Innate Immune Recognition of an AT-Rich Stem-Loop DNA Motif in the Plasmodium falciparum Genome

Abstract

SUMMARY Although Toll-like receptor 9 (TLR9) has been implicated in regulating cytokine and type I interferon (IFN) production during malaria in humans and mice, the high AT content of the Plasmodium falciparum genome prompted us to examine the possibility that malarial DNA triggered TLR9-independent DNA sensing pathways. Over 6000 ATTTTTAC (“AT-rich”) motifs are present in the genome of P. falciparum, which we show here potently induce type I IFNs. Parasite DNA, parasitized erythrocytes and oligonucleotides containing the AT-r motif induce type I IFNs via a pathway that did not involve previously described sensors including TLR9, DAI, RNA polymerase-III or IFI16/p204. Rather, AT-rich DNA sensing involved an unknown receptor that coupled to STING, TBK1 and IRF3-IRF7 signaling pathway. Mice lacking both IRF3 and IRF7, the kinase TBK1 or the type I IFN receptor were resistant to otherwise lethal cerebral malaria. Collectively, these observations implicate AT-rich DNA sensing via STING, TBK1 and IRF3-IRF7 in P. falciparum malaria.

Suppression of systemic autoimmunity by the innate immune adaptor STING

“…Furthermore, IRF3 deficiency does not affect the disease course of MRL/lpr, and therefore it is likely that a STING-dependent but IRF3-independent pathway mediates the effects we observed. Intriguingly, some evidence exists for the role of IRF3/7 heterodimers in inducing type I IFNs downstream of STING (37). However, a definitive role for IRF7 has not yet been evaluated in lupus and may contribute to lupus pathology downstream of both STING and TLRs.…”

Acute Plasmodium chabaudi Infection Dampens Humoral Responses to a Secondary T-Dependent Antigen but Enhances Responses to a Secondary T-Independent Antigen

“…Interestingly, type I IFN previously has been shown to skew follicular B cell Ab responses against TI-2 Ags toward an IgG2c isotype (48). Type I IFN is produced during Plasmodium infection (49) and permits B cells to become responsive to IL-12 and become B effector 1 (Be1) cells (50). Sustained expression of IFN-g and T-bet by Be1 cells is maintained through a signaling loop involving dendritic cells (DCs) producing IL-12 and IL-18 leading to expression of IFN-g by Th1 cells and B cells (23,51).…”

Interfering with Immunity: Detrimental Role of Type I IFNs during Infection

“…Multiple innate-sensing pathways were shown to mediate type I IFN induction by the parasite. In addition to TLR7/TLR9-dependent mechanisms (160,161), type I IFNs can be induced in a STING, TBK1, IRF3/IRF7-dependent manner via AT-rich stem-loop DNA (162). P. berghei-derived RNA also can trigger IFN-b production in a melanoma differentiation-associated protein 5/MAVS-dependent manner (163).…”

“…Type I IFNs were shown to mediate protection against blood-stage (164) and liver-stage (163,165) malaria in infected animals. However, recent studies revealed that type I IFNs increase host susceptibility to cerebral malaria (162,166).…”