Effects of type I interferons in malaria

Abstract

<p id="d403368e161">Type I interferons (IFNs) are a family of cytokines with a wide range of biological activities including anti‐viral and immune‐regulatory functions. Here, we focus on the protozoan parasitic disease malaria, and examine the effects of type I <span style="fixed-case">IFN</span>‐signalling during <i>Plasmodium</i> infection of humans and experimental mice. Since the 1960s, there have been many studies in this area, but a simple explanation for the role of type I <span style="fixed-case">IFN</span> has not emerged. Although epidemiological data are consistent with roles for type I <span style="fixed-case">IFN</span> in influencing malaria disease severity, functional proof of this remains sparse in humans. Several different rodent‐infective <i>Plasmodium</i> species have been employed in <i>in vivo</i> studies of parasite‐sensing, experimental cerebral malaria, lethal malaria, liver‐stage infection, and adaptive T‐cell and B‐cell immunity. A range of different outcomes in these studies suggests a delicately balanced, multi‐faceted and highly complex role for type I <span style="fixed-case">IFN</span>‐signalling in malaria. This is perhaps unsurprising given the multiple parasite‐sensing pathways that can trigger type I <span style="fixed-case">IFN</span> production, the multiple isoforms of <span style="fixed-case">IFN</span>‐ <i>α</i>/ <i>β</i> that can be produced by both immune and non‐immune cells, the differential effects of acute versus chronic type I <span style="fixed-case">IFN</span> production, the role of low level ‘tonic’ type I <span style="fixed-case">IFN</span>‐signalling, and that signalling can occur via homodimeric <span style="fixed-case">IFNAR</span>1 or heterodimeric <span style="fixed-case">IFNAR</span>1/2 receptors. Nevertheless, the data indicate that type I <span style="fixed-case">IFN</span>‐signalling controls parasite numbers during liver‐stage infection, and depending on host–parasite genetics, can be either detrimental or beneficial to the host during blood‐stage infection. Furthermore, type I <span style="fixed-case">IFN</span> can promote cytotoxic T lymphocyte immune pathology and hinder <span style="fixed-case">CD</span>4 ⁺ T helper cell‐dependent immunity during blood‐stage infection. Hence, type I <span style="fixed-case">IFN</span>‐signalling plays highly context‐dependent roles in malaria, which can be beneficial or detrimental to the host. </p>