Apoptosis of Mycobacterium avium-infected macrophages is mediated by both tumour necrosis factor (TNF) and Fas, and involves the activation of caspases

Mycobacterium avium causes disseminated infection in AIDS patients and seve ral forms of infection in immunocompetent hosts. Recent studies have shown that M. avium infection of macrophages in vitro leads to apoptosis of signi ficant numbers of infected cells. Several strains of M. avium used to infec t human macrophages for 5 days (multiplicity of infection of 10) triggered 28-46% higher levels of apoptosis than observed with uninfected macrophages at the same time points. Mycobacterium avium strains unable to replicate i ntracellularly (rep(-)) resulted in a 15% rate of apoptosis, while M. smegm atis-infected monolayers showed the same percentage of apoptotic cells as t he uninfected macrophage control. The presence of anti-TNF-alpha antibody r educed apoptosis to 17% and the presence of anti-Fas antibody reduced apopt osis to 10%. When both antibodies were used together, the apoptosis level w as 5% above the control. Treatment with TGF-beta also reduced the number of apoptotic cells in infected monolayers. If intracellular growth was inhibi ted, apoptosis of macrophages decreased significantly. It was also shown th at apoptosis was associated with IL-1 beta-converting enzyme (ICE) activati on and was significantly reduced by a caspase inhibitor. Gaining understand ing of the mechanisms of M. avium-associated apoptosis of macrophages will provide important insight into M. avium pathogenesis.