Perforin-2 Breaches the Envelope of Phagocytosed Bacteria Allowing Antimicrobial Effectors Access to Intracellular Targets

Bai, Fangfang; McCormack, Ryan; Hower, Suzanne; Plano, Gregory V.; Lichtenheld, Mathias G.; Munson, George P.

doi:10.4049/jimmunol.1800365

Cited by 21 publications

(32 citation statements)

References 62 publications

(101 reference statements)

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“…Although the precise details are under investigation, perforin-2 is trafficked to endo/phagosomes where it polymerizes into a pre-pore structure that subsequently transitions to a pore conformation upon phagosome acidification (2,4,8). These pores perforate the envelope of phagocytosed pathogens, rendering them more susceptible to antimicrobial effector such as proteases, other hydrolases, and reactive oxygen and nitrogen species (2,5). Studies of Mpeg1 knockout mice have shown that deficiencies in this protein lead to uncontrolled, disseminated infection from the gut and skin, as well as a host of other immunologic consequences (2)(3)(4).…”

Section: Discussionmentioning

confidence: 99%

“…MPEG1 expression is constitutive in phagocytes and inducible in parenchymal cell lines by interferons or bacterial infection (1,2). Its function in innate immunity is vital for intracellular pathogen elimination such that Mpeg1 knockout mice exhibit increased susceptibility to infections (2)(3)(4)(5). MPEG1 variants can confer an immunodeficiency hallmarked by polymicrobial infections (1).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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 nonsense 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-g) by significantly increasing the expression of MPEG1. IFN-g 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

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…The addition of minute quantities of lysozyme, however, were sufficient to kill pre-treated M. smegmatis, putatively indicating MPEG1 perforates the outer membrane but does not affect the integrity of the peptidoglycan layer (90). Indeed, more recent studies have found MPEG1 facilitates the entry of myriad anti-microbial effectors into cells including; proteases, reactive oxygen and nitrogen species, bactericidal peptides and the harsh acidic environment of the phagosome (93). Notably, recombinant MPEG1 possesses lytic activity which is strictly dependent on low pH (82,83).…”

Section: Mpeg1 Function In Immunitymentioning

confidence: 99%

Ancient but Not Forgotten: New Insights Into MPEG1, a Macrophage Perforin-Like Immune Effector

et al. 2020

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Macrophage-expressed gene 1 [MPEG1/Perforin-2 (PRF2)] is an ancient metazoan protein belonging to the Membrane Attack Complex/Perforin (MACPF) branch of the MACPF/Cholesterol Dependent Cytolysin (CDC) superfamily of pore-forming proteins (PFPs). MACPF/CDC proteins are a large and extremely diverse superfamily that forms large transmembrane aqueous channels in target membranes. In humans, MACPFs have known roles in immunity and development. Like perforin (PRF) and the membrane attack complex (MAC), MPEG1 is also postulated to perform a role in immunity. Indeed, bioinformatic studies suggest that gene duplications of MPEG1 likely gave rise to PRF and MAC components. Studies reveal partial or complete loss of MPEG1 causes an increased susceptibility to microbial infection in both cells and animals. To this end, MPEG1 expression is upregulated in response to proinflammatory signals such as tumor necrosis factor a (TNFa) and lipopolysaccharides (LPS). Furthermore, germline mutations in MPEG1 have been identified in connection with recurrent pulmonary mycobacterial infections in humans. Structural studies on MPEG1 revealed that it can form oligomeric pre-pores and pores. Strikingly, the unusual domain arrangement within the MPEG1 architecture suggests a novel mechanism of pore formation that may have evolved to guard against unwanted lysis of the host cell. Collectively, the available data suggest that MPEG1 likely functions as an intracellular pore-forming immune effector. Herein, we review the current understanding of MPEG1 evolution, regulation, and function. Furthermore, recent structural studies of MPEG1 are discussed, including the proposed mechanisms of action for MPEG1 bactericidal activity. Lastly limitations, outstanding questions, and implications of MPEG1 models are explored in the context of the broader literature and in light of newly available structural data.

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“…Other bactericidal molecules have been found to be less effective in the absence of P2, suggesting that P2 is essential for the activity of mammalian immune defense mechanisms. It has recently been shown that P2 facilitates the delivery of proteases and other antimicrobial effectors to the sites of bacterial infection leading to effective killing of phagocytosed bacteria (4).…”

Section: Introductionmentioning

confidence: 99%

Impaired B Cell Function in Mice Lacking Perforin-2

et al. 2020

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Perforin-2 (P2) is a pore-forming protein with cytotoxic activity against intracellular bacterial pathogens. P2 knockout (P2KO) mice are unable to control infections and die from normally non-lethal bacterial infections. Here we show that P2KO mice as compared to WT mice show significantly higher levels of systemic inflammation, measured by inflammatory markers in serum, due to continuous microbial translocation from the gut which cannot be controlled as these mice lack P2. Systemic inflammation in young and old P2KO mice induces intrinsic B cell inflammation. Systemic and B cell intrinsic inflammation are negatively associated with in vivo and in vitro antibody responses. Chronic inflammation leads to class switch recombination defects, which are at least in part responsible for the reduced in vivo and in vitro antibody responses in young and old P2KO vs. WT mice. These defects include the reduced expression of activation-induced cytidine deaminase (AID), the enzyme for class switch recombination, somatic hypermutation and IgG production and of its transcriptional activators E47 and Pax5. Of note, the response of young P2KO mice is not different from the one observed in old WT mice, suggesting that the chronic inflammatory status of mice lacking P2 may accelerate, or be equivalent, to that seen in old mice. The inflammatory status of the splenic B cells is associated with increased frequencies and numbers of the pro-inflammatory B cell subset called Age-associated B Cells (ABCs) in the spleen and the visceral adipose tissue (VAT) of P2KO old mice. We show that B cells differentiate into ABCs in the VAT following interaction with the adipocytes and their products, and this occurs more in the VAT of P2KO mice as compared to WT controls. This is to our knowledge the first study on B cell function and antibody responses in mice lacking P2.

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Perforin-2 Breaches the Envelope of Phagocytosed Bacteria Allowing Antimicrobial Effectors Access to Intracellular Targets

Cited by 21 publications

References 62 publications

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

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

Ancient but Not Forgotten: New Insights Into MPEG1, a Macrophage Perforin-Like Immune Effector

Impaired B Cell Function in Mice Lacking Perforin-2

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