Journal article
Hemozoin-mediated inflammasome activation limits long-lived anti-malarial immunity
Cell reports (Cambridge), Vol.36(8), pp.109586-109586
08/24/2021
DOI: 10.1016/j.celrep.2021.109586
PMCID: PMC8432597
PMID: 34433049
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.
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•Hemozoin engages NLRP3 to reduce CD8α+ dendritic cell (DC) number and function•Impaired DC responses compromise the B cell helper functions of CD4+ T cells•The accumulation of hemozoin reduces memory B cell and plasma cell responses•NLRP3 deficiency boosts humoral immune memory-mediated protection
Using genetic, chimeric, and pharmacologic approaches, Pack et al. demonstrate that the parasite-derived crystal hemozoin erodes conventional CD8α+ type 1 dendritic cell (cDC1) abundance and function in an NLRP3 inflammasome-dependent manner, which results in reduced CD4+ T follicular helper cell differentiation and impaired anti-Plasmodium humoral immunity.
Details
- Title: Subtitle
- Hemozoin-mediated inflammasome activation limits long-lived anti-malarial immunity
- Creators
- Angela D Pack - University of IowaPatrick V Schwartzhoff - University of IowaZeb R Zacharias - University of IowaDaniel Fernandez-Ruiz - University of MelbourneWilliam R Heath - University of MelbournePrajwal Gurung - University of IowaKevin L Legge - University of IowaChris J Janse - Leiden UniversityNoah S Butler - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Cell reports (Cambridge), Vol.36(8), pp.109586-109586
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.celrep.2021.109586
- PMID
- 34433049
- PMCID
- PMC8432597
- ISSN
- 2211-1247
- eISSN
- 2211-1247
- Grant note
- DOI: 10.13039/501100000923, name: Australian Research Council, award: CE140100011; DOI: 10.13039/501100000925, name: National Health and Medical Research Council, award: 1113293, 1139486, 1154457, AI125446, AI127481; DOI: 10.13039/100000002, name: National Institutes of Health, award: AI127565, AI141196, AI148904, S10OD016199, T32AI007260, T32AI007511; DOI: 10.13039/100000054, name: National Cancer Institute, award: P30CA086862; DOI: 10.13039/100000097, name: National Center for Research Resources
- Language
- English
- Date published
- 08/24/2021
- Academic Unit
- Molecular Physiology and Biophysics; Microbiology and Immunology; Infectious Diseases; Pathology; Internal Medicine
- Record Identifier
- 9984186284102771
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