Malaria parasites modulate the Type-1 interferon response by inhibiting CXCL10 translation

The way pathogens evade the human innate immune system remains unknown, thus limiting our ability to cure infectious diseases. This is indeed the case when it comes to the malaria parasites Plasmodium falciparum (Pf), the instigators of malaria, one of the most devastating infectious diseases in humans. We previously revealed a mechanism of Pf DNA-dependent sensing that malaria parasites employ from a distance while growing within Red Blood Cells (RBCs). Our results show that malaria parasites secrete extracellular vesicles (EVs) containing parasitic small RNA molecules and, remarkably, parasitic genomic DNA. Upon internalization of these vesicles by human monocytes, the Pf DNA is released within the host cytosol, leading to STING-dependent DNA sensing and activation of Type-1 interferon-related genes. Here, we surprisingly found that the secretion of one of these chemokines, CXCL10, becomes impaired upon internalization of malaria EVs into monocytes. CXCL10 is known to be involved in T cell and NK cell activation and is present at high levels in the circulation of severe cerebral malaria patients. While CXCL10 mRNA levels gradually increase in the recipient cells upon internalization of malaria-derived EVs, we were not able to detect the secreted chemokine, as opposed to the rest of the Type-1-assoasiated chemokines. Further molecular investigation revealed that the parasitic EVs specifically inhibit CXCL10 translation within monocytes. We found that the RNA cargo is involved in the translation inhibition via RIG-I activation. Our results demonstrate the ability of the malaria parasites to shape the immune response while growing at a distance, inside RBCs.