Programmed cell death of Mycobacterium avium serovar 4-infected human macrophages prevents the mycobacteria from spreading and induces mycobacterial growth inhibition by freshly added, uninfected macrophages.

Abstract

Mycobacterium avium, an opportunistic pathogen in AIDS patients, replicates in human macrophages (Mphi) and induces programmed cell death (PCD). In this study we examine the effect of freshly added, uninfected Mphi on M. avium growth in apoptotic Mphi cultures. Incubation of uninfected autologous Mphi with apoptotic Mphi infected with M. avium for 6 h results in 90% inhibition of bacterial growth. The uninfected Mphi adhere to M. avium-infected apoptotic, but not to nonapoptotic M. avium-infected Mphi, suggesting a specific interaction between apoptotic and nonapoptotic Mphi. PCD of the host Mphi also prevents the release of intracellular components and the spread of the mycobacterial infection. Once the apoptotic infected Mphi reach the necrotic stage, mycobacteria and other intracellular material are released; the latter suffice to support extracellular mycobacterial replication. Necrosis of M. avium-infected Mphi is significantly augmented by the transglutaminase inhibitors dansyl-cadaverine and cystamine, indicating that apoptosis of Mphi is dependent on the extent of cross-linking of cell proteins by transglutaminases. Consequently, transglutaminase inhibitors accelerate the release of mycobacteria and intracellular components from the infected Mphi into the medium. These findings indicate that PCD of M. avium-infected Mphi is an important defense mechanism, preventing the spread of infection by sequestering the mycobacteria and by contributing to their demise by activation of newly recruited uninfected Mphi.