Correlates of exacerbated and ameliorated pathogenesis in experimental and clinical tuberculosis
Parasitology and Biology of Tropical Infectious Disease Pathogens
Final Report Abstract
Tuberculosis (TB) is globally still one of the most important infectious disease with increasing numbers of TB cases caused by drug resistant strains of the Mycobacterium tuberculosis (M. tuberculosis) complex are increasing especially in the context of emerging and re-emerging viral diseases or other comorbidities. Our study aimed to identify host specific differences in TB disease susceptibility and pathogenesis. Previously, we and others have demonstrated the detrimental role of neutrophils in cell 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 to better understand TB in vitro and in vivo primarily on transcriptomics level. Inbred female congenic mice differing in their susceptibility to M. tuberculosis infection were studied before, during and after infection and compared to human leukocyte co-cultures and RNA samples from excised human lung tissue of TB patients. 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 showed larger lung lesions and higher bacterial loads than resistant B6 mice. Immune cell phenotyping of murine lung samples characterized by flow cytometry and immunohistochemistry showed distinct lung lesions between susceptible and resistant mouse strains upon M. tuberculosis infection. Importantly, human PMN and PBMCs show infection specific transcriptional profiles skewed towards active phagocytosis. Ultimately, human lung tissue transcriptome signatures revealed differential responses from healthy but lung cancer associated tissue samples, as well as common or distinct responses from infected mouse tissue transcripts. Several interesting gene candidates differentially regulated in susceptible vs. resistant mouse strains also identified in TB patients represent putative targets for host directed therapies accompanying antibiotic treatment. Taken together, our findings 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.
