Effects of type I interferons in malaria

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.

Keywords: cytokines; interferons; malaria; mouse models; parasitology.

Figure 1

Effects of Type I interferon (IFN) during liver‐stage and blood‐stage Plasmodium infection. Liver‐stage of infection: parasite RNA is sensed partly via melanoma differentiation‐associated protein 5 (MDA5) and mitochondrial antiviral signalling protein (MAVS) in the cytosol of hepatocytes, triggering a type I IFN response dependent on IFN regulatory factor 3 (IRF3). This promotes anti‐parasitic immune responses that require involvement from monocytes and IFN‐γ‐producing natural killer T (NKT) cells. Blood‐stage of infection: Type I IFN can be produced by multiple myeloid cells including plasmacytoid dendritic cells (pDC) in the bone marrow, blood and spleen, and splenic conventional dendritic cells (cDC). This can impact on other myeloid cells, such as activating neutrophils to promote liver damage, or to suppress monocyte up‐regulation of major histocompatibility complex class II (MHCII) or interleukin‐6 (IL‐6) expression. Type I IFN can directly impede cDC from activating T helper type 1 (Th1) and follicular T helper (Tfh) differentiation in CD4⁺ T cells, with downstream negative impacts on cellular and antibody immunity. Type I IFN can also act directly on CD4⁺ T cells in the spleen to drive IL‐10 production by Type 1 regulatory (Tr1) cells. Finally, Type I IFN plays a major role in licensing cytotoxic T lymphocyte (CTL)‐mediated immune‐pathology in the brain during experimental cerebral malaria, via direct signalling to CD8⁺ T cells.