Pulmonary Tuberculosis in Humanized Mice Infected with HIV-1

Abstract

Co-infection with HIV increases the morbidity and mortality associated with tuberculosis due to multiple factors including a poorly understood microbial synergy. We developed a novel small animal model of co-infection in the humanized mouse to investigate how HIV infection disrupts pulmonary containment of Mtb. Following dual infection, HIV-infected cells were localized to sites of Mtb-driven inflammation and mycobacterial replication in the lung. Consistent with disease in human subjects, we observed increased mycobacterial burden, loss of granuloma structure, and increased progression of TB disease, due to HIV co-infection. Importantly, we observed an HIV-dependent pro-inflammatory cytokine signature (IL-1β, IL-6, TNFα, and IL-8), neutrophil accumulation, and greater lung pathology in the Mtb-co-infected lung. These results suggest that in the early stages of acute co-infection in the humanized mouse, infection with HIV exacerbates the pro-inflammatory response to pulmonary Mtb, leading to poorly formed granulomas, more severe lung pathology, and increased mycobacterial burden and dissemination.

The Goldilocks model of immune symbiosis with Mycobacteria and Candida colonizers

“…Sadly, in humans the detrimental effect of T cell hyporesponsiveness is demonstrated by the morbidity and mortality associated with TB/HIV co-infection, as HIV depletes the T cells that are needed to limit M. tuberculosis growth and dissemination. Recent studies of HIV-infected humanized mice demonstrate that acquired T cell deficiency causes an increase in proinflammatory cytokine expression, which in turn attract PMNs that cause tissue destruction 200 . This immunological chain of events is supported by histological studies of granuloma composition in TB/HIV+ individuals, which are enriched in PMNs relative to those of TB/HIV- individuals 201 .…”

Contribution of Human Lung Parenchyma and Leukocyte Influx to Oxidative Stress and Immune System-Mediated Pathology following Nipah Virus Infection

“…Human lung grafts from 2 tissue donors were surgically implanted into 44 mice as previously described (nonreconstituted mice) (15) (Fig. 1, right), and reconstitution of the human immune system in half of them was established by using the BLT reconstitution method (23,26) with the corresponding tissues from donor 1 or 2 (reconstituted mice) (Fig. 1, left).…”

“…Specifically, 21 and 23 mice received lung tissue from donors 1 and 2, respectively, as previously described (15). Next, 9 and 12 mice among the groups of 21 and 23 mice, respectively, also underwent human immune system reconstitution, as previously described, with the BLT reconstitution method (23,26) by receiving fetal liver and thymus tissue as well as CD34 ϩ fetal liver cells from the corresponding donor 1 or 2. These mice with human immune system reconstitution are referred to in this study as reconstituted mice.…”

“…The level of human immune system reconstitution in BLT mice was assessed before infection by flow cytometry and is expressed as the percentage of human leukocyte CD45 ϩ compared to murine CD45 ϩ populations in 100 l mouse peripheral blood, as previously described (23,26). The human leukocyte CD45 ϩ subpopulations were further analyzed and showed the presence of T cells (human CD3 ϩ , CD4 ϩ , and CD8 ϩ markers) and monocytes/macrophages (CD68 ϩ marker).…”

“…Humanized mouse models have been extensively used to study human diseases and virus pathogenesis (21)(22)(23)(24)(25)(26)(27)(28). These models reconstitute the microenvironment of the human lung to evaluate the host response during virus infection in the human lung.…”