Regulation of immunity to experimental Trypanosoma congolense infection: roles of regulatory T cells, natural killer cells, and myeloid-derived suppressor cells

Simple item page
dc.contributor.authorOnyilagha, Chukwunonso
dc.contributor.examiningcommitteeSoussi Gounni, Abdelilah (Immunology)
dc.contributor.examiningcommitteeKung, Sam (Immunology)
dc.contributor.examiningcommitteeKeynan, Yoav (Medical Microbiology and Infectious Diseases)
dc.contributor.examiningcommitteeKaushik, Radhey (South Dakota State University)
dc.contributor.supervisorUzonna, Jude (Immunology)en_US
dc.date.accessioned2018-03-02T18:31:21Z
dc.date.available2018-03-02T18:31:21Z
dc.date.issued2014-03en_US
dc.degree.disciplineImmunologyen_US
dc.degree.levelDoctor of Philosophy (Ph.D.)en_US
dc.description.abstractAfrican trypanosomiasis is a fatal disease that affects human and livestock and poses massive agricultural and economic problems in the affected regions. There is currently no vaccine or satisfactory treatment for this disease. Understanding various regulatory mechanisms that influence resistance and/or susceptibility to the disease could help identify novel targets for treatment and/or development of a vaccine against the disease. This thesis focuses on investigating the contributions of regulatory T cells (Tregs), natural killer (NK) cells and myeloid-derived suppressor cells (MDSCs) in the immunopathogenesis of experimental T. congolense infection. Repeated low dose intradermal (i.d.) T. congolense infections predispose mice to enhanced susceptibility to an otherwise non-infectious dose challenge. I explored the mechanisms behind this and found that akin to intraperitoneal infection, low dose i.d. infection elicited strong immune response and expansion of Tregs in both the spleens and lymph nodes draining the infection site. Depletion of Tregs during primary or before challenge infection completely abolished low dose-induced enhanced susceptibility. Next, I found that infection with T. congolense is associated with increased numbers of NK cells in multiple tissue compartments. Depletion of NK cells prior to infection led to increased parasitemia and a significant reduction in numbers of IFN-g-producing cells in the spleens and liver of infected mice. NFIL3-/- mice (that genetically lack NK cell development) succumb acutely to infection, and this was accompanied by significant reduction in IFN-g and TNF-α production by CD3+ T cells in the infected mice. Adoptive transfer of wild-type NK cells into NFIL3-/- mice before infection rescued them from acute death, strongly confirming that NK cells may be contributing to optimal resistance following infection. Lastly, using cell analysis and depletion studies, I found that MDSC numbers increased during T. congolense infection and these cells contribute to enhanced susceptibility to the infection by suppressing CD4+ T cell proliferation and IFN-g production in an arginase-1-dependent manner. Collectively, the results of my studies identified important roles played by Tregs, NK cells, and MDSCs during T. congolense infection. They revealed important mechanisms that regulate susceptibility and resistance to this disease, which could be novel therapeutic targets in African trypanosomiasis.en_US
dc.description.noteMay 2018en_US
dc.identifier.citationOnyilagha, C., Okwor, I., Kuriakose, S., Singh, R., & Uzonna, J. (2014). Low-Dose Intradermal Infection with Trypanosoma congolense Leads to Expansion of Regulatory T Cells and Enhanced Susceptibility to Reinfection. Infection and Immunity, 82(3), 1074–1083. http://doi.org/10.1128/IAI.01028-13en_US
dc.identifier.urihttp://hdl.handle.net/1993/32892
dc.language.isoengen_US
dc.publisherInfection and Immunity (American Society for Microbiology)en_US
dc.rightsopen accessen_US
dc.subjectTrypanosoma congolenseen_US
dc.subjectRegulatory T cellsen_US
dc.subjectNatural killer cellsen_US
dc.subjectMyeloid-derived suppressor cellsen_US
dc.subjectInfectionen_US
dc.subjectCytokinesen_US
dc.subjectAdoptive transferen_US
dc.subjectResistanceen_US
dc.subjectSusceptibilityen_US
dc.subjectProliferationen_US
dc.subjectImmunosuppressionen_US
dc.titleRegulation of immunity to experimental Trypanosoma congolense infection: roles of regulatory T cells, natural killer cells, and myeloid-derived suppressor cellsen_US
dc.typedoctoral thesisen_US
Files
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
ONYILAGHA_CHUKWUNONSO.pdf
Size:
3.45 MB
Format:
Adobe Portable Document Format
Description:
Download
License bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
license.txt
Size:
2.2 KB
Format:
Item-specific license agreed to upon submission
Description:
Download
Collections
FGS - Electronic Theses and Practica