2. Academic Validation
  3. MPEG1/perforin-2 mutations in human pulmonary nontuberculous mycobacterial infections

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

  • JCI Insight. 2017 Apr 20;2(8):e89635. doi: 10.1172/jci.insight.89635.
Ryan M McCormack 1,  Eva P Szymanski 2,  Amy P Hsu 2,  Elena Perez 1,  Kenneth N Olivier 3,  Eva Fisher 1,  E Brook Goodhew 1,  Eckhard R Podack 1,  Steven M Holland 2
Affiliations

Affiliations

  • 1 Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, Florida, USA.
  • 2 Laboratory of Clinical Infectious Diseases, NIAID, NIH.
  • 3 Cardiovascular and Pulmonary Branch, NHLBI, NIH, Bethesda, Maryland, USA.
PMID: 28422754 DOI: 10.1172/jci.insight.89635
Abstract

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.

Keywords

Genetics; Infectious disease.

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