Dual Engagement of the NLRP3 and AIM2 Inflammasomes by Plasmodium-Derived Hemozoin and DNA during Malaria

• Hemozoin (Hz) and plasmodial gDNA enter the cytosol by destabilizing phagolysosomes
• Plasmodial gDNA and Hz activate AIM2 and NLRP3 inflammasomes, respectively
• Parasitized erythrocytes and natural Hz induce IL-1β via NLRP3 and AIM2

SummaryHemozoin (Hz) is the crystalline detoxification product of hemoglobin in Plasmodium-infected erythrocytes. We previously proposed that Hz can carry plasmodial DNA into a subcellular compartment that is accessible to Toll-like receptor 9 (TLR9), inducing an inflammatory signal. Hz also activates the NLRP3 inflammasome in primed cells. We found that Hz appears to colocalize with DNA in infected erythrocytes, even before RBC rupture or phagolysosomal digestion. Using synthetic Hz coated in vitro with plasmodial genomic DNA (gDNA) or CpG oligodeoxynucleotides, we observed that DNA-complexed Hz induced TLR9 translocation, providing a priming and an activation signal for inflammasomes. After phagocytosis, Hz and DNA dissociate. Hz subsequently induces phagolysosomal destabilization, allowing phagolysosomal contents access to the cytosol, where DNA receptors become activated. Similar observations were made with Plasmodium-infected RBCs. Finally, infected erythrocytes activated both the NLRP3 and AIM2 inflammasomes. These observations suggest that Hz and DNA work together to induce systemic inflammation during malaria.

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