to mice immunized systemically with NP-CGG plus the adjuvant AddaVax. Our preliminary data demonstrate that despite the induction of robust spleen GC responses during Py infection, Py-induced GC B cells are inefficient at generating LLPCs in the spleen and BM and that Py-specific IgG-secreting cells in the spleen and BM exhibit decreased IgG production and affinity. These data suggest Py infections exhibit dysregulated humoral immunity by impacting the functional programming of spleen GC B cells or PCs. Py-induced splenic PCs were able to migrate towards the BM homing cytokine CXCL12, suggesting inefficient generation of LLPCs following Py infection could be attributed to functional deficiencies in the BM microenvironment that support engraftment and survival of LLPCs. Consistent with this possibility, there were decreases in the number of BM cells that provide recruitment signals for PCs and survival signals for LLPCs during Py infection that was associated with an increase in multiple cytokines in the BM, including IFN-γ. Blocking IFN-γR signaling during Py infection partially prevented the loss of BM cells and increased BM PC numbers. These observations collectively lead to the hypothesis that failure to engender LLPCs following Plasmodium infection is attributed to intrinsic differences in spleen GC B cell programming that affect PC functionality and changes in the BM microenvironment that fail to support LLPCs. The hypothesis will be tested through the following aims. Aim 1. Identify the functional deficits in spleen GC B cells and PCs following Py infection responsible for inefficient generation and function of LLPCs. Aim 2. Define the cellular and molecular mechanisms by which Py alters the BM microenvironment to impede the development of LLPCs.


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 = $790,946 )
2026	2026	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Allergy and Infectious Diseases Research	000	1	2/10/2026	NEW	$790,946
														Subtotal = $790,946

Grand Total All Awards = $790,946

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Dysregulation of humoral immunity following Plasmodium infection

Award Number: R01AI197249

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: 02/10/2026

PERIOD OF PERFORMANCE END DATE: 01/31/2031

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