Interferon-mediated reprogramming of membrane cholesterol to evade bacterial toxins

Quan D. Zhou; Xun Chi; Min Sub Lee; Wei Yuan Hsieh; Jonathan J. Mkrtchyan; An Chieh Feng; Cuiwen He; Autumn G. York; Viet L. Bui; Eliza B. Kronenberger; Alessandra Ferrari; Xu Xiao; Allison E. Daly; Elizabeth J. Tarling; Robert Damoiseaux; Philip O. Scumpia; Stephen T. Smale; Kevin J. Williams; Peter Tontonoz; Steven J. Bensinger

doi:10.1038/s41590-020-0695-4

Interferon-mediated reprogramming of membrane cholesterol to evade bacterial toxins

Quan D. Zhou
, Xun Chi
, Min Sub Lee
, Wei Yuan Hsieh
, Jonathan J. Mkrtchyan
, An Chieh Feng
, Cuiwen He
, Autumn G. York
, Viet L. Bui
, Eliza B. Kronenberger
, Alessandra Ferrari
, Xu Xiao
, Allison E. Daly
, Elizabeth J. Tarling
, Robert Damoiseaux
, Philip O. Scumpia
, Stephen T. Smale
, Kevin J. Williams
, Peter Tontonoz
, Steven J. Bensinger

Physiology

Research output: Contribution to journal › Article › peer-review

78 Scopus citations

Abstract

Plasma membranes of animal cells are enriched for cholesterol. Cholesterol-dependent cytolysins (CDCs) are pore-forming toxins secreted by bacteria that target membrane cholesterol for their effector function. Phagocytes are essential for clearance of CDC-producing bacteria; however, the mechanisms by which these cells evade the deleterious effects of CDCs are largely unknown. Here, we report that interferon (IFN) signals convey resistance to CDC-induced pores on macrophages and neutrophils. We traced IFN-mediated resistance to CDCs to the rapid modulation of a specific pool of cholesterol in the plasma membrane of macrophages without changes to total cholesterol levels. Resistance to CDC-induced pore formation requires the production of the oxysterol 25-hydroxycholesterol (25HC), inhibition of cholesterol synthesis and redistribution of cholesterol to an esterified cholesterol pool. Accordingly, blocking the ability of IFN to reprogram cholesterol metabolism abrogates cellular protection and renders mice more susceptible to CDC-induced tissue damage. These studies illuminate targeted regulation of membrane cholesterol content as a host defense strategy.

Original language	English
Pages (from-to)	746-755
Number of pages	10
Journal	Nature Immunology
Volume	21
Issue number	7
DOIs	https://doi.org/10.1038/s41590-020-0695-4
State	Published - Jul 1 2020

Bibliographical note

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.

Funding

This research was supported by NIH grants AI093768 (to S.J.B.), HL146358 (to S.J.B. and P.T.), AR073940 (to P.O.S), and HL136543 (to E.J.T.). M.S.L. is supported by Ruth L. Kirschstein National Research Service Award AI007323. The research described was also supported by an NIH/National Center for Advancing Translational Science (NCATS) UCLA CTSI grant (UL1TR001881). We thank S. Young, T. Weston and R.S. Jung for help with protein purification. We thank T. Weston for NanoSIMS sample preparation and SEM imaging. We thank A. Divakaruni for guidance with PFO permeabilization assays. We thank A. Radhakrishnan for ALO-D4 and full-length ALO plasmids. We thank S. Young, A. Hoffmann, Y. Du, R. Sun, T.-T. Wu, J. F. Miller and M. Li for thoughtful discussions.

Funders	Funder number
NIH National Center for Advancing Translational Sciences and Center for Clinical and Translational Science
UCLA CTSI
National Institutes of Health (NIH)	AR073940
National Institutes of Health (NIH)
National Heart, Lung, and Blood Institute Family Blood Pressure Program	R01HL136543, HL146358
National Heart, Lung, and Blood Institute Family Blood Pressure Program
National Center for Advancing Translational Sciences (NCATS)	UL1TR001881
National Center for Advancing Translational Sciences (NCATS)
Division of Intramural Research, National Institute of Allergy and Infectious Diseases	AI093768, AI007323
Division of Intramural Research, National Institute of Allergy and Infectious Diseases

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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10.1038/s41590-020-0695-4

Cite this

Zhou, Q. D., Chi, X., Lee, M. S., Hsieh, W. Y., Mkrtchyan, J. J., Feng, A. C., He, C., York, A. G., Bui, V. L., Kronenberger, E. B., Ferrari, A., Xiao, X., Daly, A. E., Tarling, E. J., Damoiseaux, R., Scumpia, P. O., Smale, S. T., Williams, K. J., Tontonoz, P., & Bensinger, S. J. (2020). Interferon-mediated reprogramming of membrane cholesterol to evade bacterial toxins. Nature Immunology, 21(7), 746-755. https://doi.org/10.1038/s41590-020-0695-4

