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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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| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Philipps-Universität Marburg
2023
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| Subjects: | |
| Online Access: | PDF Full Text |
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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. |
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| Item Description: | Gefördert durch den Open-Access-Publikationsfonds der UB Marburg. |
| Physical Description: | 18 Pages |
| DOI: | 10.1016/j.celrep.2022.110691 |