Suppression of Plasmodium MIF-CD74 signaling protects against severe malaria

Garcia, A.B.; Siu, E.; Leng, L.; Franke-Fayard, B.; Janse, C.J.; Howland, S.W.; Renia, L.; Lolis, E.; Bucala, R.

doi:doi:10.1096/fj.202101072R

The deadliest complication of infection by Plasmodium parasites, cerebral malaria, accounts for the majority of malarial fatalities. Although our understanding of the cellular and molecular mechanisms underlying the pathology remains incomplete, recent studies support the contribution of systemic and neuroinflammation as the cause of cerebral edema and blood-brain barrier (BBB) dysfunction. All Plasmodium species encode an orthologue of the innate cytokine, Macrophage Migration Inhibitory Factor (MIF), which functions in mammalian biology to regulate innate responses. Plasmodium MIF (PMIF) similarly signals through the host MIF receptor CD74, leading to an enhanced inflammatory response. We investigated the PMIF-CD74 interaction in the onset of experimental cerebral malaria (ECM) and liver stage Plasmodium development by using a combination of CD74 deficient (Cd74(-/-)) hosts and PMIF deficient parasites. Cd74(-/-) mice were found to be protected from ECM and the protection was...Show moreThe deadliest complication of infection by Plasmodium parasites, cerebral malaria, accounts for the majority of malarial fatalities. Although our understanding of the cellular and molecular mechanisms underlying the pathology remains incomplete, recent studies support the contribution of systemic and neuroinflammation as the cause of cerebral edema and blood-brain barrier (BBB) dysfunction. All Plasmodium species encode an orthologue of the innate cytokine, Macrophage Migration Inhibitory Factor (MIF), which functions in mammalian biology to regulate innate responses. Plasmodium MIF (PMIF) similarly signals through the host MIF receptor CD74, leading to an enhanced inflammatory response. We investigated the PMIF-CD74 interaction in the onset of experimental cerebral malaria (ECM) and liver stage Plasmodium development by using a combination of CD74 deficient (Cd74(-/-)) hosts and PMIF deficient parasites. Cd74(-/-) mice were found to be protected from ECM and the protection was associated with the inability of brain microvessels to present parasite antigen to sequestered and pathogenic Plasmodium-specific CD8(+) T cells. Infection of WT hosts with PMIF-deficient sporozoites or infection of Cd74(-/-) hosts with WT sporozoites impacted the survival of infected hepatocytes and subsequently reduced blood-stage associated inflammation, contributing to protection from ECM. We recapitulated these finding with a novel pharmacologic PMIF-selective antagonist that reduced PMIF/CD74 signaling 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.Show less

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Suppression of Plasmodium MIF-CD74 signaling protects against severe malaria