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title = "Interferon-mediated reprogramming of membrane cholesterol to evade bacterial toxins",

abstract = "Plasma membranes of animal cells are enriched for cholesterol. Cholesterol-dependent cytolysins (CDCs) are pore-forming toxins secreted by bacteria that target membrane cholesterol for their effector function. Phagocytes are essential for clearance of CDC-producing bacteria; however, the mechanisms by which these cells evade the deleterious effects of CDCs are largely unknown. Here, we report that interferon (IFN) signals convey resistance to CDC-induced pores on macrophages and neutrophils. We traced IFN-mediated resistance to CDCs to the rapid modulation of a specific pool of cholesterol in the plasma membrane of macrophages without changes to total cholesterol levels. Resistance to CDC-induced pore formation requires the production of the oxysterol 25-hydroxycholesterol (25HC), inhibition of cholesterol synthesis and redistribution of cholesterol to an esterified cholesterol pool. Accordingly, blocking the ability of IFN to reprogram cholesterol metabolism abrogates cellular protection and renders mice more susceptible to CDC-induced tissue damage. These studies illuminate targeted regulation of membrane cholesterol content as a host defense strategy.",

author = "Zhou, \{Quan D.\} and Xun Chi and Lee, \{Min Sub\} and Hsieh, \{Wei Yuan\} and Mkrtchyan, \{Jonathan J.\} and Feng, \{An Chieh\} and Cuiwen He and York, \{Autumn G.\} and Bui, \{Viet L.\} and Kronenberger, \{Eliza B.\} and Alessandra Ferrari and Xu Xiao and Daly, \{Allison E.\} and Tarling, \{Elizabeth J.\} and Robert Damoiseaux and Scumpia, \{Philip O.\} and Smale, \{Stephen T.\} and Williams, \{Kevin J.\} and Peter Tontonoz and Bensinger, \{Steven J.\}",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.",

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Zhou, QD, Chi, X, Lee, MS, Hsieh, WY, Mkrtchyan, JJ, Feng, AC, He, C, York, AG, Bui, VL, Kronenberger, EB, Ferrari, A, Xiao, X, Daly, AE, Tarling, EJ, Damoiseaux, R, Scumpia, PO, Smale, ST, Williams, KJ, Tontonoz, P & Bensinger, SJ 2020, 'Interferon-mediated reprogramming of membrane cholesterol to evade bacterial toxins', Nature Immunology, vol. 21, no. 7, pp. 746-755. https://doi.org/10.1038/s41590-020-0695-4

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AU - Hsieh, Wei Yuan

AU - Mkrtchyan, Jonathan J.

AU - Feng, An Chieh

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AU - York, Autumn G.

AU - Bui, Viet L.

AU - Kronenberger, Eliza B.

AU - Ferrari, Alessandra

AU - Xiao, Xu

AU - Daly, Allison E.

AU - Tarling, Elizabeth J.

AU - Damoiseaux, Robert

AU - Scumpia, Philip O.

AU - Smale, Stephen T.

AU - Williams, Kevin J.

AU - Tontonoz, Peter

AU - Bensinger, Steven J.

PY - 2020/7/1

Y1 - 2020/7/1

N2 - Plasma membranes of animal cells are enriched for cholesterol. Cholesterol-dependent cytolysins (CDCs) are pore-forming toxins secreted by bacteria that target membrane cholesterol for their effector function. Phagocytes are essential for clearance of CDC-producing bacteria; however, the mechanisms by which these cells evade the deleterious effects of CDCs are largely unknown. Here, we report that interferon (IFN) signals convey resistance to CDC-induced pores on macrophages and neutrophils. We traced IFN-mediated resistance to CDCs to the rapid modulation of a specific pool of cholesterol in the plasma membrane of macrophages without changes to total cholesterol levels. Resistance to CDC-induced pore formation requires the production of the oxysterol 25-hydroxycholesterol (25HC), inhibition of cholesterol synthesis and redistribution of cholesterol to an esterified cholesterol pool. Accordingly, blocking the ability of IFN to reprogram cholesterol metabolism abrogates cellular protection and renders mice more susceptible to CDC-induced tissue damage. These studies illuminate targeted regulation of membrane cholesterol content as a host defense strategy.

AB - Plasma membranes of animal cells are enriched for cholesterol. Cholesterol-dependent cytolysins (CDCs) are pore-forming toxins secreted by bacteria that target membrane cholesterol for their effector function. Phagocytes are essential for clearance of CDC-producing bacteria; however, the mechanisms by which these cells evade the deleterious effects of CDCs are largely unknown. Here, we report that interferon (IFN) signals convey resistance to CDC-induced pores on macrophages and neutrophils. We traced IFN-mediated resistance to CDCs to the rapid modulation of a specific pool of cholesterol in the plasma membrane of macrophages without changes to total cholesterol levels. Resistance to CDC-induced pore formation requires the production of the oxysterol 25-hydroxycholesterol (25HC), inhibition of cholesterol synthesis and redistribution of cholesterol to an esterified cholesterol pool. Accordingly, blocking the ability of IFN to reprogram cholesterol metabolism abrogates cellular protection and renders mice more susceptible to CDC-induced tissue damage. These studies illuminate targeted regulation of membrane cholesterol content as a host defense strategy.

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Interferon-mediated reprogramming of membrane cholesterol to evade bacterial toxins

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

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