Differential Macrophage Response to Slow- and Fast-Growing Pathogenic Mycobacteria

Abstract

Nontuberculous mycobacteria (NTM) have recently been recognized as important species that cause disease even in immunocompetent individuals. The mechanisms that these species use to infect and persist inside macrophages are not well characterised. To gain insight concerning this process we used THP-1 macrophages infected with M. abscessus, M. fortuitum, M. celatum, and M. tuberculosis. Our results showed that slow-growing mycobacteria gained entrance into these cells with more efficiency than fast-growing mycobacteria. We have also demonstrated that viable slow-growing M. celatum persisted inside macrophages without causing cell damage and without inducing reactive oxygen species (ROS), as M. tuberculosis caused. In contrast, fast-growing mycobacteria destroyed the cells and induced high levels of ROS. Additionally, the macrophage cytokine pattern induced by M. celatum was different from the one induced by either M. tuberculosis or fast-growing mycobacteria. Our results also suggest that, in some cases, the intracellular survival of mycobacteria and the immune response that they induce in macrophages could be related to their growth rate. In addition, the modulation of macrophage cytokine production, caused by M. celatum, might be a novel immune-evasion strategy used to survive inside macrophages that is different from the one reported for M. tuberculosis.

Differential Responses by Human Macrophages to Infection With Mycobacterium tuberculosis and Non-tuberculous Mycobacteria

“…Helguera-Repetto et al (2014) compared THP-1 cells infected with M. abscessus, M. fortuitum, M. celatum, and MTB. They found that over a two day period of infection, there was increased growth of M. abscessus and M. fortuitum but the number of M. celatum and MTB remain relatively constant temporally (Helguera-Repetto et al, 2014). The significant differences in the experiments conducted between their study and ours -including differences in MOI used, times of infection before washing the cell culture, maximum time of infection, NTM species used, and macrophage effector function assayed -make these two studies complementary.…”

“…Others have also compared various species of NTM with or without comparison to MTB in macrophage models of infection (Helguera-Repetto et al, 2014;Sousa et al, 2015Sousa et al, , 2019. While mycobacterial burden was consistently quantified in these studies, significant differences in the times of infection and in the assays analyzed make these studies and ours complementary.…”

“…But characterization of MTB with various species of NTM in the context of macrophage infection and the analysis of their effector functions are incomplete. Previous studies have investigated bacterial burden, biofilm formation by RGM (but not M. abscessus), apoptotic and phagosome-lysosome markers among NTM, macrophage monolayer disruption, and production of reactive oxygen intermediates (Helguera-Repetto et al, 2014;Sousa et al, 2015Sousa et al, , 2019. In this study, we compared bacterial burden in macrophages infected with a laboratory strain of MTB with various SGM and RGM species and correlated this marker with some of the known effector mechanisms of killing by macrophages.…”

The microbiome at the pulmonary alveolar niche and its role in Mycobacterium tuberculosis infection

“…In contrast, fast-growing mycobacteria, such as M. tuberculosis , destroy the cells and induce high levels of ROS. The modulation of macrophage cytokine production caused by NTM may constitute an immune-evasion strategy used to survive inside macrophages that is different from the one reported for M. tuberculosis (Helguera-Repetto, et al, 2014). …”

“…Slow growing mycobacteria such as M. abscessus , M. fortuitum , M. celatum, and M. tuberculosis can gain entrance into human macrophages with much more efficiency than fast-growing mycobacteria (Helguera-Repetto et al, 2014). Viable, slow-growing Mycobacteria p ersist inside macrophages without causing cell damage or inducing reactive oxygen species (ROS).…”