Browsing by Author "Brombacher, F"

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    Effects of Trypanosoma brucei brucei on spatial learning and memory
    (2023) Moses, Blessing; Brombacher, F; Brombacher, T
    Human African trypanosomiasis (HAT), or sleeping sickness, is a sub-Saharan African disease caused by trypanosome parasites and transmitted through tsetse flies. The HAT is clinically defined by two diagnostic stages, commencing with an early-stage also known as the haemolymphatic stage where parasites appear to be localised in the blood and lymphatic systems, then a late-stage/ meningoencephalytic stage where the parasites are localised in the central nervous system. In the late stage, the parasite crosses the blood-brain barrier to disrupt the physiological function of the brain which results in marked sleep disorder. Studies on the Trypanosoma evansi infection mice model has shown that in addition to the sleep disorder caused by trypanosomiasis disease, learning and memory formation were impaired. Besides, only a little research has been conducted to validate this claim. Thus, this study aims to; i) understand the impact of behavioural Morris water maze (MWM) training test on immune cytokine levels in the brain with or without infection, ii) investigate the impact of Trypanosoma brucei brucei infection on spatial learning and memory, also, finally iii) evaluate infection severity with or without the behavioural training test. To address these objectives, three simultaneous studies were conducted whereby C57BL6 mice were grouped into four and two groups were infected with Trypanosoma brucei brucei. At first, we showed that the MWM training task did not affect the basal level of brain immune composition in naïve mice. Secondly, our result revealed that Trypanosoma brucei brucei infection resulted in spatial learning and memory impairment. Additionally, the consequential effect of infection resulted in an upregulated pro-inflammatory and antiinflammatory cytokine (IL-6, IFNγ, TNF, IL-10) immune response in the three brain areas of focus: the prefrontal cortex, hippocampus, and hypothalamus. Lastly, it was interesting to find that the MWM training task reduced the characteristic pathology associated with the disease. In conclusion, the study indicates that the increased immune cytokine composition in the brain above the basal level following Trypanosoma brucei brucei infection could contribute to the impairment in spatial learning and memory whereas, training during infection could potentially help to dampen the inflammatory and pathological severity of the disease.
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    Investigating role of IL-4 receptor alpha (IL-4Ra) in murine models of atopic dermatitis
    (2021) Scibiorek, Martyna; Brombacher, F; Hadebe, S
    Atopic dermatitis (AD) is a common pruritic inflammatory skin disease with complex environmental and genetic predisposition factors. Primary skin barrier dysfunction and aberrant T helper 2 (TH2) responses to common allergens, together with increased serum IgE antibodies, characterise the disease. B and T cells are essential in the disease manifestation, however, the exact mechanism of how these cells are involved in skin sensitization to allergens is unclear. Clinical studies investigating the efficacy of monoclonal antibody to IgE such as omalizumab and ligelizumab do not show efficacy in AD patients. However, targeting IL-4/IL-13 signalling axis with dupilumab show efficacy in AD. We investigated the importance of interleukin 4 receptor alpha (IL- 4Rα) signalling specifically on B and T cells to understand the requirement of this signalling axis in epicutaneous skin sensitisation during AD. We investigated 3 models of AD using House dust mite (HDM), Ovalbumin (OVA) and low-calcemic analog of vitamin D (MC903) on mouse strains lacking IL-4Ra on various B and T cells. We used mb1creIL-4Rα-/lox (mice lacking IL-4Rα on B cells), iLcKCre IL-4Rα-/lox (mice lacking IL-4Rα on all T cells), LcKCre IL-4Rα-/lox (mice lacking IL-4Rα on CD4+ and CD8+ T cells), CD4Cre IL-4Rα-/lox (mice lacking IL-4Rα on CD4+ Tcells), Foxp3Cre IL-4Rα-/lox (mice lacking IL-4Rα on Foxp3+ T regulatory cells) and IL-4Rα-/lox littermate controls. We analysed cellular infiltrate in the skin and inguinal lymph nodes (LN) by flow cytometry, histology of the skin, serum antibodies and cytokines by ELISA. Mice lacking IL-4Rα-responsive B cells showed a reduced serum IgE levels, but no significant differences in epidermal thickening compared to littermate control in HDM or MC903 models. Mice investigated in the T cell arm of the study showed reduced epidermal thickening in pan-T cell IL-4Rα knock-out, but not in groups lacking IL-4Rα signalling in adaptive T cells, suggesting importance of IL4/IL13 signalling axis in ydT cells during AD. Overall, our results suggest that deletion of IL-4Rα on innate T cells regulates inflammatory response in atopic dermatitis.
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    The role of host and microbial factors in the pathogenesis of chronic schistosomiasis in mice
    (2021) Mpotje, Thabo Rantanta Victor; Brombacher, F; Gray, Clive
    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.