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

McCormack, Ryan; Szymanski, Eva P.; Hsu, Amy P.; Perez, Elena E.; Olivier, Kenneth N.; Fisher, Eva; Goodhew, E. Brook; Podack, Eckhard R.; Holland, Steven M.

doi:10.1172/jci.insight.89635

Cited by 32 publications

(35 citation statements)

References 38 publications

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“…Finally, our work sheds new lights on B cell immunity in zebrafish and may open new perspectives in the field of comparative immunology. As expression of perforin‐2 in professional phagocytes is tied to microbicidal activity, it was tempting to speculate that mpeg1 could discriminate functionally distinct B cell populations in the zebrafish. This hypothesis was further supported by evidence from the literature that B cells in teleosts are capable to phagocytose particles and microorganisms and also display microbicidal activity .…”

Section: Discussionmentioning

confidence: 99%

Themacrophage-expressed gene(mpeg)1identifies a subpopulation of B cells in the adult zebrafish

Ferrero

Gomez

lyer

et al. 2020

Journal of Leukocyte Biology

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The mononuclear phagocytic system consists of many cells, in particular macrophages, scattered throughout the body. However, there is increasing evidence for the heterogeneity of tissue‐resident macrophages, leading to a pressing need for new tools to discriminate mononuclear phagocytic system subsets from other hematopoietic lineages. Macrophage‐expressed gene (Mpeg)1.1 is an evolutionary conserved gene encoding perforin‐2, a pore‐forming protein associated with host defense against pathogens. Zebrafish mpeg1.1:GFP and mpeg1.1:mCherry reporters were originally established to specifically label macrophages. Since then more than 100 peer‐reviewed publications have made use of mpeg1.1‐driven transgenics for in vivo studies, providing new insights into key aspects of macrophage ontogeny, activation, and function. Whereas the macrophage‐specific expression pattern of the mpeg1.1 promoter has been firmly established in the zebrafish embryo, it is currently not known whether this specificity is maintained through adulthood. Here we report direct evidence that beside macrophages, a subpopulation of B‐lymphocytes is marked by mpeg1.1 reporters in most adult zebrafish organs. These mpeg1.1+ lymphoid cells endogenously express mpeg1.1 and can be separated from mpeg1.1+ macrophages by virtue of their light‐scatter characteristics using FACS. Remarkably, our analyses also revealed that B‐lymphocytes, rather than mononuclear phagocytes, constitute the main mpeg1.1‐positive population in irf8null myeloid‐defective mutants, which were previously reported to recover tissue‐resident macrophages in adulthood. One notable exception is skin macrophages, whose development and maintenance appear to be independent from irf8, similar to mammals. Collectively, our findings demonstrate that irf8 functions in myelopoiesis are evolutionary conserved and highlight the need for alternative macrophage‐specific markers to study the mononuclear phagocytic system in adult zebrafish.

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Section: Discussionmentioning

confidence: 99%

Themacrophage-expressed gene(mpeg)1identifies a subpopulation of B cells in the adult zebrafish

Ferrero

Gomez

lyer

et al. 2020

Journal of Leukocyte Biology

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“…P‐2 is a highly conserved innate protein with unique properties to kill intracellular (both Gram‐positive and Gram‐negative) bacteria. P‐2, encoded by mpeg1 gene, is a transmembrane protein inserted in membrane vesicles that forms pores on targets (intracellular bacteria) entrapped by membrane vesicles . In professional phagocytic cells, P‐2 is expressed constitutively, where in other cells, P‐2 expression can be induced by interferon (IFN), LPS and TNF‐α, or by bacterial infection …”

Section: Discussionmentioning

confidence: 99%

“…Recently, it was shown that enteropathogenic E. coli and Y. pseudotuberculosis inhibit P‐2‐dependent killing by blocking its intracellular trafficking through bacterial effector protein Cif . Also, it has been shown that individuals with P‐2 haploinsufficiency suffer to higher rates of chronic and recurring infectious disease than the general population …”

Section: Discussionmentioning

confidence: 99%

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Single cell analyses reveal specific distribution of anti‐bacterial molecule Perforin‐2 in human skin and its modulation by wounding and Staphylococcus aureus infection

