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MPEG1/perforin-2 mutations in human pulmonary nontuberculous mycobacterial infections
Ryan M McCormack1, Eva P Szymanski2, Amy P Hsu2
1Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, Florida, USA.
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.
Insights
Perforin-2, a key immune protein, is crucial for fighting bacterial infections. Genetic defects in perforin-2 (MPEG1) in humans can lead to increased susceptibility to persistent mycobacterial diseases.
Area of Science:
- Immunology
- Genetics
- Microbiology
Background:
- Perforin-2 is a conserved pore-forming protein essential for innate immunity.
- Perforin-2-deficient mice exhibit susceptibility to bacterial infections.
- No human diseases were previously linked to perforin-2 deficiencies.
Purpose of the Study:
- To investigate the role of perforin-2 (MPEG1) in human susceptibility to intracellular bacterial infections.
- To identify genetic variations in MPEG1 associated with persistent nontuberculous mycobacterial infections.
Main Methods:
- Clinical evaluation of four patients with persistent nontuberculous mycobacterial infections.
- Genetic analysis to identify heterozygous MPEG1 mutations.
- In vitro functional assays of patient-derived immune cells (neutrophils, macrophages, B cells).
- CRISPR mutagenesis to validate the impact of identified mutations.
Main Results:
- Four patients with persistent nontuberculous mycobacterial infections carried heterozygous MPEG1 mutations.
- Patient immune cells showed impaired killing of Mycobacterium avium in vitro.
- CRISPR mutagenesis confirmed the detrimental effect of these mutations on antibacterial activity.
- Perforin-2 haploinsufficiency was linked to reduced ability to control intracellular bacteria.
Conclusions:
- Heterozygous mutations in MPEG1 (perforin-2) can cause human immunodeficiency.
- Perforin-2 haploinsufficiency contributes to susceptibility to intracellular bacterial infections like nontuberculous mycobacteria.
- This study identifies a novel genetic basis for susceptibility to mycobacterial diseases.