Development of a Humanized Mouse Model to Understand M.tb and HIV/M.tb Co-infection

Mycobacterium tuberculosis (M.tb) is the most common co-infection and leading cause of death among HIV+ individuals. Several animal models are available to study TB infection although many do not reproduce disease pathology similar to humans. The human host tropism of HIV limits its study in animal models. The lack of a small animal model to study HIV/M.tb co-infection has limited our abilities to fully understand how HIV induces defects in the host immune response to increase susceptibility to M.tb. The goal of these studies is to develop the humanized BLT mouse as a small animal model to study HIV/M.tb co-infection and identify mechanisms of HIV-mediated immune dysfunction that alter the protective response against M.tb infection. Humanized BLT mice are infected with M.tb and develop progressive bacterial infection in the lung that disseminates to other organs (liver, spleen). Pathology displays organized granulomas with cellular cuffing, bacilli localized to the periphery, and caseous necrosis in the center. Other important characteristics of human TB are also observed, including bronchial obstruction, foamy macrophages, lipid deposits, and cholesterol crystal formations. Human T cells (CD3+) are organized at sites of infection in the lung and liver, allowing for the study of mechanisms of immune protection and bacterial evasion. HIV/M.tb co-infected mice develop productive viral infection which disseminates to various organs (lung, liver, spleen). Similar to humans, mice displayed reduced peripheral CD4+ T cell numbers. Granulomatous lesions that vary in size and organization are observed in the lung from necrotic granulomas filled with bacilli surrounded by epitheliod-like macrophages and actively replicating virus, to caseous necrosis granulomas with bacilli localized to the periphery but minimal viral replication. Human T cells (CD4+, CD8+) are scattered throughout the lesions and tissues, and an array of cytokines (Th1, pro-inflammatory) and chemokines are also expressed by co-infected mice, demonstrating the potential to study how HIV alters cell-mediated immunity specifically at sites of infection. These results provide evidence for use of the BLT mouse as a complementary animal model in the study of M.tb infection. Additionally, these results support its use as a small animal model to begin understanding the mechanisms of immune dysfunction to M.tb in HIV-positive populations.