Abstract
Pathogens are thought to use host molecular cues to control when to initiate life-cycle transitions, but these signals are mostly unknown, particularly for the parasitic disease malaria caused by Plasmodium falciparum. The chemokine CXCL10 is present at high levels in fatal cases of cerebral malaria patients, but is reduced in patients who survive and do not have complications. Here we show a Pf ‘decision-sensing-system’ controlled by CXCL10 concentration. High CXCL10 expression prompts P. falciparum to initiate a survival strategy via growth acceleration. Remarkably, P. falciparum inhibits CXCL10 synthesis in monocytes by disrupting the association of host ribosomes with CXCL10 transcripts. The underlying inhibition cascade involves RNA cargo delivery into monocytes that triggers RIG-I, which leads to HUR1 binding to an AU-rich domain of the CXCL10 3’UTR. These data indicate that when the parasite can no longer keep CXCL10 at low levels, it can exploit the chemokine as a cue to shift tactics and escape.
Highlights
Pathogens are thought to use host molecular cues to control when to initiate life-cycle transitions, but these signals are mostly unknown, for the parasitic disease malaria caused by Plasmodium falciparum
We verified the absence of the protein within the cells using an ELISA assay for the cell protein extract (Fig. 1D). These results indicate that parasitic extracellular vesicles (EVs) do not affect CXCL10 secretion, but rather abolish its expression within the cells, a lack-of-CXCL10-expression feature similar to the nontreated monocytes
Even introducing cells pretreated with P. falciparum (Pf)-derived EVs to the stimulating poly(dA:dT) cells starkly reduced the cellular level of CXCL10, as observed by both western blot (Fig. 1E) and ELISA (Fig. 1F) analyses
Summary
Pathogens are thought to use host molecular cues to control when to initiate life-cycle transitions, but these signals are mostly unknown, for the parasitic disease malaria caused by Plasmodium falciparum. The underlying inhibition cascade involves RNA cargo delivery into monocytes that triggers RIG-I, which leads to HUR1 binding to an AU-rich domain of the CXCL10 3’UTR These data indicate that when the parasite can no longer keep CXCL10 at low levels, it can exploit the chemokine as a cue to shift tactics and escape. CXCL10 is a ~10-kDa inflammatory chemokine that binds to CXCR3 (G protein-coupled receptor 9 (GPR9), CD183) to mediate immune responses through the activation and recruitment of leukocytes, such as T cells and NK cells[9] It is induced by IFN-γ and TNF and secreted by various cell types, such as monocytes and neutrophils[10]. CXCL10 neutralization or genetic deletion in a malaria mice model alleviates brain intravascular inflammation and protects Plasmodium berghei ANKA-infected mice from CM13 While these studies point to CXCL10 as an attractive therapeutic target, the molecular mechanism underpinning CXCL10’s involvement in malaria is yet to be determined
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