Department of Microbiology and Immunology, University of Iowa, Iowa City, IA, USA
Patrick V. Schwartzhoff
Department of Microbiology and Immunology, University of Iowa, Iowa City, IA, USA
Zeb R. Zacharias
Department of Pathology, University of Iowa, Iowa City, IA, USA
Daniel Fernandez-Ruiz
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, VIC 3000, Australia
William R. Heath
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, VIC 3000, Australia; ARC Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, VIC 3010, Australia
Prajwal Gurung
Department of Internal Medicine, University of Iowa, Iowa City, IA, USA; Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA, USA
Kevin L. Legge
Department of Pathology, University of Iowa, Iowa City, IA, USA; Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA, USA
Chris J. Janse
Leiden Malaria Research Group, Centre of Infectious Diseases, Leiden University Medical Centre, Leiden 233 ZA, the Netherlands
Noah S. Butler
Department of Microbiology and Immunology, University of Iowa, Iowa City, IA, USA; Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA, USA; Corresponding author
Summary: 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.
