Type I Interferons and Malaria: A Double-Edge Sword Against a Complex Parasitic Disease

Abstract

Type I interferons (IFN-Is) are important cytokines playing critical roles in various infections, autoimmune diseases, and cancer. Studies have also shown that IFN-Is exhibit ‘conflicting’ roles in malaria parasite infections. Malaria parasites have a complex life cycle with multiple developing stages in two hosts. Both the liver and blood stages of malaria parasites in a vertebrate host stimulate IFN-I responses. IFN-Is have been shown to inhibit liver and blood stage development, to suppress T cell activation and adaptive immune response, and to promote production of proinflammatory cytokines and chemokines in animal models. Different parasite species or strains trigger distinct IFN-I responses. For example, a Plasmodium yoelii strain can stimulate a strong IFN-I response during early infection, whereas its isogenetic strain does not. Host genetic background also greatly influences IFN-I production during malaria infections. Consequently, the effects of IFN-Is on parasitemia and disease symptoms are highly variable depending on the combination of parasite and host species or strains. Toll-like receptor (TLR) 7, TLR9, melanoma differentiation-associated protein 5 (MDA5), and cyclic GMP-AMP synthase (cGAS) coupled with stimulator of interferon genes (STING) are the major receptors for recognizing parasite nucleic acids (RNA/DNA) to trigger IFN-I responses. IFN-I levels in vivo are tightly regulated, and various novel molecules have been identified to regulate IFN-I responses during malaria infections. Here we review the major findings and progress in ligand recognition, signaling pathways, functions, and regulation of IFN-I responses during malaria infections.

Experimental Babesia rossi infection induces hemolytic, metabolic, and viral response pathways in the canine host

“…In the context of Plasmodium infection, parasite DNA and RNA have been shown to bind to receptors that activate downstream production of IFN-Is. For one, toll-like receptor 9 (TLR9) recognizes parasite DNA [ 89 , 90 ]. Cyclic GMP-AMP synthase (cGAS) also binds to parasite DNA in the cytoplasm and catalyzes the synthesis of cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), which acts as a second messenger to activate the downstream signal adaptor, stimulator of interferon genes (STING) [ 89 , 91 , 92 ].…”

“…For one, toll-like receptor 9 (TLR9) recognizes parasite DNA [ 89 , 90 ]. Cyclic GMP-AMP synthase (cGAS) also binds to parasite DNA in the cytoplasm and catalyzes the synthesis of cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), which acts as a second messenger to activate the downstream signal adaptor, stimulator of interferon genes (STING) [ 89 , 91 , 92 ]. Furthermore, major cytosolic receptor for sensing malaria parasite RNA is melanoma differentiation-associated protein 5 (MDA5) [ 92 , 93 ].…”

“…Furthermore, major cytosolic receptor for sensing malaria parasite RNA is melanoma differentiation-associated protein 5 (MDA5) [ 92 , 93 ]. Parasite RNA also possibly stimulates the retinoic acid-inducible gene I (RIG-I) pathway [ 94 ], though this has yet to be confirmed in vivo [ 89 ]. It is likely that Babesia parasite DNA and RNA similarly activate receptors that activate downstream production of IFN-Is.…”

“…It is likely that Babesia parasite DNA and RNA similarly activate receptors that activate downstream production of IFN-Is. Of note, it is possible that different sensors are activated by parasite DNA and RNA at different developmental stages, and IFN-I subtypes (IFN-α and IFN-β) have different biological and immunological roles in viral infections [ 89 ]. Future experiments will explore the mechanistic roles of IFN-Is in B. rossi infection.…”

Recent Advances in Understanding the Inflammatory Response in Malaria: A Review of the Dual Role of Cytokines

“…The protective effect occurs especially when the level increases early in the evolution of the infection. However, chronic high levels will often lead to immune suppression [47]. Levels of type I IFNs are influenced by processes such as ubiquitination, phosphorylation, and ADP-ribosylation of the molecules involved in type I IFN pathways.…”