Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria

Abstract

Excessive release of proinflammatory cytokines by innate immune cells is an important component of the pathogenic basis of malaria. Proinflammatory cytokines are a direct output of Toll-like receptor (TLR) activation during microbial infection. Thus, interference with TLR function is likely to render a better clinical outcome by preventing their aberrant activation and the excessive release of inflammatory mediators. Herein, we describe the protective effect and mechanism of action of E6446, a synthetic antagonist of nucleic acid-sensing TLRs, on experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA. We show that in vitro, low doses of E6446 specifically inhibited the activation of human and mouse TLR9. Tenfold higher concentrations of this compound also inhibited the human TLR8 response to single-stranded RNA. In vivo, therapy with E6446 diminished the activation of TLR9 and prevented the exacerbated cytokine response observed during acute Plasmodium infection. Furthermore, severe signs of ECM, such as limb paralysis, brain vascular leak, and death, were all prevented by oral treatment with E6446. Hence, we provide evidence that supports the involvement of nucleic acid-sensing TLRs in malaria pathogenesis and that interference with the activation of these receptors is a promising strategy to prevent deleterious inflammatory responses that mediate pathogenesis and severity of malaria.immunotherapy | innate immunity | nucleic acid recognition | inflammation

Effect of malaria components on blood mononuclear cells involved in immune response

“…In addition, previous investigations studying immune response of malaria infection demonstrated that TLR1, TLR2, and TLR4 were induced in PBMCs from both experimentally and naturally acquired malaria infections [26,36] . These findings suggest that activation of TLRs by parasites such as GPIs and hemozoin transmits signals by intracellular pathway [25,37] , leading to activation of transcription factor NF-κB, which in turn propagates signals to the nucleus to regulate the expression of pro-inflammatory cytokines [26] .…”

New approaches in antimalarial drug discovery and development: a review

“…Evidence supports the role of type 1 pro-inflammatory cytokines that increase the expression of adhesion molecules on vascular endothelium and iRBC sequestration (Schofield & Grau 2005). Experimental data demonstrate that E6446, a synthetic antagonist of nucleic acid-sensing tool-like receptors (TLRs), diminishes the activation of TLR9 and prevents the increased production of cytokines in response to Plasmodium infections, consequently preventing severe malaria symptoms (Franklin et al 2011).…”

The role of Vitamin D in malaria

“…Malaria hemozoin is immunologically inert but radically enhances innate responses by activating TLR-9 [33][34]. Therapy with a synthetic antagonist of nucleic acid-sensing TLRs (E6446) diminishes the activation of human and mouse TLR-9 and prevents the exacerbated cytokine response observed during acute Plasmodium infection [35]. TLR-1 variants are involved in the recognition of P. falciparum and are both susceptible to and a manifestation of malaria in pregnancy [36].…”