MPEG1/Perforin-2 Haploinsufficiency Associated Polymicrobial Skin Infections and Considerations for Interferon-γ Therapy - PubMed (original) (raw)

Case Reports

MPEG1/Perforin-2 Haploinsufficiency Associated Polymicrobial Skin Infections and Considerations for Interferon-γ Therapy

Leidy C Merselis et al. Front Immunol. 2020.

Abstract

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.

Keywords: MPEG1 p.Tyr430*; case report; interferon gamma; membrane attack complex; perforin-2; primary immunodeficiency.

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Figures

Figure 1

Relative location of Tyr430 within perforin-2 and demonstration of reduced killing capacity of the patient’s phagocytes. (A) Domain organization of perforin-2 with its signal peptide, membrane-attack-complex-perforin (MACPF) domain (blue), EGF-like domain (dark blue), perforin-2 domain (yellow), and carboxy-terminal transmembrane domain (brown, red). (B) Top and side view of the acid-dependent perforin-2 pore (6). Each polymer comprises 16 subunits with MACPF and P2 domains lining the interior and exterior of the polymer. Tyr430 is depicted as magenta spheres within the P2 domain. Horizontal bars represent the approximate location of the target lipid bilayer. (C) Neutrophil killing assay showing fold change over time of intracellular bacterial colony forming units. (D) Macrophage killing assay showing fold change over time of intracellular bacterial colony forming units. log2FC = log2(CFU at time X) – log2(CFU at time initial). **P < 0.04 to age and gender (A&G) shipping control, and P < 0.02 to non-matched, unrelated control.

Figure 2

Infection and IFN-γ induction of MPEG1. (A) Purulent abscesses in the right breast. (B) MPEG1 transcripts are induced after treatment in vitro with IFN-γ.

References

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MPEG1/Perforin-2 Haploinsufficiency Associated Polymicrobial Skin Infections and Considerations for Interferon-γ Therapy - PubMed (original) (raw)