Mechanisms of Innate Immune Dysfunction During Mycobacterium tuberculosis and HIV Co-infection

Mycobacterium tuberculosis (Mtb), the etiologic agent of Tuberculosis (TB), remains a significant public health threat causing over 1.4 million deaths annually. People living with HIV are among the most susceptible to contracting or reactivating Mtb infection due to a deterioration of essential immunity during co-infection. Although cell-mediated and innate immunity are known to contribute, the mechanisms leading to exacerbated pulmonary inflammation and increased pathogenesis are largely unknown. The long-term goal of this study is to characterize innate immune signaling responses of macrophages, which drive excessive inflammation during Mtb and HIV co-infection. We previously identified that synergistic inflammasome activation within macrophages, the cellular host of both Mtb and HIV, leads to a caspase-1 dependent increase in IL-1β secretion and cell death in vitro. To target the inflammasome pathway for host-directed therapy, the selective caspase-1 inhibitor, VX-765, was used. VX-765 treatment diminished caspase-1 enzyme activity within human macrophage cell lines in a dose-dependent manner. Although VX-765 was effective in vitro, only mild and non-significant effects on disease progression during in vivo TB and TB/HIV co-infection models were observed. Additionally, this work identified a novel role for the CLR Macrophage Galactose-type Lectin-1 (MGL-1) in a mouse model (C57BL/6 and MGL-1-/-) of experimental tuberculosis. Murine macrophages upregulated MGL-1 following in vitro and in vivo exposure to Mtb, while MGL+ cells accumulated at sites of mycobacteria-driven inflammation in the lung. Pulmonary macrophages from MGL-1-deficient mice infected with Mtb displayed increased pro-inflammatory cytokine levels (IL-1β, IL-6, and IFN-g) associated with significant lipid accumulation. Surprisingly for a CLR, we also observed MGL-1-dependent anti-mycobacterial activity, evidenced by greater Mtb proliferation in BMDMs and the lung of MGL-1 deficient mice. Human CLR expression was further evaluated in a humanized mouse model of Mtb, HIV, and co-infection. Surface expression of MGL was increased following early HIV infection (two weeks) but was later diminished seven weeks post-HIV as disease progressed. In contrast, other CLRs (DC-SIGN) persisted through the course of HIV and Mtb infections. Similar to the murine model, Mtb infection in humanized mice resulted in significant MGL expression on pulmonary macrophages. These results identify MGL and CLR signaling as a mechanism of innate immune regulation against Mtb which HIV may manipulate in the co-infection environment. Taken together, these studies serve as potential host-directed therapeutic targets to limit excessive inflammation and disease progression during Mtb and HIV co-infection.

Name thesis:degree_name

Experimental Pathology (Doctoral)

Grantor

The University of Texas Medical Branch at Galveston

Year dc:date.issued

2021

Author dc:creator

• Naqvi, Kubra

• Biology, Microbiology
• Health Sciences, Immunology
• Health Sciences, Pathology

Handle dc:identifier.uri

https://hdl.handle.net/2152.3/12482

OAI identifier oai:identifier

oai:utmb-ir.tdl.org:2152.3/12482