Pulmonary Tuberculosis in Humanized Mice Infected with HIV-1

Area of Science:

• Immunology
• Infectious Diseases
• Microbiology

Background:

• Co-infection with HIV significantly increases tuberculosis (TB) morbidity and mortality.
• The microbial synergy between HIV and Mycobacterium tuberculosis (Mtb) is not well understood.
• HIV's impact on pulmonary containment of Mtb requires further investigation.

Purpose of the Study:

• To investigate how HIV infection disrupts pulmonary containment of Mtb.
• To characterize the early stages of Mtb and HIV co-infection in a humanized mouse model.
• To elucidate the mechanisms underlying exacerbated TB disease in the context of HIV co-infection.

Main Methods:

• Development of a novel small animal model using humanized mice for Mtb and HIV co-infection.
• Localization of HIV-infected cells within Mtb-driven inflammatory sites in the lung.
• Analysis of mycobacterial burden, granuloma structure, cytokine profiles, neutrophil accumulation, and lung pathology.

Main Results:

• HIV-infected cells were found at sites of Mtb inflammation and replication.
• Co-infection led to increased mycobacterial burden, disrupted granuloma structure, and advanced TB disease.
• An HIV-dependent pro-inflammatory cytokine signature (IL-1β, IL-6, TNFα, IL-8), neutrophil influx, and exacerbated lung pathology were observed.

Conclusions:

• HIV co-infection exacerbates the pro-inflammatory response to pulmonary Mtb in the early stages.
• This heightened inflammation results in poorly formed granulomas and increased lung pathology.
• HIV exacerbates Mtb dissemination, leading to increased mycobacterial burden and disease severity.