Molecular regulation of Trypanosoma congolense-induced proinflammatory cytokine production in macrophages and its modulation by diminazene aceturate (Berenil)

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dc.contributor.supervisor Dr. Jude Uzonna, Deapartment of Immunology en_US
dc.contributor.author Kuriakose, Shiby
dc.date.accessioned 2016-09-12T16:09:57Z
dc.date.available 2016-09-12T16:09:57Z
dc.date.issued 2016-05-19, 2014-08-21, 2014-10-20, 2012-11. en_US
dc.identifier.uri http://hdl.handle.net/1993/31677
dc.description.abstract African trypanosomiasis remains a major health problem to both humans and animals due to lack of effective treatment or vaccine to control the disease. Animal trypanosomiasis is considered one of the most important diseases affecting livestock production and agricultural development in sub-Saharan Africa. Although the use of trypanocides remain the most important method for controlling the disease in animals, the mechanisms of action of these compounds are not completely known. The overall aim of this thesis is to decipher the molecular mechanisms involved in Trypanosoma congolense-induced cytokine production and how this is modulated by the trypanocide, Diminazene aceturate (Berenil). First, I investigated the molecular and biochemical mechanisms of action of Berenil to determine whether in addition to trypanolytic effect, it exerts a modulatory effect on the host immune system. Although it is known that T. congolense infection in mice is associated with increased production of pro-inflammatory cytokines by macrophages, the intracellular signaling pathways leading to the production of these cytokines remain unknown. Therefore, I investigated the innate receptors and intracellular signaling pathways that are involved in T. congolense-induced pro-inflammatory cytokine production in macrophages. Next I further determined whether the inhibitory effect of Berenil on proinflammatory cytokine production in macrophages is specific to T. congolense. I found that Berenil treatment significantly reduced the immune activation and proinflammatory cytokine production in infected mice suggesting that in addition to its direct trypanolytic effect, Berenil also modulates the host immune response to the parasite. Next, I show that T. congolense induced pro-inflammatory cytokine production in macrophages is dependent on phosphorylation of mitogen-activated protein kinase (MAPK) and signal transducer and activation of transcription (STAT) proteins in a TLR2-dependent manner. I further show that Berenil treatment downregulates T. congolense as well as LPS induced cytokine production by affecting the phosphorylation of MAPK and STAT proteins. Collectively, the results from this thesis provide novel insights into T. congolense-induced activation of the innate immune system and modulation of host immune response by Berenil. These findings are significant and could help in developing newer and better therapeutic strategies against the disease, in particular, and inflammatory responses in general. en_US
dc.publisher PLOS, Frontiers in Immunology, Elsevier, Sage en_US
dc.subject Macrophages en_US
dc.subject Proinflammtory cytokines en_US
dc.subject African trypanosomes en_US
dc.subject Immunity en_US
dc.title Molecular regulation of Trypanosoma congolense-induced proinflammatory cytokine production in macrophages and its modulation by diminazene aceturate (Berenil) en_US
dc.degree.discipline Immunology en_US
dc.contributor.examiningcommittee Dr. George Mutwiri (University of Saskatchewan), Dr. Sam P.Kung (University of Manitoba) Dr. Abdelilah Soussi Gounni (University of Manitoba) Dr. Kangmin Duan (Department of Oral Biology) en_US
dc.degree.level Doctor of Philosophy (Ph.D.) en_US
dc.description.note October 2016 en_US

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