Human TLR8 Senses RNA From Plasmodium falciparum-Infected Red Blood Cells Which Is Uniquely Required for the IFN-γ Response in NK Cells

Abstract

During blood-stage malaria, the innate immune system initiates the production of pro-inflammatory cytokines, including IFN-γ, that are critical to host defense and responsible for severe disease. Nonetheless, the innate immune pathways activated during this process in human malaria remain poorly understood. Here, we identify TLR8 as an essential sensor of Plasmodium falciparum -infected red blood cells (iRBC). In human immune cells, iRBC and RNA purified from iRBC were detected by TLR8 but not TLR7 leading to IFN-γ induction in NK cells. While TLR7 and 9 have been shown to lead to IFN-γ in mice, our data demonstrate that TLR8 was the only TLR capable of inducing IFN-γ release in human immune cells. This unique capacity was mediated by the release of IL-12p70 and bioactive IL-18 from monocytes, the latter via a hitherto undescribed pathway. Altogether, our data are the first reported activation of TLR8 by protozoan RNA and demonstrate both the critical role of TLR8 in human blood-stage malaria and its unique functionality in the human immune system. Moreover, our study offers important evidence that mouse models alone may not be sufficient to describe the human innate immune response to malaria.

Activation of Human γδ T Cells: Modulation by Toll-Like Receptor 8 Ligands and Role of Monocytes

“…Ligands for some TLRs like TLR2 (di-or triacetylated lipopeptides) and TLR4 (lipopolysaccharide, LPS) prime monocytes for IL-1β production (i.e., induce pro-IL-1β); however, IL-1β secretion requires additional inflammasome activation, e.g., by the bacterial toxin nigericin [17]. In contrast, IL-1β (and TNF-α) secretion can be stimulated by TLR8 ligands in human monocytes also in a caspase-1 independent pathway [19,20]. Importantly, inflammasome activation in monocytes triggers pyroptosis, a highly inflammatory form of programmed cell death [21].…”

Immune Sensing Mechanisms that Discriminate Self from Altered Self and Foreign Nucleic Acids

“…However, this TLR8-TLR13 equivalency only applies to pathogens containing the TLR13 consensus sequence. TLR8 also senses plasmodia RNA in humans, ( Coch et al., 2019 ), which activates TLR7, not TLR13 in mice. Indeed, how TLR8 senses non-self RNA is an unresolved question.…”

Targeting the innate immune receptor TLR8 using small-molecule agents

“…Meanwhile, the relationship between TLR8 and autoimmune diseases has received considerable attention (Farrugia & Baron, 2017), with well known examples including systemic lupus erythematosus (Devarapu & Anders, 2018) and rheumatoid arthritis (Elshabrawy et al, 2017). Since TLR8 (and TLR7) senses and responds to various kinds of RNA viruses (Marcken et al, 2019;Coch et al, 2019), TLR8 deficiency has been proposed to cause viral infections; however, it has been reported that TLR8 deletion accelerates autoimmunity in mice (Tran et al, 2015).…”