Suppression of Plasmodium MIF-CD74 Signaling Protects Against Severe Malaria [article]

Alvaro Baeza Garcia, Edwin Siu, Xin Du, Lin Leng, Blandine Franke-Fayard, Chris J Janse, Shanshan W Howland, Laurent Rénia, Elias Lolis, Richard Bucala
2021 bioRxiv   pre-print
AbstractMalaria begins when mosquito-borne Plasmodium sporozoites invade hepatocytes and usurp host pathways to support the differentiation and multiplication of erythrocyte-infective, merozoite progeny. All Plasmodium species encode an orthologue of the innate cytokine, Macrophage Migration Inhibitory Factor (MIF), which functions in mammalian biology to regulate innate responses. Using a genetically-targeted strain of Plasmodium berghei, we demonstrate that the Plasmodium MIF orthologue,
more » ... IF orthologue, PMIF, activates the cognate host MIF receptor, CD74, to inhibit the host-protective apoptosis response of infected hepatocytes and sustain Plasmodium development and replication. Infection of CD74 deficient (Cd74−/−) mice revealed a significantly reduced liver burden of Plasmodium parasites compared with WT mice and protection from experimental cerebral malaria (ECM) development. Protection from ECM additionally was associated with the inability of Cd74−/− brain microvessel endothelial cells to present parasite antigen to sequestered, Plasmodium-specific CD8+ T cells. A novel pharmacologic PMIF-selective antagonist reduced PMIF/CD74 signaling and liver-stage parasite burden, and fully protected mice from ECM. These findings reveal a conserved mechanism for Plasmodium usurpation of host CD74 signaling and suggest a tractable approach for new pharmacologic intervention.
doi:10.1101/2021.02.14.430970 fatcat:zo7pflqgnneldlppuec6ey566e