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Title: Macrophage Migration Inhibitory Factor (MIF) of the protozoan parasite Eimeria influences the components of the immune system of its host, the chicken

Author
item Miska, Kate
item KIM, SUNGWON - Virginia Polytechnic Institution & State University
item Fetterer, Raymond
item DALLOUL, RAMI - Virginia Polytechnic Institution & State University
item Jenkins, Mark

Submitted to: Parasitology Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/8/2013
Publication Date: 5/20/2013
Citation: Miska, K.B., Kim, S., Fetterer, R.H., Dalloul, R., Jenkins, M.C. 2013. Macrophage Migration Inhibitory Factor (MIF) of the protozoan parasite Eimeria influences the components of the immune system of its host, the chicken. Parasitology Research. 112:1935-1944.

Interpretive Summary: Macrophage Migration Inhibitor Factor (MIF) is a cytokine or a molecule that modulates the immune system in animals that have developed adaptive immune responses. A copy of the MIF gene was found in single cell protozoan parasites (Eimeria), which are the causative agent of gastrointestinal disease in chickens. The purpose of this study was to determine the location of the MIF protein in the parasite, what happens to it after the parasite invades the host, and whether it has any effect on the host (the chicken). It appears that MIF is not sequestered to any particular organelle present in the parasite, but that it is spread evenly throughout the cytosol and the nucleus. MIF is released into the host tissues upon infection, and is also seen in the later stages of the developing parasite. Most importantly, parasite MIF has an inhibitory effect on chicken macrophages (cells of the immune system responsible for recognition and clearing of pathogens). Therefore, it is possible that parasite MIF can have an effect on the host’s immune system. It is to the parasite’s advantage to modulate the host’s reaction to invasion in a way that ensures parasite survival. MIF is the first molecule isolated from Eimeria that may play a role in modulating that immune response of the host.

Technical Abstract: Macrophage migration inhibitory factor (MIF) is a soluble factor produced by sensitized T lymphocytes that inhibits the random migration of macrophages. Homologues of MIF from invertebrates have been identified making it an interesting molecule from a functional perspective. In the present study, the localization of a parasite MIF protein as well as its effect on the host was characterized. Western blot analysis shows that Eimeria MIF (EMIF) is found during all parasite developmental stages tested. Transmission electron microscopy (TEM) shows that MIF is distributed throughout cytosol and nucleus of Eimeria acervulina merozoites. Immunohistochemical analysis (IHC) suggests that EMIF may be released into the surrounding tissues as early as 24 hours (hr) after infection, while later during oocyst formation MIF expression is localized to areas immediately surrounding oocysts, as well as in wall forming bodies. The chemotaxis assay revealed inhibitory function of EMIF on chicken macrophage migration. Quantitative real-time PCR (qRT-PCR) was performed to examine the effect of EMIF on host immune system by measuring the transcripts of inflammatory mediators. An ex vivo stimulation study showed that E. acervulina MIF (EaMIF) enhanced expression of pro-inflammatory cytokines and chemokines in the presence of lipopolysaccharide (LPS). Furthermore, sequential treatment of PBMCs with EaMIF, chicken MIF (ChMIF) and LPS in 2 hr intervals led to the highest levels of IL-1', CCLi3, IL-18 and IFN-' mRNA. This study shows that parasite MIF is widely expressed, and may have potential effects on the immune system of the host.