The role of host and microbial factors in the pathogenesis of chronic schistosomiasis in mice

dc.contributor.advisorBrombacher, F
dc.contributor.advisorGray, Clive
dc.contributor.authorMpotje, Thabo Rantanta Victor
dc.date.accessioned2021-09-14T18:08:16Z
dc.date.available2021-09-14T18:08:16Z
dc.date.issued2021
dc.date.updated2021-09-14T07:43:36Z
dc.description.abstractThere is burgeoning interest in the complex tripartite interplays between the commensal microbiota, host's genetic factors, and immune response during helminth infections which are still poorly understood. The study explores this relationship in the context of chronic schistosomiasis-driven pathology. In the first part of the thesis, removal of the host Basic Leucine Zipper ATF-Like Transcription Factor 2 (Batf2) gene in 129Sv (Batf2-/- ) mice resulted in alteration of the intestinal microbial composition and reduced granulomatous inflammatory immune response. These changes associated with rescue from pre-mature mortality and improved fitness of Batf2-/- mice during chronic experimental schistosomiasis in relation to control wild type mice. The prolonged survival and reduced immunopathology were diminished by treatment with α-CD8 antibody highlighting the significance of CD8-expressing immune mediators during chronic Schistosomiasis. Transfer of the altered intestinal microbiota from Batf2-/- mice to wild type mice by co-housing was enough to rescue the latter from exacerbated granulomatous inflammation and prolonged their survival during chronic schistosomiasis. These observations suggest, for the first time, a central role of the host gut microbiota in decisively regulating the tissue immune response, the elicited pathology and host survival during schistosomiasis. To validate the robustness of this tripartite interaction during chronic schistosomiasis around the gut microbiota, the second part of the present work analysed two genetically identical murine models (C57BL/6) housed under two different specific Pathogen free environments (SPF1 and SPF2) and presenting differential susceptibility to chronic schistosomiasis. Our work revealed a higher susceptibility of C57BL/6 mice from the SPF2 facility in relation to C57BL/6 mice from the SPF1 facility. In confirmation with our first series of experiments, that demonstrated a central role of the host intestinal microbiota in regulating the immune responses, the pathology, and the survival of the host during schistosomiasis, the second series of experiments further presented an ameliorated immunological, pathological and vital prognosis of vulnerable SPF2 C57BL/6 mice receiving the intestinal microbiota of more resistant SPF1 C57BL/6 mice. Therefore, the study demonstrates the genetic regulation of gut microbiota which in turn, and/or in concert with the genetic make-up, influence the immunological, pathological, and vital host response during chronic schistosomiasis. The present work expands the conventional knowledge on schistosomiasis disease regulation and presents the gene-microbiota-immune-response interactome as a core piece of the regulatory machinery of this infection as exploitable to alter disease progression in the context of drug and vaccine development.
dc.identifier.apacitationMpotje, T. R. V. (2021). <i>The role of host and microbial factors in the pathogenesis of chronic schistosomiasis in mice</i>. (). ,Faculty of Health Sciences ,Department of Pathology. Retrieved from http://hdl.handle.net/11427/33888en_ZA
dc.identifier.chicagocitationMpotje, Thabo Rantanta Victor. <i>"The role of host and microbial factors in the pathogenesis of chronic schistosomiasis in mice."</i> ., ,Faculty of Health Sciences ,Department of Pathology, 2021. http://hdl.handle.net/11427/33888en_ZA
dc.identifier.citationMpotje, T.R.V. 2021. The role of host and microbial factors in the pathogenesis of chronic schistosomiasis in mice. . ,Faculty of Health Sciences ,Department of Pathology. http://hdl.handle.net/11427/33888en_ZA
dc.identifier.ris TY - Doctoral Thesis AU - Mpotje, Thabo Rantanta Victor AB - There is burgeoning interest in the complex tripartite interplays between the commensal microbiota, host's genetic factors, and immune response during helminth infections which are still poorly understood. The study explores this relationship in the context of chronic schistosomiasis-driven pathology. In the first part of the thesis, removal of the host Basic Leucine Zipper ATF-Like Transcription Factor 2 (Batf2) gene in 129Sv (Batf2-/- ) mice resulted in alteration of the intestinal microbial composition and reduced granulomatous inflammatory immune response. These changes associated with rescue from pre-mature mortality and improved fitness of Batf2-/- mice during chronic experimental schistosomiasis in relation to control wild type mice. The prolonged survival and reduced immunopathology were diminished by treatment with α-CD8 antibody highlighting the significance of CD8-expressing immune mediators during chronic Schistosomiasis. Transfer of the altered intestinal microbiota from Batf2-/- mice to wild type mice by co-housing was enough to rescue the latter from exacerbated granulomatous inflammation and prolonged their survival during chronic schistosomiasis. These observations suggest, for the first time, a central role of the host gut microbiota in decisively regulating the tissue immune response, the elicited pathology and host survival during schistosomiasis. To validate the robustness of this tripartite interaction during chronic schistosomiasis around the gut microbiota, the second part of the present work analysed two genetically identical murine models (C57BL/6) housed under two different specific Pathogen free environments (SPF1 and SPF2) and presenting differential susceptibility to chronic schistosomiasis. Our work revealed a higher susceptibility of C57BL/6 mice from the SPF2 facility in relation to C57BL/6 mice from the SPF1 facility. In confirmation with our first series of experiments, that demonstrated a central role of the host intestinal microbiota in regulating the immune responses, the pathology, and the survival of the host during schistosomiasis, the second series of experiments further presented an ameliorated immunological, pathological and vital prognosis of vulnerable SPF2 C57BL/6 mice receiving the intestinal microbiota of more resistant SPF1 C57BL/6 mice. Therefore, the study demonstrates the genetic regulation of gut microbiota which in turn, and/or in concert with the genetic make-up, influence the immunological, pathological, and vital host response during chronic schistosomiasis. The present work expands the conventional knowledge on schistosomiasis disease regulation and presents the gene-microbiota-immune-response interactome as a core piece of the regulatory machinery of this infection as exploitable to alter disease progression in the context of drug and vaccine development. DA - 2021_ DB - OpenUCT DP - University of Cape Town KW - Pathology LK - https://open.uct.ac.za PY - 2021 T1 - The role of host and microbial factors in the pathogenesis of chronic schistosomiasis in mice TI - The role of host and microbial factors in the pathogenesis of chronic schistosomiasis in mice UR - http://hdl.handle.net/11427/33888 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/33888
dc.identifier.vancouvercitationMpotje TRV. The role of host and microbial factors in the pathogenesis of chronic schistosomiasis in mice. []. ,Faculty of Health Sciences ,Department of Pathology, 2021 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/33888en_ZA
dc.language.rfc3066eng
dc.publisher.departmentDepartment of Pathology
dc.publisher.facultyFaculty of Health Sciences
dc.subjectPathology
dc.titleThe role of host and microbial factors in the pathogenesis of chronic schistosomiasis in mice
dc.typeDoctoral Thesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationlevelPhD
Files
Original bundle
Now showing 1 - 1 of 1
Loading...
Thumbnail Image
Name:
thesis_hsf_2021_mpotje thabo rantanta victor.pdf
Size:
7.1 MB
Format:
Adobe Portable Document Format
Description:
License bundle
Now showing 1 - 1 of 1
Loading...
Thumbnail Image
Name:
license.txt
Size:
0 B
Format:
Item-specific license agreed upon to submission
Description:
Collections