MPEG1/perforin-2 mutations in human pulmonary nontuberculous mycobacterial infections

<jats:p> Perforin-2 is a highly conserved pore-forming protein encoded by macrophage expressed gene 1 ( <jats:italic>MPEG1</jats:italic> ). A number of studies have shown that Perforin-2–deficient mice are unable to survive following a bacterial challenge that is nonlethal in WT mice. There is also recent evidence that <jats:italic>Mpeg1</jats:italic> <jats:sup>+/–</jats:sup> heterozygous mice display an intermediate killing ability compared with <jats:italic>Mpeg1</jats:italic> WT and <jats:italic>Mpeg1</jats:italic> <jats:sup>–/–</jats:sup> mice. Despite these in vivo findings, to date, no perforin-2 deficiencies have been associated with human disease. Here, we report four patients with persistent nontuberculous mycobacterial infection who had heterozygous <jats:italic>MPEG1</jats:italic> mutations. In vitro, neutrophils, macrophages, and B cells from these patients were unable to kill <jats:italic>Mycobacterium avium</jats:italic> as efficiently as normal controls. CRISPR mutagenesis validated the deleterious antibacterial activity of these mutations. These data suggest that perforin-2 haploinsufficiency may contribute to human susceptibility to infections with intracellular bacteria. </jats:p>