PT  - JOURNAL ARTICLE
AU  - Alvaro Baeza Garcia
AU  - Edwin Siu
AU  - Xin Du
AU  - Lin Leng
AU  - Blandine Franke-Fayard
AU  - Chris J Janse
AU  - Shanshan W Howland
AU  - Laurent Rénia
AU  - Elias Lolis
AU  - Richard Bucala
TI  - Suppression of <em>Plasmodium</em> MIF-CD74 Signaling Protects Against Severe Malaria
AID  - 10.1101/2021.02.14.430970
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.02.14.430970
4099  - http://biorxiv.org/content/early/2021/04/07/2021.02.14.430970.short
4100  - http://biorxiv.org/content/early/2021/04/07/2021.02.14.430970.full
AB  - Malaria begins when mosquito-borne Plasmodium sporozoites invade hepatocytes and usurp host pathways to support the differentiation and multiplication of erythrocyte-infective merozoite progeny. The deadliest complication of infection, 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) using CD74 deficient (Cd74−/−) mice, which were found to be protected from ECM. The protection was associated with the inability of brain microvessels from Cd74−/− hosts to present parasite antigen to sequestered Plasmodium-specific CD8+ T cells. Infection of mice with PMIF-deficient sporozoites (PbAmif-) also protected mice from ECM, highlighting the pivotal role of PMIF in the pre-erythrocytic stage of the infection. A novel pharmacologic PMIF-selective antagonist 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.Competing Interest StatementThe authors have declared no competing interest.