TLR8 is activated by 5ʹ-methylthioinosine, a Plasmodium falciparum-derived intermediate of the purine salvage pathway

TLR8 is activated by 5ʹ-methylthioinosine, a Plasmodium falciparum-derived intermediate of the purine salvage pathway

The innate immune recognition of the malaria-causing pathogen Plasmodium falciparum (P. falciparum) is not fully explored. Here, we identify the nucleoside 5ʹ-methylthioinosine (MTI), a Plasmodium-specific intermediate of the purine salvage pathway, as a pathogen-derived Toll-like receptor 8 (TLR8)...

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Bibliographic Details
Published in:Cell reports (Cambridge) Vol. 39; no. 2; p. 110691
Main Authors: Köllisch, Gabriele, Solis, Francisco Venegas, Obermann, Hannah-Lena, Eckert, Jeannine, Müller, Thomas, Vierbuchen, Tim, Rickmeyer, Thomas, Muche, Simon, Przyborski, Jude M., Heine, Holger, Kaufmann, Andreas, Baumeister, Stefan, Lingelbach, Klaus, Bauer, Stefan
Format: Journal Article
Language:English
Published: United States Elsevier Inc 12-04-2022
Subjects:
5ʹ-methylthioadenosine
5ʹ-methylthioinosine
CU-CPT9a
Humans
immucillin
Malaria, Falciparum
Methylthioinosine - analogs & derivatives
monocytes
MTA
MTI
Nucleosides
PBMC
Plasmodium falciparum
Plasmodium falciparum - metabolism
Purine-Nucleoside Phosphorylase - metabolism
Purines
TLR8
Toll-Like Receptor 8 - metabolism
CP: Immunology
Plasmodium falciparum
monocytes
immucillin
MTI
CU-CPT9a
5ʹ-methylthioinosine
TLR8
MTA
PBMC
5ʹ-methylthioadenosine
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Summary:The innate immune recognition of the malaria-causing pathogen Plasmodium falciparum (P. falciparum) is not fully explored. Here, we identify the nucleoside 5ʹ-methylthioinosine (MTI), a Plasmodium-specific intermediate of the purine salvage pathway, as a pathogen-derived Toll-like receptor 8 (TLR8) agonist. Co-incubation of MTI with the TLR8 enhancer poly(dT) as well as synthetic or P. falciparum-derived RNA strongly increase its stimulatory activity. Of note, MTI generated from methylthioadenosine (MTA) by P. falciparum lysates activates TLR8 when MTI metabolism is inhibited by immucillin targeting the purine nucleoside phosphorylase (PfPNP). Importantly, P. falciparum-infected red blood cells incubated with MTI or cultivated with MTA and immucillin lead to TLR8-dependent interleukin-6 (IL-6) production in human monocytes. Our data demonstrate that the nucleoside MTI is a natural human TLR8 ligand with possible in vivo relevance for innate sensing of P. falciparum. [Display omitted] •Plasmodium falciparum-derived 5ʹ-methylthioinosine (MTI) activates Toll-like receptor 8•Co-incubation with GU-rich RNA increases MTI stimulatory activity•Plasmodium falciparum-derived MTI synergizes with RNA to stimulate human immune cells•Plasmodium falciparum-infected erythrocytes induce IL-6 in an MTI- and TLR8-dependent manner Köllisch et al. identify 5ʹ-methylthioinosine (MTI), a Plasmodium-derived metabolite of the purine salvage pathway, as Toll-like receptor 8 (TLR8) ligand. In vitro infection experiments with human PBMC and P. falciparum-infected red blood cells suggest that MTI serves as TLR8-dependent pathogen-associated molecular pattern (PAMP) for innate immune sensing.
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ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2022.110691