Abstract
BackgroundSeveral inflammatory molecules participate in the immune response to malaria. Interleukin (IL)-18 is an inflammatory cytokine activated by NLRP3 inflammasomes. In clinical falciparum malaria, with and without HIV co-infection, data on IL-18 and in particular on its binding protein, IL-18bp, is scarce.MethodsClinical data and blood samples were collected from adults in Mozambique with P. falciparum infection, with (n = 70) and without (n = 61) HIV co-infection, from HIV-infected patients with similar symptoms without malaria (n = 58) and from healthy controls (n = 52). In vitro studies were performed in endothelial cells using hemozoin crystals.Results(i) IL-18 and IL-18bp were markedly up-regulated during falciparum malaria with particular high levels in malaria patients co-infected with HIV and severe malaria disease. (ii) In the malaria group as a whole, both IL-18 and IL-18bp were positively correlated with disease severity, parasitemia, and endothelial cell activation as assessed by vWF in plasma. (iii) Whereas there was no change in IL-18 levels in malaria patients co-infected with HIV during follow-up, the patients with malaria only had slightly increased IL-18 levels. Further, the IL-18pb levels declined and thereby contributed to an increase in IL-18/IL-18bp ratio in all subgroups of malaria patients. (iv) IL-27, previously shown to be up-regulated in this malaria cohort, markedly induced a release of IL-18bp from endothelial cells in vitro, and notably, this presumably anti-inflammatory effect was counteracted by hemozoin.ConclusionsOur findings suggest that the IL-18 system could be an important mediator in the immune pathogenesis during falciparum malaria, potentially also representing a target for therapy.
Highlights
Plasmodium falciparum (P. falciparum) malaria is an important cause of morbidity and mortality in sub-Saharan Africa
IL‐18, IL‐18bp and their ratio in P. falciparum infection with and without HIV infection The patient population is described in Table 1, consisting of three groups of patients: (i) HIV-infected patients with similar symptoms as malaria patients but with negative test for P. falciparum infection (n = 58), (ii) malaria patients without HIV infection (n = 61) and (iii) malaria patients co-infected with HIV (n = 70)
Plasma levels of IL-18 binding protein (IL-18bp) showed a similar pattern as IL-18 with a marked increase in all the three patient groups compared to healthy controls with the highest levels in the malaria patients co-infected with HIV and severe disease (Fig. 1B)
Summary
Plasmodium falciparum (P. falciparum) malaria is an important cause of morbidity and mortality in sub-Saharan Africa. The interaction between the parasite and the immune system has been extensively examined both in Interleukin (IL)-18 is an inflammatory cytokine, activated by NLRP3 inflammasomes, and released from the cell promoting inflammatory responses (e.g., induction of interferon (IFN) γ release) in T cells and natural killer (NK) cells. Otterdal et al BMC Infect Dis (2021) 21:1073 by the IL-18 binding protein (IL-18bp) which acts as a soluble decoy receptor and circulates at > tenfold higher level than IL-18. Whereas IL-18 may have protective effects in various models of experimental malaria [5], high levels of IL-18 have been associated with disease severity in clinical P. falciparum infection [6,7,8]. Few studies, with a relative low number of patients, have examined circulating IL-18 levels in falciparum malaria [6,7,8]. With and without HIV coinfection, data on IL-18 and in particular on its binding protein, IL-18bp, is scarce
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