Abstract
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 IFN-signalling during Plasmodium 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 IFN has not emerged. Although epidemiological data are consistent with roles for type I IFN in influencing malaria disease severity, functional proof of this remains sparse in humans. Several different rodent-infective Plasmodium species have been employed in in vivo 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 IFN-signalling in malaria. This is perhaps unsurprising given the multiple parasite-sensing pathways that can trigger type I IFN production, the multiple isoforms of IFN-α/β that can be produced by both immune and non-immune cells, the differential effects of acute versus chronic type I IFN production, the role of low level 'tonic' type I IFN-signalling, and that signalling can occur via homodimeric IFNAR1 or heterodimeric IFNAR1/2 receptors. Nevertheless, the data indicate that type I IFN-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 IFN can promote cytotoxic T lymphocyte immune pathology and hinder CD4(+) T helper cell-dependent immunity during blood-stage infection. Hence, type I IFN-signalling plays highly context-dependent roles in malaria, which can be beneficial or detrimental to the host.