Interferons and Interferon Regulatory Factors in Malaria

Table 2

List of malarial ligands that stimulate different signaling molecules to trigger diverse immune responses and affect disease outcome in various experimental models.

Ligand	Signalling molecules involved	Cell types/mice	Immune responses/functions	Ref.
GPI	TLR1-TLR2 heterodimer	BMDM, PBMC	Stimulates production of TNF-𝛼, IL-12, IL-6, and NO	[99]
	TLR2/TLR1, TLR4, MyD88, ERK1/2, p38, JNK1/2, NF-𝜅B, AP-1 (c-Jun, ATF-2)	BMDM, PBMC, HEK, MPM		[62, 100, 101]
	MAPK2	BMDM	Stimulates production of TNF-𝛼; Controls production of IL-12	[102]
	IκB-𝜁	BMDM	Involved in IL-12 expression	[103]
Hz (Pf 3D7)/; synthetic Hz	TLR9, MyD88	Murine splenocytes, BMDDC	Stimulates production of TNF-𝛼, IL-12p40, MCP-1, and IL-6	[104]
		Knockout C57BL/6 or 129/Ola x C57BL/6	Increases serum level of MCP-1 and IL-6
	TLR2, TLR9, MyD88	Knockout C57BL/6	Involved in ECM development; Promotes parasite and leukocyte sequestration in brain sections; Stimulates production of IFN-𝛾, TNF-𝛼, and IL-12p40	[63]
Malarial CpG DNA; (Pf 3D7)	TLR9, MyD88	BMDDC	Stimulates production of IL-12p40 and Rantes	[105]
Host fibrinogen	TLR4, CD11b/CD18-integrin	PBMC	Stimulates release of ROS, TNF, and MCP-1	[106]
Heme	TLR4, CD14, MyD88, I𝜅B-𝛼, ERK1/2, NF-𝜅B	MPM, BMDDC, human monocyte-derived macrophages, PBMC	Stimulates production of TNF-𝛼 and KC; Controls release of PGE2	[107, 108]
MPs from infected mouse	TLR4, MyD88	BMDM	Upregulate expression of CD40; Stimulate production of TNF	[109]
Malarial AT-rich motif	STING, TBK1, IRF-3, IRF-7	BMDM, HEK293, knockout C57BL/6	Involved in ECM development; Stimulates production of IFN-I, TNF-𝛼, IL-6, and IL-15	[61]
Plasmodium DNA/RNA	MDA5, MAVS, RIG-1, CD14/IL-1R, p38	Knockout C57BL/6, RAW264.7	Stimulates production of IFN-I; Controls parasitemia; Prevents parasite sequestration in the brain capillaries and apoptosis in the spleen; Promotes phagocytosis activity of macrophages	[85]
Unknown in PbA infection	TLR2/4, MyD88	Knockout C57BL/6	Involved in ECM development initiated with sporozoites; Partially involved in ECM development initiated with iRBCs; Regulates production of IFN-𝛾, MCP-1, TNF-𝛼, and IL-10	[80]
Unknown ligand in Py 17XNL infection	TLR9, MyD88	Knockout C57BL/6	Controls parasitemia and promotes survival; Essential Th1 development and cell-mediated immunity; Stimulates production of TNF-𝛼 and IL-12 by DC; Controls production of IL-10 and IL-4 by DC; Induces cytotoxic activity in NK and CD8^+ T cells	[86]
Unknown	TLR7, TLR9	NK cells, 𝛾𝛿 T cells, CD4^+ T cells	TLR7 mediates IFN-𝛾 production by NK cells 24 h after infection; TLR7 stimulates production of IFN-I, IFN-𝛾, IL-10, and IL-12; TLR9 mediates IFN-𝛾 production by CD4^+ cells and stimulates production of TNF 6 days after infection	[110]
Plasmodium RNA	MDA5, MAVS, IRF-3, IRF-7	Knockout C57BL/6J, BMDDC, MPH	Stimulates production of IFN-I; Controls leukocyte recruitment which limits parasite growth in the liver and induction of erythrocytic stage infection	[92]
PfTyrRs	Unknown	Mouse splenocytes, PBMC, RAW 264.7, THP-1	Stimulates production of TNF-𝛼, IL-6, IL-1𝛼, and IL-1𝛽 which upregulate expression of ICAM-1 and VCAM-1 receptors	[111]
PfHMGB	Unknown	Mouse splenocytes, RAW 264.7	Stimulates production of TNF-𝛼, IL-6, IL-8, and IL-1𝛽 and upregulates mRNA expression of iNOS	[112]

BMDM: mouse bone marrow-derived macrophages (C57BL/6 unless otherwise stated); BMDDC: mouse bone marrow-derived dendritic cells; PBMC: human peripheral blood mononuclear cells; HEK: human embryonic kidney epithelial cells; Hz: Hemozoin; iNOS: inducible nitric oxide synthetase; KC: keratinocyte chemokine; MCP-1: monocyte chemoattractant protein-1; MP: microparticles; MPH: mouse primary hepatocytes; MPM: murine peritoneal macrophages; PGE₂: prostaglandin E2; PfTyrRS: P. falciparum tyrosyl-tRNA synthetase; PfHMGB: P. falciparum high mobility group box protein; RAW264.7: murine macrophage-like cell line; ROS: reactive oxide species; THP-1: human monocytic leukemia cell line.