Protein-DNA complex is the exclusive malaria parasite component that activates dendritic cells and triggers innate immune responses

Xianzhu Wu, Nagaraj M. Gowda, Sanjeev Kumar, D. Channe Gowda

Research output: Contribution to journalArticle

100 Citations (Scopus)

Abstract

Dendritic cells (DCs) play a crucial role in the development of protective immunity to malaria. However, it remains unclear how malaria parasites trigger immune responses in DCs. In this study, we purified merozoites, food vacuoles, and parasite membrane fragments released during the Plasmodium falciparum schizont burst to homogeneity and tested for the activation of bone marrow-derived DCs from wild-type and TLR2-/-, TLR4-/-, TLR9-/-, and MyD88-/- C57BL/6J mice. The results demonstrate that a protein-DNA complex is the exclusive parasite component that activates DCs by a TLR9-dependent pathway to produce inflammatory cytokines. Complex formation with proteins is essential for the entry of parasite DNA into DCs for TLR9 recognition and, thus, proteins convert inactive DNA into a potent immunostimulatory molecule. Exogenous cationic polymers, polylysine and chitosan, can impart stimulatory activity to parasite DNA, indicating that complex formation involves ionic interactions. Merozoites and DNA-protein complex could also induce inflammatory cytokine responses in human blood DCs. Hemozoin is neither a TLR9 ligand for DCs nor functions as a carrier of DNA into cells. Additionally, although TLR9 is critical for DCs to induce the production of IFN-γ by NK cells, this receptor is not required for NK cells to secret IFN-γ, and cell-cell contact among myeloid DCs, plasmacytoid DCs, and NK cells is required for IFN-γ production. Together, these results contribute substantially toward the understanding of malaria parasite-recognition mechanisms. More importantly, our finding that proteins and carbohydrate polymers are able to confer stimulatory activity to an otherwise inactive parasite DNA have important implications for the development of a vaccine against malaria.

Original languageEnglish (US)
Pages (from-to)4338-4348
Number of pages11
JournalJournal of Immunology
Volume184
Issue number8
DOIs
StatePublished - Apr 15 2010

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Innate Immunity
Dendritic Cells
Malaria
Parasites
DNA
Proteins
Merozoites
Natural Killer Cells
Polymers
Natural Killer Cell Receptors
Cytokines
Schizonts
Malaria Vaccines
Polylysine
Chitosan
Myeloid Cells
Plasmodium falciparum
Vacuoles
Inbred C57BL Mouse
Immunity

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

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abstract = "Dendritic cells (DCs) play a crucial role in the development of protective immunity to malaria. However, it remains unclear how malaria parasites trigger immune responses in DCs. In this study, we purified merozoites, food vacuoles, and parasite membrane fragments released during the Plasmodium falciparum schizont burst to homogeneity and tested for the activation of bone marrow-derived DCs from wild-type and TLR2-/-, TLR4-/-, TLR9-/-, and MyD88-/- C57BL/6J mice. The results demonstrate that a protein-DNA complex is the exclusive parasite component that activates DCs by a TLR9-dependent pathway to produce inflammatory cytokines. Complex formation with proteins is essential for the entry of parasite DNA into DCs for TLR9 recognition and, thus, proteins convert inactive DNA into a potent immunostimulatory molecule. Exogenous cationic polymers, polylysine and chitosan, can impart stimulatory activity to parasite DNA, indicating that complex formation involves ionic interactions. Merozoites and DNA-protein complex could also induce inflammatory cytokine responses in human blood DCs. Hemozoin is neither a TLR9 ligand for DCs nor functions as a carrier of DNA into cells. Additionally, although TLR9 is critical for DCs to induce the production of IFN-γ by NK cells, this receptor is not required for NK cells to secret IFN-γ, and cell-cell contact among myeloid DCs, plasmacytoid DCs, and NK cells is required for IFN-γ production. Together, these results contribute substantially toward the understanding of malaria parasite-recognition mechanisms. More importantly, our finding that proteins and carbohydrate polymers are able to confer stimulatory activity to an otherwise inactive parasite DNA have important implications for the development of a vaccine against malaria.",
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Protein-DNA complex is the exclusive malaria parasite component that activates dendritic cells and triggers innate immune responses. / Wu, Xianzhu; Gowda, Nagaraj M.; Kumar, Sanjeev; Gowda, D. Channe.

In: Journal of Immunology, Vol. 184, No. 8, 15.04.2010, p. 4338-4348.

Research output: Contribution to journalArticle

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