AUTHOR=Bohórquez José Alejandro  , Adduri Sitaramaraju , Ansari Danish , John Sahana , Florence Jon , Adejare Omoyeni , Singh Gaurav , Konduru Nagarjun V. , Jagannath Chinnaswamy , Yi Guohua 

TITLE=A novel humanized mouse model for HIV and tuberculosis co-infection studies

JOURNAL=Frontiers in Immunology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1395018

DOI=10.3389/fimmu.2024.1395018

ISSN=1664-3224

ABSTRACT=<sec><title>Background</title><p>Tuberculosis (TB), caused by <italic>Mycobacterium tuberculosis</italic> (<italic>Mtb</italic>), continues to be a major public health problem worldwide. The human immunodeficiency virus (HIV) is another equally important life-threatening pathogen. HIV infection decreases CD4+ T cell levels markedly increasing <italic>Mtb</italic> co-infections. An appropriate animal model for HIV/<italic>Mtb</italic> co-infection that can recapitulate the diversity of the immune response in humans during co-infection would facilitate basic and translational research in HIV/<italic>Mtb</italic> infections. Herein, we describe a novel humanized mouse model.</p></sec><sec><title>Methods</title><p>The irradiated NSG-SGM3 mice were transplanted with human CD34+ hematopoietic stem cells, and the humanization was monitored by staining various immune cell markers for flow cytometry. They were challenged with HIV and/or <italic>Mtb</italic>, and the CD4+ T cell depletion and HIV viral load were monitored over time. Before necropsy, the live mice were subjected to pulmonary function test and CT scan, and after sacrifice, the lung and spleen homogenates were used to determine <italic>Mtb</italic> load (CFU) and cytokine/chemokine levels by multiplex assay, and lung sections were analyzed for histopathology. The mouse sera were subjected to metabolomics analysis.</p></sec><sec><title>Results</title><p>Our humanized NSG-SGM3 mice were able to engraft human CD34+ stem cells, which then differentiated into a full-lineage of human immune cell subsets. After co-infection with HIV and <italic>Mtb</italic>, these mice showed decrease in CD4+ T cell counts overtime and elevated HIV load in the sera, similar to the infection pattern of humans. Additionally, <italic>Mtb</italic> caused infections in both lungs and spleen, and induced granulomatous lesions in the lungs. Distinct metabolomic profiles were also observed in the tissues from different mouse groups after co-infections.</p></sec><sec><title>Conclusion</title><p>The humanized NSG-SGM3 mice are able to recapitulate the pathogenic effects of HIV and <italic>Mtb</italic> infections and co-infection at the pathological, immunological and metabolism levels and are therefore a reproducible small animal model for studying HIV/<italic>Mtb</italic> co-infection.</p></sec>