&lt;b&gt;&lt;i&gt;Toxoplasma gondii-&lt;/i&gt;&lt;/b&gt;Derived Profilin Triggers Human Toll-Like Receptor 5-Dependent Cytokine Production

Gonzalez, Rosa Maria Salazar; Shehata, Hesham M.; O’Connell, Michael J.; Yang, Yanfen; Moreno‐Fernandez, Maria E.; Chougnet, Claire; Aliberti, Júlio

doi:10.1159/000362367

Cited by 41 publications

(33 citation statements)

References 31 publications

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“…These findings are inconsistent with a recent report by Salazar Gonzalez et al . (28) who showed that TgPRF stimulates human monocytes to secrete IL-6 and IL-12 in a TLR5-dependent manner. The basis of this discrepancy is unclear but we speculate that it may stem from monocyte purification techniques employed by these authors which differ from those used here.…”

Section: Discussionmentioning

confidence: 99%

The IL-12 Response of Primary Human Dendritic Cells and Monocytes to Toxoplasma gondii Is Stimulated by Phagocytosis of Live Parasites Rather Than Host Cell Invasion

Tosh

Mittereder

Bonne-Année

et al. 2016

The Journal of Immunology

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As a major natural host for Toxoplasma gondii, the mouse is widely used for the study of the immune response to this medically important protozoan parasite. However, murine innate recognition of toxoplasma depends on the interaction of parasite profilin with TLR11 and TLR12, two receptors that are functionally absent in humans. This raises the question of how human cells detect and respond to T. gondii. Here, we show that primary monocytes and dendritic cells from peripheral blood of healthy donors produce IL-12 and other proinflammatory cytokines when exposed to toxoplasma tachyzoites. Cell fractionation studies determined that IL-12 and TNFα secretion is limited to CD16+ monocytes and the CD1c+ subset of dendritic cells. In direct contrast to their murine counterparts, human myeloid cells fail to respond to soluble tachyzoite extracts and instead require contact with live parasites. Importantly, we found that tachyzoite phagocytosis, but not host cell invasion, is required for cytokine induction. Together these findings identify CD16+ monocytes and CD1c+ dendritic cells as the major myeloid subsets in human blood producing innate cytokines in response to T. gondii and demonstrate an unappreciated requirement for phagocytosis of live parasites in that process. This form of pathogen sensing is distinct from that utilized by mice, possibly reflecting a direct involvement of rodents and not humans in the parasite life cycle.

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Section: Discussionmentioning

confidence: 99%

The IL-12 Response of Primary Human Dendritic Cells and Monocytes to Toxoplasma gondii Is Stimulated by Phagocytosis of Live Parasites Rather Than Host Cell Invasion

Tosh

Mittereder

Bonne-Année

et al. 2016

The Journal of Immunology

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“…Expression of TLR5 occurs in intestinal epithelial cells, mainly at the basolateral surface; it recognizes invading flagellated pathogenic bacteria by identifying a protein called flagellin [33]. The amino acid sequence of TLR5 appears to be similar to those of TLR11 and TLR12 [115]; the latter two TLRs form a complex and recognize profilin-like proteins in Toxoplasma gondii (protozoan parasite) [108]. Finally, TLR10 may sense ligands derived from within the host rather than from microbes [102].…”

Section: Tlr Ligandsmentioning

confidence: 99%

Activation of toll-like receptor signaling pathways leading to nitric oxide-mediated antiviral responses

2016

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Toll-like receptors (TLRs), well-characterized pattern-recognizing receptors of the innate arm of the immune system, are vital in detecting pathogen-associated molecular patterns (PAMPs). The TLR-PAMP interaction initiates an intracellular signaling cascade, predominantly culminating in upregulation of antiviral components, including inducible nitric oxide synthase (iNOS). After activation, various TLR pathways can promote iNOS production via the myeloid differentiation primary response-88 (MyD-88) adapter protein. Subsequently, iNOS facilitates production of nitric oxide (NO), a highly reactive and potent antiviral molecule that can inhibit replication of RNA and DNA viruses. Furthermore, NO can diffuse freely across cell membranes and elicit antiviral mechanisms in various ways, including direct and indirect damage to viral genomes. This review emphasizes current knowledge of NO-mediated antiviral responses elicited after activation of TLR signaling pathways.

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“…Moreover, we observed that direct parasite-host cell contact is critical for TNF and IL-12 induction. 42 These findings are at odds with a recent study by Salazar Gonzalez et al , 43 who showed that T. gondii profilin stimulates human monocytes to secrete IL-6 and IL-12 in a TLR5-dependent manner. The basis of this discrepancy is unclear but may relate to the purity of the profilin or cell populations employed by the two laboratories.…”

Section: The Response Of Human Myeloid Cells To T Gondii Requires Phmentioning

confidence: 86%

Innate recognition of Toxoplasma gondii in humans involves a mechanism distinct from that utilized by rodents

2016

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Toxoplasma gondii is an intracellular protozoan parasite that infects rodents as part of its natural transmission cycle and induces disease in humans, an end-stage host. As one of the natural hosts of T. gondii, the mouse has been used extensively for elucidating the cellular and molecular basis of immunity to this pathogen while relatively few studies have focused on the response of humans. In our recent work, we identified CD16+ monocytes and DC1 dendritic cells as the major myeloid cell populations that respond to T. gondii in human peripheral blood. Interestingly, these myeloid subsets represent the opposite counterparts from those triggered by the parasite in mice. Moreover, whereas the innate cytokine response to T. gondii in the mouse involves stimulation of Toll-like receptors by a soluble parasite ligand, the response of human cells instead requires phagocytosis of the live pathogen. We speculate that these marked distinctions in the pathways utilized for innate recognition of toxoplasma in mouse and man reflect the differing roles of the two hosts in the biology of this parasite.

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<b><i>Toxoplasma gondii-</i></b>Derived Profilin Triggers Human Toll-Like Receptor 5-Dependent Cytokine Production

Cited by 41 publications

References 31 publications

The IL-12 Response of Primary Human Dendritic Cells and Monocytes to Toxoplasma gondii Is Stimulated by Phagocytosis of Live Parasites Rather Than Host Cell Invasion

The IL-12 Response of Primary Human Dendritic Cells and Monocytes to Toxoplasma gondii Is Stimulated by Phagocytosis of Live Parasites Rather Than Host Cell Invasion

Activation of toll-like receptor signaling pathways leading to nitric oxide-mediated antiviral responses

Innate recognition of Toxoplasma gondii in humans involves a mechanism distinct from that utilized by rodents

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