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Investigation of filarial associated immune modulation and effects on HIV susceptibility
Investigation of filarial associated immune modulation and effects on HIV susceptibility
Despite coordinated global activities supported by the WHO, lymphatic filariasis remains a large public health problem in many parts of the world. One important reason for this is the lack of treatment options available for the ~40 million peo-ple who suffer from chronic pathology (lymphedema or hydrocele), most of whom live in already poor communities in sub-Saharan Africa. Lymphatic filaria-sis is typically found in rural, hard to reach areas which can make it difficult for researchers to preserve samples from infected individuals. Because of this, we developed a novel whole blood flow cytometry method to minimize the amount of blood required (over the standard method), which maintains the integrity of ex-tracellular markers, and eliminates the need for a -80°C freezer. This method was thoroughly tested and implemented in ongoing clinical trials in rural Ghana-ian and Tanzanian field laboratories; our aim was to investigate immunological alterations in patients with lymphatic filariasis pathology as compared to those asymptomatically infected and control individuals, particularly regarding CD4+ T cell activation and CD8+ T cell exhaustion. We saw an increase of immune acti-vation – defined by HLADR/CD38 expression on CD4+ T cells – in lymphedema individuals as compared to filarial infected individuals without pathology as well as uninfected individuals from the same area. In addition, for the first time, we observed an increase of activation corresponding to lymphedema stage in sam-ples from both Tanzania and Ghana. We next investigated the role of exhausted CD8+ T cells in W. bancrofti infections by looking at a number of markers asso-ciated with exhaustion on both whole blood and PBMC samples since cells would be expected to proceed through activation to exhaustion with constant antigen exposure. Interestingly, we found that the cells from lymphedema pa-tients displayed altered expression on exhausted CD8+ T cell subsets when compared to uninfected controls and asymptomatic W. bancrofti infections. Also notable is that the asymptomatic W. bancrofti-infected individuals showed com-parable results to the control samples in all of the markers examined. This thesis enhances the knowledge on the immune response of individuals to both asymp-tomatic W. bancrofti infections as well as the chronic pathology disease state through the development of a novel field method and flow cytometric analysis. This knowledge might help to prevent debilitating manifestations in filarial infect-ed individuals in the future.
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Horn, Sacha
2021
English
Universitätsbibliothek der Ludwig-Maximilians-Universität München
Horn, Sacha (2021): Investigation of filarial associated immune modulation and effects on HIV susceptibility. Dissertation, LMU München: Faculty of Medicine
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Abstract

Despite coordinated global activities supported by the WHO, lymphatic filariasis remains a large public health problem in many parts of the world. One important reason for this is the lack of treatment options available for the ~40 million peo-ple who suffer from chronic pathology (lymphedema or hydrocele), most of whom live in already poor communities in sub-Saharan Africa. Lymphatic filaria-sis is typically found in rural, hard to reach areas which can make it difficult for researchers to preserve samples from infected individuals. Because of this, we developed a novel whole blood flow cytometry method to minimize the amount of blood required (over the standard method), which maintains the integrity of ex-tracellular markers, and eliminates the need for a -80°C freezer. This method was thoroughly tested and implemented in ongoing clinical trials in rural Ghana-ian and Tanzanian field laboratories; our aim was to investigate immunological alterations in patients with lymphatic filariasis pathology as compared to those asymptomatically infected and control individuals, particularly regarding CD4+ T cell activation and CD8+ T cell exhaustion. We saw an increase of immune acti-vation – defined by HLADR/CD38 expression on CD4+ T cells – in lymphedema individuals as compared to filarial infected individuals without pathology as well as uninfected individuals from the same area. In addition, for the first time, we observed an increase of activation corresponding to lymphedema stage in sam-ples from both Tanzania and Ghana. We next investigated the role of exhausted CD8+ T cells in W. bancrofti infections by looking at a number of markers asso-ciated with exhaustion on both whole blood and PBMC samples since cells would be expected to proceed through activation to exhaustion with constant antigen exposure. Interestingly, we found that the cells from lymphedema pa-tients displayed altered expression on exhausted CD8+ T cell subsets when compared to uninfected controls and asymptomatic W. bancrofti infections. Also notable is that the asymptomatic W. bancrofti-infected individuals showed com-parable results to the control samples in all of the markers examined. This thesis enhances the knowledge on the immune response of individuals to both asymp-tomatic W. bancrofti infections as well as the chronic pathology disease state through the development of a novel field method and flow cytometric analysis. This knowledge might help to prevent debilitating manifestations in filarial infect-ed individuals in the future.