Štrbo

Pastar

Romero

et al. 2019

Experimental Dermatology

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Perforin‐2 (P‐2) is a recently described antimicrobial protein with unique properties to kill intracellular bacteria. We investigated P‐2 expression pattern and cellular distribution in human skin and its importance in restoration of barrier function during wound healing process and infection with the common wound pathogen Staphylococcus aureus. We describe a novel approach for the measurement of P‐2 mRNA within individual skin cells using an amplified fluorescence in situ hybridization (FISH) technique. The unique aspect of this approach is simultaneous detection of P‐2 mRNA in combination with immune‐phenotyping for cell surface proteins using fluorochrome‐conjugated antibodies. We detected P‐2 transcript in both hematopoietic (CD45+) and non‐hematopoietic (CD45−) cutaneous cell populations, confirming the P‐2 expression in both professional and non‐professional phagocytes. Furthermore, we found an induction of P‐2 during wound healing. P‐2 overexpression resulted in a reduction of intracellular S. aureus, while infection of human wounds by this pathogen resulted in P‐2 suppression, revealing a novel mechanism by which S. aureus may escape cutaneous immunity to cause persistent wound infections.

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“…new perspectives in the field of comparative immunology. As expression of perforin-2 in professional phagocytes is tied to microbicidal activity 12,13,37,41 , it was tempting to speculate that mpeg1 could discriminate functionally distinct B cell populations in the zebrafish. This hypothesis was further supported by evidence from the literature that B cells in teleosts are capable to phagocytose particles and microorganisms and also display microbicidal activity 42,43 .…”

Section: Finally Our Work Sheds New Lights On B Cell Immunity In Zebmentioning

confidence: 99%

Themacrophage-expressed gene(mpeg)1identifies a subpopulation of B cells in the adult zebrafish

Ferrero

Gomez

Iyer

et al. 2019

Preprint

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SENTENCEMpeg1 is not a restricted macrophage marker, but also labels B cells in the adult zebrafish. Therefore, previously identified irf8-independent macrophages likely consist of B lymphocytes. 2 ABSTRACTThe mononuclear phagocytic system (MPS) consists of many cells, in particular macrophages, scattered throughout the body. However, there is increasing evidence for the heterogeneity of tissue-resident macrophages, leading to a pressing need for new tools to discriminate MPS subsets from other hematopoietic lineages. Mpeg1.1 is an evolutionary conserved gene encoding perforin-2, a pore-forming protein associated with host defense against pathogens. Zebrafish mpeg1.1:GFP and mpeg1.1:mCherry reporters were originally established to specifically label macrophages. Since, more than 100 peer-reviewed publications have made use of mpeg1.1-driven transgenics for in vivo studies, providing new insights into key aspects of macrophage ontogeny, activation and function. However, while the macrophagespecific expression pattern of the mpeg1.1 promoter has been firmly established in the zebrafish embryo, it is currently not known whether this specificity is maintained through adulthood. Here we report direct evidence that beside macrophages, a subpopulation of B-lymphocytes is marked by mpeg1.1 reporters in most adult zebrafish organs. These mpeg1.1 + lymphoid cells endogenously express mpeg1.1 and can be separated from mpeg1.1 + macrophages by virtue of their light-scatter characteristics using FACS. Remarkably, our analyses also revealed that Blymphocytes, rather than mononuclear phagocytes, constitute the main mpeg1.1positive population in irf8 null myeloid-defective mutants, which were previously reported to recover tissue-resident macrophages in adulthood. One notable exception are skin macrophages, whose development and maintenance appear to be independent from irf8, similar to mammals. Collectively, our findings demonstrate that irf8 functions in myelopoiesis are evolutionary conserved and highlight the need for alternative macrophage-specific markers to study the MPS in adult zebrafish.

show abstract

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

Cited by 32 publications

References 38 publications

Themacrophage-expressed gene(mpeg)1identifies a subpopulation of B cells in the adult zebrafish

Themacrophage-expressed gene(mpeg)1identifies a subpopulation of B cells in the adult zebrafish

Single cell analyses reveal specific distribution of anti‐bacterial molecule Perforin‐2 in human skin and its modulation by wounding and Staphylococcus aureus infection

Themacrophage-expressed gene(mpeg)1identifies a subpopulation of B cells in the adult zebrafish

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