Tijani, Hawanot Olaitan2025-04-072025-04-072024-10-24https://epub.uni-luebeck.de/handle/zhb_hl/3414Host response to tuberculosis were compared at the cellular and transcriptome level, with the purpose of identifying putative target for host-directed therapy as an adjunct to antibiotic treatment.In tuberculosis (TB) studies, the extent to which host genome as well as transcriptome contribute to susceptibility and pathology has not been clearly defined. Globally still one of the most abundant infectious disease, numbers of TB cases caused by drug resistant agents of the Mycobacterium tuberculosis (M. tuberculosis) complex are increasing especially with onset of emerging and re-emerging viral diseases and other comorbidities. Our study aims to identify host specific differences in TB disease susceptibility and pathogenesis. Previously, we and others have demonstrated the detrimental role of neutrophils in necrosis, tissue damage and bacterial spread. We hypothesized that cell death modalities during the interaction of neutrophils and other myeloid cells in the lung determines pathogen restriction or spread and ultimately, disease exacerbation. We therefore designed an integrative systems biology approach from genome to cellular, tissue and animal model to better understand TB in vitro and in vivo. Inbred female congenic mice differing in their susceptibility to M. tuberculosis infection were studied before, during and after infection and compared to human leukocytes and RNA samples from excised lung tissue. Murine bone marrow derived macrophages from wild-type B6 in comparison to susceptible C3HeBFeJ and B6.C3Hsst1 mice showed differential responses to M. tuberculosis. Upon aerosol infection with M. tuberculosis, immune-competent but susceptible B6.I-9.3.19.8 and B6.C3Hsst1 had bigger lung lesions and higher bacterial loads than resistant B6 mice. Immune cell phenotyping of murine lung samples characterized by flow cytometry and immunohistochemistry revealed distinct composition of immune cells between susceptible and resistant mouse strains. Importantly, human PMN and PBMCs showed infection specific transcriptional profiles in vitro skewed towards active phagocytosis. Comparative analyses of both murine and human transcriptome identified unique genes for each data set and shared genes across the samples. Taken together, our findings will contribute to better understand TB disease processes in order to break disease transmission, reducing bacterial burden in active TB patients, shortening treatment duration, and eventually preventing disease development in latent TB cases.enTuberculosisTranscriptomeHumanMouseNeutrophils500thesis.doctoralurn:nbn:de:gbv:841-202504071