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Title: Ostertagia ostertagi macrophage migration inhibition factor is present at all developmental stages and may cross-regulate host functions through host receptor

Author
item QU, G - Shandong Binzhou Academy Of Animal Science And Veterinary Medicine
item Fetterer, Raymond
item LENG, L - Yale School Of Medicine
item DU, X - Yale School Of Medicine
item Zarlenga, Dante
item SHEN, Z - Shandong Binzhou Academy Of Animal Science And Veterinary Medicine
item HAN, W - Jilin University
item BUCALA, R - Yale School Of Medicine
item Tuo, Wenbin

Submitted to: International Journal for Parasitology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/15/2013
Publication Date: 5/1/2014
Citation: Qu, G., Fetterer, R.H., Leng, L., Du, X., Zarlenga, D.S., Shen, Z., Han, W., Bucala, R., Tuo, W. 2014. Ostertagia ostertagi macrophage migration inhibition factor is present at all developmental stages and may cross-regulate host functions through host receptor. International Journal for Parasitology. 44(6):355-367.

Interpretive Summary: Ostertagia ostertagi is a cattle stomach worm prevalent in temperate regions of the U.S., causing ostertagiasis in cattle of all ages and resulting in production losses to the cattle industry. Ostertagiasis has been controlled by anthelmintics in the past; however, alternative control measures are needed because drug resistance in this parasite is emerging. The present study investigates the structure, distribution, and function an O. ostertagi-derived protein, macrophage migration inhibition factor (OoMIF) and its potential to be used as a vaccine candidate. This study showed that there are at least 3 distinct copies of OoMIF, the OoMIF1a with potential function has been characterized in this study. OoMIF1 was and present at all stages of the development localized to major organs of the parasite. OoMIF1a could form multi-unit complexes and had tautomerase activity which was inhibited by specific antibodies. OoMIF1a was taken up by immune cells, possibly through binding to a MIF receptor. OoMIF1a was able to regulate immune responses of the host cells. Taken together, OoMIF1 is a functional immune modulator which may help the parasite escape the host immune surveillance by cross-regulating the anti-parasite immunity. This research will benefit the cattle industry.

Technical Abstract: Macrophage migration inhibition factor (MIF) of Ostertagia ostertagi, a parasitic nematode infecting the bovine abomasum, is characterized in the present study. Phylogenetic analysis indicates that there appears to be at least 3 OoMIFs encoded by distinct transcripts, including OoMIF1a, OoMIF1b, and OoMIF2. OoMIF2 is only distantly related to OoMIF1s, but has higher sequence homology with the Caenorhabditis elegans MIF2. OoMIF1a is identical to TcMIF1 of the sister parasite, Taledorsagia circumcincta, although the coding sequences are divergent. Recombinant OoMIF1a is catalytically active as a tautomerase. Point mutation at Pro2 or Pro2 duplication resulted in reduced oligomerization and loss of tautomerase activity. Tautomerase activity of rOoMIF1a was only partially inhibited by ISO-1, but was abrogated by rOoMIF1a-specific antibodies. OoMIF1 was detectable at all developmental stages and abundant in embryonated eggs and L3 larvae, and excretory/secretory (ES) OoMIF1 was also detected in adult worm ES product. OoMIF1 was localized to hypodermis/muscle, reproductive tract and intestine, but not cuticles. rOoMIF1a, but not rOoMIF1aP2G, was able to specifically bind to human CD74, a MIF receptor, with comparable affinity with human MIF. Macrophages were able to take up rOoMIF1a and internalized rOoMIF1a was detectable by immunostaining, suggesting that secretory OoMIF1 internalization in animals may be receptor-mediated. Furthermore, this study has demonstrated that rOoMIF1a was able to restore glucocorticoid-suppressed, lipopolysaccharide (LPS)-induced cytokine production in human and bovine immune cells. The present study showed that OoMIF1 is secretory and may play a role in parasitic development during early stages and host-parasite cross-interactions during infection. This parasitic cytokine may be a potential vaccine candidate against O. ostertagi infection in cattle.