Toll-like receptor 9 mediates innate immune activation by the malaria pigment hemozoin

Malaria parasites within red blood cells digest host hemoglobin into a hydrophobic heme polymer, known as hemozoin (HZ), which is subsequently released into the blood stream and then captured by and concentrated in the reticulo-endothelial system. Accumulating evidence suggests that HZ is immunologically active, but the molecular mechanism(s) through which HZ modulates the innate immune system has not been elucidated. This work demonstrates that HZ purified from Plasmodium falciparum is a novel non-DNA ligand for Toll-like receptor (TLR)9. HZ activated innate immune responses in vivo and in vitro, resulting in the production of cytokines, chemokines, and up-regulation of costimulatory molecules. Such responses were severely impaired in TLR9−/− and myeloid differentiation factor 88 (MyD88)−/−, but not in TLR2, TLR4, TLR7, or Toll/interleukin 1 receptor domain–containing adaptor-inducing interferon β−/− mice. Synthetic HZ, which is free of the other contaminants, also activated innate immune responses in vivo in a TLR9-dependent manner. Chloroquine (CQ), an antimalarial drug, abrogated HZ-induced cytokine production. These data suggest that TLR9-mediated, MyD88-dependent, and CQ-sensitive innate immune activation by HZ may play an important role in malaria parasite–host interactions

Colombes, 26/4/25, équipe [de football] du FC Rouen : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 100280Appartient à l’ensemble documentaire : Pho20RolAppartient à l’ensemble documentaire : HNormand1Image de press

Phase 1b Randomized Trial and Follow-Up Study in Uganda of the Blood-Stage Malaria Vaccine Candidate BK-SE36

<div><p>Background</p><p>Up to now a malaria vaccine remains elusive. The <i>Plasmodium falciparum</i> serine repeat antigen-5 formulated with aluminum hydroxyl gel (BK-SE36) is a blood-stage malaria vaccine candidate that has undergone phase 1a trial in malaria-naive Japanese adults. We have now assessed the safety and immunogenicity of BK-SE36 in a malaria endemic area in Northern Uganda.</p><p>Methods</p><p>We performed a two-stage, randomized, single-blinded, placebo-controlled phase 1b trial (Current Controlled trials ISRCTN71619711). A computer-generated sequence randomized healthy subjects for 2 subcutaneous injections at 21-day intervals in Stage1 (21–40 year-olds) to 1-mL BK-SE36 (<i>BKSE1.0</i>) (<i>n</i> = 36) or saline (<i>n</i> = 20) and in Stage2 (6–20 year-olds) to <i>BKSE1.0</i> (<i>n</i> = 33), 0.5-mL BK-SE36 (<i>BKSE0.5</i>) (<i>n</i> = 33), or saline (<i>n</i> = 18). Subjects and laboratory personnel were blinded. Safety and antibody responses 21-days post-second vaccination (Day42) were assessed. Post-trial, to compare the risk of malaria episodes 130–365 days post-second vaccination, Stage2 subjects were age-matched to 50 control individuals.</p><p>Results</p><p>Nearly all subjects who received BK-SE36 had induration (Stage1, <i>n</i> = 33, 92%; Stage2, <i>n</i> = 63, 96%) as a local adverse event. No serious adverse event related to BK-SE36 was reported. Pre-existing anti-SE36 antibody titers negatively correlated with vaccination-induced antibody response. At Day42, change in antibody titers was significant for seronegative adults (1.95-fold higher than baseline [95% CI, 1.56–2.43], <i>p</i> = 0.004) and 6–10 year-olds (5.71-fold [95% CI, 2.38–13.72], <i>p</i> = 0.002) vaccinated with <i>BKSE1.0.</i> Immunogenicity response to <i>BKSE0.5</i> was low and not significant (1.55-fold [95% CI, 1.24–1.94], <i>p</i> = 0.75). In the ancillary analysis, cumulative incidence of first malaria episodes with ≥5000 parasites/µL was 7 cases/33 subjects in <i>BKSE1.0</i> and 10 cases/33 subjects in <i>BKSE0.5 vs.</i> 29 cases/66 subjects in the control group. Risk ratio for <i>BKSE1.0</i> was 0.48 (95% CI, 0.24–0.98; <i>p</i> = 0.04).</p><p>Conclusion</p><p>BK-SE36 is safe and immunogenic. The promising potential of BK-SE36, observed in the follow-up study, warrants a double-blind phase 1/2b trial in children under 5 years.</p><p>Trial Registration</p><p>Controlled-Trials.com ISRCTN71619711 <a href="http://www.controlled-trials.com/ISRCTN71619711" target="_blank">ISRCTN71619711</a></p></div