Macrophage migration inhibitory factor (MIF) has been implicated in mediating both innate and adaptive immune responses in inflammatory and infectious diseases. The sequence and structure of MIF is highly conserved across the avian phylogeny, which underlies high sequence homology and functional similarities between turkey and chicken MIFs. Turkey MIF (TkMIF) inhibited cell migration and promoted cell proliferation with production of inflammatory mediators, comparable to the biological properties of chicken MIF (ChMIF), thus indicating the biological cross-reactivity between turkey and chicken MIFs. This study identified the cell surface receptor(s) that could bind ChMIF and the biological roles triggered by such interactions. In addition to CD74, a previously identified receptor, CXCR4 also interacts with ChMIF. Moreover, the formation of receptor complexes was shown between CXCR4 and CD74. MIF signaling through CXCR4 and CD74 led to cell chemotaxis and proliferation activity as well as intracellular calcium influx. Intriguingly, Eimeria MIF (EMIF), a homologue secreted following parasitic infection, also interacted with CD74 leading to comparable biological functions to those of ChMIF. Given such observations, we hypothesized that CXCR4 and CD74 are receptors for ChMIF leading to the functional consequences similarly manifested by EMIF interaction with the corresponding receptors. EMIF, predominantly secreted from the invasive merozoite stage, may help the parasite exploit the host immune response by interacting with common ChMIF receptors. This may lead to functional mimicry thus provoking the question of whether EMIF would modulate the biological functions of ChMIF to manipulate the host defense that allows more efficient invasion of the host. To evaluate this concept, a transgenic E. tenella lacking MIF was generated by in vivo passage of E. tenella transfected with a CRISPR plasmid targeting EMIF. Although not fully disrupted, reduction of EMIF expression was observed in the transgenic E. tenella itself as well as in inoculated cells, which resulted in enhanced survival of host cells. Herein, we achieved a better characterization of the functional roles of both avian and parasite MIFs underlying the interaction with common host receptors, along with the essential role of parasite MIF promoting host cell death during parasitic infection. / PHD / When animals get infected or injured, their immune system senses invading pathogens or damaged tissues as danger signals, which often elicits the production of inflammatory mediators. These are chemical messengers secreted mostly by immune cells that initiate cellular communication and infiltration of immune cells to the infection/damaged site leading to inflammatory responses to eliminate the infectious agents and repair damaged tissues. Among many inflammatory mediators, macrophage migration inhibitory factor (MIF) is involved in inflammatory and immune response by regulating cell migration. Interestingly, MIF is secreted by Eimeria parasites (that cause the costly coccidiosis disease in poultry) as well as by chickens (host animal) after infection with this pathogen. Toward a better understanding of the impacts of both avian and parasite MIFs on the host immune response, three specific studies were completed. First, MIF displayed high degree of gene sequence identity and functional similarity between chicken and turkey, supporting the evolutionarily conservation of MIF across birds. The second study identified the MIF receptors and their complexes, which engage in the biological functions of chicken MIF. Through binding to these cell surface receptors, chicken MIF can regulate cell migration and proliferation with calcium release. Intriguingly, Eimeria MIF secreted after parasitic infection is able to bind the same receptors leading to comparable biological functions to those of chicken MIF. Lastly, the role of Eimeria MIF was further evaluated by disrupting its gene in the parasite. Although not fully disrupted in the transgenic parasites, its expression was decreased resulting in enhanced survival of host cells, thus suggesting a deleterious effect of Eimeria MIF on the host, as well as its potential as a therapeutic target to control coccidiosis in poultry.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/97565 |
| Date | 16 October 2018 |
| Creators | Park, Myeongseon |
| Contributors | Animal and Poultry Sciences, Dalloul, Rami A., Jenkins, Mark Christopher, Lee, Kiho, Leeth, Caroline M., Wong, Eric A. |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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