Establishing a Human Immune System Mouse Model for Pulmonary and Disseminated Tuberculosis

Animal models have long existed as part of the canonical approach to study a wide array of human infectious pathogens such as Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB) disease. These models have served reasonably well in understanding the heterogeneity of pulmonary granulomas which are the main pathological hallmark of TB in humans. Nevertheless, there are several differences between the human immune system and the immune system of these species that play a role in TB pathogenesis. Ergo, in this thesis: a small animal model capable of delineating the human immune response in regards to TB granuloma heterogeneity is introduced which can serve as a pre-clinical drug platform. The NOD/SCID/IL-2 receptor gamma null (NSG) mouse is an immunodeficient strain capable of supporting human cell engraftment and was thus supplemented with human fetal liver derived stem cells. Upon human immune system (HIS) reconstitution, HIS NSG mice were infected with ultra-low dose aerosolized Mtb. HIS NSG mice developed a range of lung lesions; in particular caseous necrotic granulomas, with a cellular phenotypic spatial-organization similar to that observed in certain TB patients. The core consisted of neutrophilic and monocytic cellular debris, with an inner rim that consisted of elongated macrophages, and an outer lymphocyte cuff that consisted of T and B cells. In addition, disseminated TB was observed in other organs including spleen, liver, kidney and bone marrow. Furthermore, parameters such as cell phenotype, immune and inflammatory biomolecules and spatial-cellular organization were assessed as the disease progressed, leading to the observation that a primarily proinflammatory immune response was generated. This thesis shows that the HIS NSG mouse can provide in vivo validation of prior TB studies with focus on the human immune response. Finally, the HIS NSG mouse lays the groundwork as a novel animal model for investigating TB pathogenesis, TB drug development and eventually HIV-TB coinfection.