TY - JOUR
T1 - Pulmonary Tuberculosis in Humanized Mice Infected with HIV-1
AU - Nusbaum, Rebecca J.
AU - Calderon, Veronica E.
AU - Huante, Matthew B.
AU - Sutjita, Putri
AU - Vijayakumar, Sudhamathi
AU - Lancaster, Katrina L.
AU - Hunter, Robert L.
AU - Actor, Jeffrey K.
AU - Cirillo, Jeffrey D.
AU - Aronson, Judith
AU - Gelman, Benjamin B.
AU - Lisinicchia, Joshua G.
AU - Valbuena, Gustavo
AU - Endsley, Janice J.
N1 - Funding Information:
The authors wish to express gratitude to Dr. David McMurray at Texas A&M University for many helpful discussions. We additionally thank Mr. Mark Griffin in the UTMB Flow Cytometry and Cell Sorting Core Facility and the staff of the UTMB Animal Resource Core for their expert assistance. We further acknowledge funding from NIH (R21A1089362) and the UTMB Sealy Center for Vaccine Development. Fellowship support was provided for V. Calderon through the UTMB McLaughlin Endowment and for M. Huante through the NIH/ NIAID T32 training program in Biodefense (AI060549T32), the UTMB Kempner Scholar Foundation, and American Society for Microbiology Watkins Fellowship Program.
PY - 2016/2/24
Y1 - 2016/2/24
N2 - 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.
AB - 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.
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U2 - 10.1038/srep21522
DO - 10.1038/srep21522
M3 - Article
C2 - 26908312
AN - SCOPUS:84959422471
SN - 2045-2322
VL - 6
JO - Scientific reports
JF - Scientific reports
M1 - 21522
ER -