Department of Medicine, Division of Infectious Diseases and Immunology
Animals; Carrier Proteins; Cells, Cultured; DNA, Protozoan; Erythrocytes; Hemeproteins; Humans; Inflammasomes; Interleukin-1beta; Malaria; Mice; Mice, Inbred C57BL; Nuclear Proteins; Phagocytosis; Plasmodium; Toll-Like Receptor 9
Amino Acids, Peptides, and Proteins | Immunity | Immunology and Infectious Disease | Immunology of Infectious Disease | Infectious Disease | Molecular Genetics | Parasitic Diseases
Hemozoin (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.
DOI of Published Version
Cell Rep. 2014 Jan 16;6(1):196-210. doi: 10.1016/j.celrep.2013.12.014. Epub 2014 Jan 2. Link to article on publisher's site
Kalantari P, DeOliveira RB, Chan J, Corbett Y, Rathinam VA, Stutz A, Latz E, Gazzinelli RT, Golenbock DT, Fitzgerald KA. (2014). Dual engagement of the NLRP3 and AIM2 inflammasomes by plasmodium-derived hemozoin and DNA during malaria. Infectious Diseases and Immunology Publications. https://doi.org/10.1016/j.celrep.2013.12.014. Retrieved from https://escholarship.umassmed.edu/infdis_pp/185
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