Hemozoin-mediated inflammasome activation limits long-lived anti-malarial immunity.

Abstract

During acute malaria, most individuals mount robust inflammatory responses that limit parasite burden. However, long-lived sterilizing anti-malarial memory responses are not efficiently induced, even following repeated Plasmodium exposures. Using multiple Plasmodium species, genetically modified parasites, and combinations of host genetic and pharmacologic approaches, we find that the deposition of the malarial pigment hemozoin directly limits the abundance and capacity of conventional type 1 dendritic cells to prime helper T cell responses. Hemozoin-induced dendritic cell dysfunction results in aberrant Plasmodium-specific CD4 T follicular helper cell differentiation, which constrains memory B cell and long-lived plasma cell formation. Mechanistically, we identify that dendritic cell-intrinsic NLRP3 inflammasome activation reduces conventional type 1 dendritic cell abundance, phagocytosis, and T cell priming functions in vivo. These data identify biological consequences of hemozoin deposition during malaria and highlight the capacity of the malarial pigment to program immune evasion during the earliest events following an initial Plasmodium exposure.

• Authors: Angela D Pack, Patrick V Schwartzhoff, Zeb R Zacharias, Daniel Fernandez-Ruiz, William R Heath, Prajwal Gurung, Kevin L Legge, Chris J Janse, Noah S Butler
• Journal: Cell reports (Cell Rep) Vol. 36 Issue 8 Pg. 109586 (08 24 2021) ISSN: 2211-1247 [Electronic] United States
• PMID: 34433049 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Antimalarials
• Hemeproteins
• Inflammasomes
• hemozoin

Topics

• Animals
• Antimalarials (pharmacology)
• Dendritic Cells (immunology)
• Hemeproteins (pharmacology)
• Inflammasomes (drug effects, metabolism)
• Lymphocyte Activation (immunology)
• Malaria (drug therapy, immunology)
• Memory B Cells (drug effects, immunology)
• Mice, Inbred C57BL
• Phagocytosis (physiology)
• Plasmodium (immunology)
• T-Lymphocytes, Helper-Inducer (immunology)
• Mice