Functional Characterization Of Plasmodium Yoelii Macrophage Migration Inhibitory Factor In Immune Response Against Malaria

Malaria, caused by the protozoan Plasmodium spp., is one of the most fatal infectious diseases in the world with 200 million new diagnoses and almost one million deaths each year. More than 85% of malaria cases and 90% of malaria-related deaths occur in sub-saharan Africa, mainly in young children. While in some cases, infection by the malarial parasite can become severe and lead to death, malarial infection usually results in an uncomplicated, mild febrile disease. The mild disease manifestation is result of the balance of the immune response that causes the acute febrile symptoms (clinical immunity) and the immune response that attacks parasites and/or inhibits their replication (anti-parasite immunity). The production of a highly inflammatory cytokine milieu is an important aspect of the immune response to malarial infection. These inflammatory cytokines have the capacity to control rapidly propagating parasites, mediate clinical symptoms, and influence immune memory.Macrophage migration inhibitory factor (MIF) is one of the first cytokines to be discovered. MIF was found to be a critical upstream regulator of innate immunity that sustains activation responses by mediating the immunosuppressive action of glucocorticoids and inhibiting stimulus-induced apoptosis. Highly homologous orthologous of MIF have been described in parasitic organisms, and have been found to have almost identical structure and similar biological activity as mammalian MIF (MmMIF). Both host MIF and PMIF were detected rapid released in malaria patients. It is doubt why malarial parasites synthesize a molecule homologous with host MIF. What’s more, the relationship between host MIF and PMIF is still unknown.In this study, we further explored the function of PMIF during the host-parasite immune response using a highly lethal rodent malaria model, Plasmodium yoelii 17XL (Py17XL). We first constructed a strain of malaria in which PMIF is genetically deleted (MIF-KO Py17XL). We found pro-inflammatory cytokine production was significantly decreased in MIF-KO Pyl7XL-infected mice relative to mice infected with a wild-type (WT) strain of malaria. These results correlate with findings of Sun, et al., and provide additional support for the finding that PMIF enhances the inflammatory response.To further explore the role of PyMIF in the malarial inflammatory response, we examined the effect of PyMIF on cells within the spleen. Using FACS analysis, we found that CD11b+Ly6c+ cells accumulated in the spleens of WT Py17XL-treated mice as compared to MIF-KO Py17XL-treated, suggesting that PyMIF may contribute to the chemotaxis of CD11b+Ly6c+ cells, which confirmed in vitro afterwards. Further examination revealed that cell receptors CXCR2, CXCR4, as well as cell surface markers ICAM-1 and VLA-4 were associated with the ability of PyMIF to elicit a chemotaxic effect on CD11b+Ly6c+ cells.Taken together, these studies demonstrate that PyMIF enhances the inflammatory response in rodent malaria model by stimulating CD11b+Ly6c+ cells accumulating in spleen, revealing a new approach of PMIF to enhance malaria inflammatory response. Based on our results, we hypothesize that PMIF may be an immune regulating factor, as well as a self-restricting factor. PMIF is constitutively expressed, with levels directly increasing in accordance with parasite replication, enhancing the host immune response synergistically with MmMIF. Thus parasite was suggested to be feedback regulated, and restricted in a certain range to be coexistence with host, which may be an evolutionary adaptation of parasites to prolong their own survival.