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

AD Pack; PV Schwartzhoff; ZR Zacharias; D Fernandez-Ruiz; WR Heath; P Gurung; KL Legge; CJ Janse; NS Butler

Journal article

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

AD Pack, PV Schwartzhoff, ZR Zacharias, D Fernandez-Ruiz, WR Heath, P Gurung, KL Legge, CJ Janse, NS Butler

Cell Reports | Published : 2021

DOI: 10.1016/j.celrep.2021.109586

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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 memor..

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University of Melbourne Researchers

William Heath Author

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Awarded by National Institutes of Health

Funding Acknowledgements

The authors acknowledge the late Shahid M. Khan (University of Leiden) for his contributions to generating and characterizing the mutant parasites used throughout this study. We also thank members of the Butler lab for thoughtful discussions. The research reported in this publication was supported by the NCI (grant number P30CA086862) and the National Center for Research Resources of the NIH (grant number S10OD016199). A.D.P. was supported by the NIH (grant number T32AI007511). P.G. was supported by the NIH (grant number AI148904). Z.R.Z. was supported by the NIH (grant number T32AI007260). K.L.L. was supported by the NIH (grant numbers AI141196 and AI127565). W.R.H. was supported by the Australian Research Council (grant number CE140100011) and the National Health and Medical Research Council (NHMRC; grant numbers 1113293 and 1154457). D.F-R. was supported by the National Health and Medical Research Council (grant number 1139486). N.S.B. was supported by the NIH (grant numbers AI125446 and AI127481).