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

Abstract

Human immune system mice are highly valuable for in vivo 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 Mycobacterium tuberculosis 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.

Recent Advancements and Applications of Human Immune System Mice in Preclinical Immuno-Oncology

“…To complete and validate the characterization of human immune reconstitution by flow cytometry, immunohistochemistry (IHC) offers spatial context and histopathology to better understand tissue homing of human cells and identify instances of GvHD, that is, inflammatory lesions dominated by T cells (CD4þ mainly) and macrophages, which must be considered in data interpretation. [71][72][73] Despite technological advances, the evaluation of human immune cells by flow cytometry and IHC is limited by technical constraints. Most flow cytometers are limited to 12-18 parameters per single sample and issues with spectral overlap make analysis difficult.…”

Humanized Mice for Live-Attenuated Vaccine Research: From Unmet Potential to New Promises

“…NSG-HIS mice have been reported to mimic clinical features of human tuberculosis infection [325]. Following aerosol infection, pulmonary lesions and necrotic granulomas displaying similarities with those observed in patients could be observed.…”

One Size Fits All? Not in In Vivo Modeling of Tuberculosis Chemotherapeutics

“…Efficacy in acute and chronic infection, (Calderon et al, 2013;Arrey et al, 2019) Guinea Pig Dunkin-Harley strain (Mtb H37Rv and clinical strains) 300-1,000 g (>3 months) 4-6 per group -outbred Cellular lesions, granulocytic pneumonia, caseous necrotic lesions, Efficacy in acute and chronic disease, HDT, modeling comorbidities (Lenaerts et al, 2007;Clark et al, 2011;Clark et al, 2014;Chen et al, (Manabe et al, 2008;Subbian et al, 2012;Via et al, 2012;Subbian et al, 2016;Tsenova et al, 2020) (Lin et al, 2013;Rayner et al, 2013;Coleman et al, 2014a;Scanga and Flynn, 2014;Sharpe et al, 2017) a Laboratory Animal Medicine (Fox et al, 2015).…”

“…Despite the expense of humanized mice, they have significant advantages including the availability of human immunological reagents and mimicking human immune system (Calderon et al, 2013). After Mtb infection, humanized mice have more homogeneous bacterial loads and similar heterogeneity of lesion pathology resulting in a more consistent and reproducible mouse model (Arrey et al, 2019) when compared to the C3HeB/ FeJ mice, (Irwin et al, 2015;Li et al, 2015). Collaborative Cross (CC) mice are a panel of recombinant inbred mice that are derived from eight genetically diverse sets of founder mice, consisting of five inbred laboratory strains including: C57BL/C and A/J, as well as three wild-derived lines using a specific mating scheme (Svenson et al, 2012).…”