Mediators of Inflammation / 2014 / Article / Tab 2

Review Article

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.

LigandSignalling molecules involvedCell types/miceImmune responses/functionsRef.

GPITLR1-TLR2 heterodimerBMDM, PBMC Stimulates production of TNF- , IL-12, IL-6, and NO[99]
TLR2/TLR1, TLR4, MyD88, ERK1/2, p38, JNK1/2, NF- B, AP-1 (c-Jun, ATF-2)BMDM, PBMC, HEK, MPM[62, 100, 101]
MAPK2BMDMStimulates production of TNF-
Controls production of IL-12
IκB- BMDMInvolved in IL-12 expression[103]

Hz (Pf 3D7)/
synthetic Hz
TLR9, MyD88 Murine splenocytes, BMDDCStimulates production of TNF- , IL-12p40, MCP-1, and IL-6 [104]
Knockout C57BL/6 or 129/Ola x C57BL/6Increases serum level of MCP-1 and IL-6
TLR2, TLR9, MyD88Knockout C57BL/6Involved in ECM development
Promotes parasite and leukocyte sequestration in brain sections
Stimulates production of IFN- , TNF- , and IL-12p40

Malarial CpG DNA
(Pf 3D7)
TLR9, MyD88BMDDCStimulates production of IL-12p40 and Rantes[105]

Host fibrinogenTLR4, CD11b/CD18-integrinPBMCStimulates release of ROS, TNF, and MCP-1[106]

HemeTLR4, CD14, MyD88, I B- , ERK1/2, NF- BMPM, BMDDC, human monocyte-derived macrophages, PBMCStimulates production of TNF- and KC
Controls release of PGE2
[107, 108]

MPs from infected mouseTLR4, MyD88BMDMUpregulate expression of CD40
Stimulate production of TNF

Malarial AT-rich motifSTING, TBK1, IRF-3, IRF-7BMDM, HEK293, knockout C57BL/6Involved in ECM development
Stimulates production of IFN-I, TNF- , IL-6, and IL-15

Plasmodium DNA/RNAMDA5, MAVS, RIG-1, CD14/IL-1R, p38Knockout C57BL/6, RAW264.7Stimulates production of IFN-I
Controls parasitemia
Prevents parasite sequestration in the brain capillaries and apoptosis in the spleen
Promotes phagocytosis activity of macrophages

Unknown in PbA infectionTLR2/4, MyD88Knockout C57BL/6Involved in ECM development initiated with sporozoites
Partially involved in ECM development initiated with iRBCs
Regulates production of IFN- , MCP-1, TNF- , and IL-10

Unknown ligand in Py 17XNL infectionTLR9, MyD88Knockout C57BL/6Controls parasitemia and promotes survival
Essential Th1 development and cell-mediated immunity
Stimulates production of TNF- and IL-12 by DC
Controls production of IL-10 and IL-4 by DC
Induces cytotoxic activity in NK and CD8+ T cells

UnknownTLR7, TLR9NK cells, T cells, CD4+ T cells TLR7 mediates IFN- production by NK cells 24 h after infection
TLR7 stimulates production of IFN-I, IFN- , IL-10, and IL-12
TLR9 mediates IFN- production by CD4+ cells and stimulates production of TNF 6 days after infection

Plasmodium RNAMDA5, MAVS, IRF-3, IRF-7Knockout C57BL/6J, BMDDC, MPHStimulates production of IFN-I
Controls leukocyte recruitment which limits parasite growth in the liver and induction of erythrocytic stage infection

PfTyrRsUnknownMouse splenocytes, PBMC, RAW 264.7, THP-1 Stimulates production of TNF- , IL-6, IL-1 , and IL-1 which upregulate expression of ICAM-1 and VCAM-1 receptors[111]

PfHMGBUnknownMouse splenocytes, RAW 264.7Stimulates production of TNF- , IL-6, IL-8, and IL-1 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.