Humanized Mouse Model Mimicking Pathology of Human Tuberculosis for in vivo Evaluation of Drug Regimens

• Published in: Frontiers in immunology Vol. 10; p. 89
• Main Authors: Arrey, Frida, Löwe, Delia, Kuhlmann, Stefanie, Kaiser, Peggy, Moura-Alves, Pedro, Krishnamoorthy, Gopinath, Lozza, Laura, Maertzdorf, Jeroen, Skrahina, Tatsiana, Skrahina, Alena, Gengenbacher, Martin, Nouailles, Geraldine, Kaufmann, Stefan H E
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 2019
• Subjects: Animals; Antitubercular Agents - therapeutic use; Disease Models, Animal; Drug Therapy, Combination; Female; granuloma; Granuloma - drug therapy; Granuloma - pathology; Hematopoietic Stem Cell Transplantation; human immune system mice; humanized mouse models; Humans; Immunology; infection; lung; Lung - immunology; Lung - microbiology; Male; Mice; Mice, Inbred C57BL; Moxifloxacin - therapeutic use; Mycobacterium tuberculosis; Mycobacterium tuberculosis - physiology; Tuberculosis, Pulmonary - drug therapy; Tuberculosis, Pulmonary - pathology; lung; infection; humanized mouse models; pathology; Mycobacterium tuberculosis; granuloma; human immune system mice; antibiotics
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2019.00089

Human immune system mice are highly valuable for dissection of human immune responses. Although they were employed for analyzing tuberculosis (TB) disease, there is little data on the spatial organization and cellular composition of human immune cells in TB granuloma pathology in this model. We demonstrate that human immune system mice, generated by transplanted human fetal liver derived hematopoietic stem cells develop a continuum of pulmonary lesions upon aerosol infection. In particular, caseous necrotic granulomas, which contribute to prolonged TB treatment time, developed, and had cellular phenotypic spatial-organization similar to TB patients. By comparing two recommended drug regimens, we confirmed observations made in clinical settings: Adding Moxifloxacin to a classical chemotherapy regimen had no beneficial effects on bacterial eradication. We consider this model instrumental for deeper understanding of human specific features of TB pathogenesis and of particular value for the pre-clinical drug development pipeline.