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MPEG1/Perforin-2 Haploinsufficiency Associated Polymicrobial Skin Infections and Considerations for Interferon-γ
Leidy C Merselis1, Shirley Y Jiang2, Stanley F Nelson3,4,5
1University of Miami Miller School of Medicine, Department of Microbiology and Immunology, Miami, FL, United States.
Introduction:
Macrophage expressed gene 1 (MPEG1) is highly expressed in macrophages and other phagocytes. The gene encodes a bactericidal pore-forming protein, dubbed Perforin-2. Structural-, animal-, and cell-based studies have established that perforin-2 facilitates the destruction of phagocytosed microbes upon its activation within acidic phagosomes. Relative to wild-type controls, Mpeg1 knockout mice suffer significantly higher mortality rates when challenged with gram-negative or -positive pathogens. Only four variants of MPEG1 have been functionally characterized, each in association with pulmonary infections. Here we report a new MPEG1 non-sense variant in a patient with the a newly described association with persistent polymicrobial infections of the skin and soft tissue.
Case Description:
A young adult female patient was evaluated for recurrent abscesses and cellulitis of the breast and demonstrated a heterozygous, rare variant in MPEG1 p.Tyr430*. Multiple courses of broad-spectrum antimicrobials and surgical incision and drainage failed to resolve the infection. Functional studies revealed that the truncation variant resulted in significantly reduced capacity of the patient's phagocytes to kill intracellular bacteria. Patient-derived macrophages responded to interferon gamma (IFN-γ) by significantly increasing the expression of MPEG1. IFN-γ treatment supported perforin-2 dependent bactericidal activity and wound healing.
Conclusions:
This case expands the phenotype of MPEG1 deficiency to include severe skin and soft tissue infection. We showed that haploinsufficiency of perforin-2 reduced the bactericidal capacity of human phagocytes. Interferon-gamma therapy increases expression of perforin-2, which may compensate for such variants. Thus, treatment with IFN-γ could help prevent infections.
Insights
A novel Macrophage expressed gene 1 (MPEG1) variant causes severe skin infections by impairing phagocyte function. Interferon-gamma therapy may restore bactericidal activity and aid healing.
Area of Science:
- Immunology
- Genetics
- Microbiology
Background:
- Macrophage expressed gene 1 (MPEG1) encodes Perforin-2, a bactericidal protein crucial for phagocyte defense against microbes.
- MPEG1 deficiency in mice leads to increased susceptibility to pathogens.
- Previous studies linked MPEG1 variants to pulmonary infections.
Observation:
- A patient with recurrent skin and soft tissue infections presented with a rare, heterozygous nonsense variant in MPEG1 (p.Tyr430*).
- The patient's phagocytes exhibited reduced intracellular bacterial killing capacity.
- Interferon-gamma (IFN-γ) treatment increased MPEG1 expression and enhanced phagocyte bactericidal activity.
Findings:
- This case identifies a new association between MPEG1 variants and persistent polymicrobial skin and soft tissue infections.
- Haploinsufficiency of Perforin-2 impairs human phagocyte bactericidal capacity.
- IFN-γ therapy can upregulate Perforin-2 expression, potentially compensating for genetic variants.
Implications:
- The phenotype of MPEG1 deficiency is expanded to include severe skin and soft tissue infections.
- IFN-γ treatment represents a potential therapeutic strategy for patients with MPEG1 variants.
- Understanding Perforin-2's role in innate immunity can inform strategies for managing recurrent infections.
