McCormack Ryan M, Szymanski Eva P, Hsu Amy P, Perez Elena, Olivier Kenneth N, Fisher Eva, Goodhew E Brook, Podack Eckhard R, Holland Steven M
Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, Florida, USA.
Laboratory of Clinical Infectious Diseases, NIAID, NIH.
JCI Insight. 2017 Apr 20;2(8). doi: 10.1172/jci.insight.89635.
Perforin-2 is a highly conserved pore-forming protein encoded by macrophage expressed gene 1 (MPEG1). 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 Mpeg1+/- heterozygous mice display an intermediate killing ability compared with Mpeg1 WT and Mpeg1-/- 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 MPEG1 mutations. In vitro, neutrophils, macrophages, and B cells from these patients were unable to kill Mycobacterium avium 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.
穿孔素-2是一种由巨噬细胞表达基因1（MPEG1）编码的高度保守的成孔蛋白。多项研究表明，穿孔素-2缺陷型小鼠在受到对野生型小鼠无致死性的细菌攻击后无法存活。最近也有证据表明，与Mpeg1野生型和Mpeg1 -/- 小鼠相比，Mpeg1 +/- 杂合小鼠表现出中等的杀伤能力。尽管有这些体内研究结果，但迄今为止，尚未发现穿孔素-2缺陷与人类疾病有关。在此，我们报告了四名患有持续性非结核分枝杆菌感染的患者，他们具有MPEG1杂合突变。在体外，这些患者的中性粒细胞、巨噬细胞和B细胞杀灭鸟分枝杆菌的效率不如正常对照。CRISPR诱变验证了这些突变的有害抗菌活性。这些数据表明，穿孔素-2单倍体不足可能导致人类对细胞内细菌感染的易感性。
