Treatment of Virulent Mycobacterium tuberculosis and HIV Coinfected Macrophages with Gallium Nanoparticles Inhibits Pathogen Growth and Modulates Macrophage Cytokine Production

Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a global threat. The course of TB is negatively impacted by coexistent infection with human immunodeficiency virus type 1 (HIV). Macrophage infection with these pathogens modulates their production of pro- and anti-inflammatory cytokines, which could play a crucial role in pathogenesis. Despite the important role of macrophages in containing infection by a variety of microbes, both HIV and M. tuberculosis infect and replicate within these cells during the course of HIV-M. tuberculosis coinfection. Both M. tuberculosis and HIV require iron for growth and replication. We have previously shown that gallium encapsulated in nanoparticles, which interferes with cellular iron acquisition and utilization, inhibited the growth of HIV and an attenuated strain of M. tuberculosis within human monocyte-derived macrophages (MDMs) in vitro. Whether this was true for a fully virulent strain of M. tuberculosis and whether gallium treatment modulates cytokine production by HIV- and/or M. tuberculosis-infected macrophages have not been previously addressed. Therefore, coinfection of MDMs with HIV and a virulent M. tuberculosis strain (H37Rv) was studied in the presence of different gallium nanoparticles (GaNP). All GaNP were readily internalized by the MDMs, which provided sustained drug (gallium) release for 15 days. This led to significant growth inhibition of both HIV and M. tuberculosis within MDMs for up to 15 days after loading of the cells with all GaNP tested in our study. Cytokine analysis showed that HIV-M. tuberculosis coinfected macrophages secreted large amounts of interleukin 6 (IL-6) and IL-8 and smaller amounts of IL-1β, IL-4, and tumor necrosis factor alpha (TNF-α) cytokines. However, all GaNP were able to regulate the release of cytokines significantly. GaNP interrupts iron-mediated enzymatic reactions, leading to growth inhibition of HIV-M. tuberculosis coinfection in macrophages, and also modulates release of cytokines that may contribute to HIV-TB pathogenesis. IMPORTANCE GaNP interrupts iron-mediated enzymatic reactions, leading to growth inhibition of virulent HIV-M. tuberculosis coinfection in macrophages, and also modulates release of cytokines that may contribute to HIV-TB pathogenesis. Macrophage-targeting GaNP are a promising therapeutic approach to provide sustained antimicrobial activity against HIV-M. tuberculosis coinfection.