Abstract
TLRs (Toll-like receptors) play an important role in the initiation of innate immune responses against invading microorganisms. Although several TLRs have been reported to be involved in the innate immune response against the blood-stage of malaria parasites, the role of TLRs in the development of the pre-erythrocytic stage is still largely unknown. Here, we found that sporozoite and its lysate could significantly activate the TLR2, and induce macrophages to release proinflammatory cytokines, including IL-6, MCP-1 and TNF-α, in a TLR2-dependent manner. Further studies showed that sporozoite and its lysate could be recognized by either TLR2 homodimers or TLR2/1 and TLR2/6 heterodimers, implicating the complexity of TLR2 agonist in sporozoite. Interestingly, the TLR2 signaling can significantly suppress the development of the pre-erythrocytic stage of Plasmodium yoelii, as both liver parasite load and subsequent parasitemia were significantly elevated in both TLR2- and MyD88-deficient mice. Additionally, the observed higher level of parasite burden in TLR2−/− mice was found to be closely associated with a reduction in proinflammatory cytokines in the liver. Therefore, we provide the first evidence that sporozoites can activate the TLR2 signaling, which in turn significantly inhibits the intrahepatic parasites. This may provide us with novel clues to design preventive anti-malaria therapies.
Highlights
TLRs (Toll-like receptors) are the main PRRs on myeloid cells and have an important role in detecting a variety of invading microorganisms and eliciting early innate immune responses
While TLR9 mediates the recognition of the CpG motif in bacterial DNA, TLR4 mediates the recognition of the LPS of Gram-negative bacteria, and TLR2 was involved in the recognition of a wide range of ligands through heterodimerization with TLR1 or TLR6, including lipopeptides[10], peptidoglycan[11], lipoteichoic acid[12], lipoarabinomannan[13] and zymosan[14]
Our reporter gene and macrophage-activation assays both demonstrated that sporozoites could activate TLR2 but not other tested TLRs
Summary
TLRs (Toll-like receptors) are the main PRRs (pattern recognition receptors) on myeloid cells and have an important role in detecting a variety of invading microorganisms and eliciting early innate immune responses. In the case of the malaria parasite, glycosylphosphatidylinositols (GPIs) of Plasmodium falciparum blood-stage were recognized by TLR2 and to some extent by TLR4 and were critical for the macrophages to generate proinflammatory cytokines[15,16]. We hypothesized that TLRs might be involved in the recognition of invading sporozoites and initiate innate immune responses against intrahepatic parasites. Our previous study showed that pre-treatment with individual TLR agonists could variously inhibit intrahepatic parasites through the upregulation of proinflammatory cytokines[20,21]. It is not known which TLRs are involved in the recognition of invading sporozoites and the suppression of pre-erythrocytic stage development during primary infection. We investigated its influence on the development of the pre-erythrocytic stage in vivo, and the underlying mechanism
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