Interferon-mediated reprogramming of membrane cholesterol to evade bacterial toxins
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...
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| Veröffentlicht in: | Nature immunology 2020-07, Vol.21 (7), p.746-755 |
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| creator | Zhou, Quan D. Chi, Xun Lee, Min Sub Hsieh, Wei Yuan Mkrtchyan, Jonathan J. Feng, An-Chieh He, Cuiwen York, Autumn G. Bui, Viet L. Kronenberger, Eliza B. Ferrari, Alessandra Xiao, Xu Daly, Allison E. Tarling, Elizabeth J. Damoiseaux, Robert Scumpia, Philip O. Smale, Stephen T. Williams, Kevin J. Tontonoz, Peter Bensinger, Steven J. |
| description | 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.
Bensinger and colleagues show that interferons promote host cell resistance to bacterial cytolysins by decreasing cholesterol synthesis and promoting the esterification of cholesterol, which alters the availability of this pool of ‘free’ cholesterol needed for pore formation. |
| doi_str_mv | 10.1038/s41590-020-0695-4 |
| format | Article |
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Bensinger and colleagues show that interferons promote host cell resistance to bacterial cytolysins by decreasing cholesterol synthesis and promoting the esterification of cholesterol, which alters the availability of this pool of ‘free’ cholesterol needed for pore formation.</description><identifier>ISSN: 1529-2908</identifier><identifier>EISSN: 1529-2916</identifier><identifier>DOI: 10.1038/s41590-020-0695-4</identifier><identifier>PMID: 32514064</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>631/250/262 ; 631/45/287 ; Animals ; Bacteria ; Bacteria - immunology ; Bacteria - metabolism ; Bacterial Infections - immunology ; Bacterial Proteins - administration & dosage ; Bacterial Proteins - immunology ; Bacterial Proteins - metabolism ; Bacterial Toxins - immunology ; Bacterial Toxins - metabolism ; Biological response modifiers ; Biomedical and Life Sciences ; Biomedicine ; Cell Membrane - metabolism ; Cell Membrane Permeability - immunology ; Cells, Cultured ; Cholesterol ; Cytolysins ; Disease Models, Animal ; Disease Susceptibility - immunology ; Esterification ; Female ; Host Microbial Interactions - immunology ; Humans ; Hydroxycholesterols - metabolism ; Immunology ; Infectious Diseases ; Interferon ; Interferons - isolation & purification ; Intravital Microscopy ; Leukocytes (neutrophilic) ; Lipid metabolism ; Macrophages ; Male ; Membranes ; Mice ; Mice, Transgenic ; Phagocytes ; Phagocytes - cytology ; Phagocytes - immunology ; Phagocytes - metabolism ; Physiological aspects ; Plasma membranes ; Primary Cell Culture ; Steroid Hydroxylases - genetics ; Steroid Hydroxylases - metabolism ; Streptolysins - administration & dosage ; Streptolysins - immunology ; Streptolysins - metabolism ; Toxins</subject><ispartof>Nature immunology, 2020-07, Vol.21 (7), p.746-755</ispartof><rights>The Author(s), under exclusive licence to Springer Nature America, Inc. 2020</rights><rights>COPYRIGHT 2020 Nature Publishing Group</rights><rights>The Author(s), under exclusive licence to Springer Nature America, Inc. 2020.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c599t-e8792f5ac44394cbd0f5ef0756d9f205ab6877af3d594b477e4615041fd997883</citedby><cites>FETCH-LOGICAL-c599t-e8792f5ac44394cbd0f5ef0756d9f205ab6877af3d594b477e4615041fd997883</cites><orcidid>0000-0002-9657-4206 ; 0000-0003-1259-0477 ; 0000-0001-5519-6037 ; 0000-0002-0184-4884 ; 0000-0002-7030-8663 ; 0000-0002-0599-0432</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32514064$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhou, Quan D.</creatorcontrib><creatorcontrib>Chi, Xun</creatorcontrib><creatorcontrib>Lee, Min Sub</creatorcontrib><creatorcontrib>Hsieh, Wei Yuan</creatorcontrib><creatorcontrib>Mkrtchyan, Jonathan J.</creatorcontrib><creatorcontrib>Feng, An-Chieh</creatorcontrib><creatorcontrib>He, Cuiwen</creatorcontrib><creatorcontrib>York, Autumn G.</creatorcontrib><creatorcontrib>Bui, Viet L.</creatorcontrib><creatorcontrib>Kronenberger, Eliza B.</creatorcontrib><creatorcontrib>Ferrari, Alessandra</creatorcontrib><creatorcontrib>Xiao, Xu</creatorcontrib><creatorcontrib>Daly, Allison E.</creatorcontrib><creatorcontrib>Tarling, Elizabeth J.</creatorcontrib><creatorcontrib>Damoiseaux, Robert</creatorcontrib><creatorcontrib>Scumpia, Philip O.</creatorcontrib><creatorcontrib>Smale, Stephen T.</creatorcontrib><creatorcontrib>Williams, Kevin J.</creatorcontrib><creatorcontrib>Tontonoz, Peter</creatorcontrib><creatorcontrib>Bensinger, Steven J.</creatorcontrib><title>Interferon-mediated reprogramming of membrane cholesterol to evade bacterial toxins</title><title>Nature immunology</title><addtitle>Nat Immunol</addtitle><addtitle>Nat Immunol</addtitle><description>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.
Bensinger and colleagues show that interferons promote host cell resistance to bacterial cytolysins by decreasing cholesterol synthesis and promoting the esterification of cholesterol, which alters the availability of this pool of ‘free’ cholesterol needed for pore formation.</description><subject>631/250/262</subject><subject>631/45/287</subject><subject>Animals</subject><subject>Bacteria</subject><subject>Bacteria - immunology</subject><subject>Bacteria - metabolism</subject><subject>Bacterial Infections - immunology</subject><subject>Bacterial Proteins - administration & dosage</subject><subject>Bacterial Proteins - immunology</subject><subject>Bacterial Proteins - metabolism</subject><subject>Bacterial Toxins - immunology</subject><subject>Bacterial Toxins - metabolism</subject><subject>Biological response modifiers</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cell Membrane - metabolism</subject><subject>Cell Membrane Permeability - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nature immunology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhou, Quan D.</au><au>Chi, Xun</au><au>Lee, Min Sub</au><au>Hsieh, Wei Yuan</au><au>Mkrtchyan, Jonathan J.</au><au>Feng, An-Chieh</au><au>He, Cuiwen</au><au>York, Autumn G.</au><au>Bui, Viet L.</au><au>Kronenberger, Eliza B.</au><au>Ferrari, Alessandra</au><au>Xiao, Xu</au><au>Daly, Allison E.</au><au>Tarling, Elizabeth J.</au><au>Damoiseaux, Robert</au><au>Scumpia, Philip O.</au><au>Smale, Stephen T.</au><au>Williams, Kevin J.</au><au>Tontonoz, Peter</au><au>Bensinger, Steven J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Interferon-mediated reprogramming of membrane cholesterol to evade bacterial toxins</atitle><jtitle>Nature immunology</jtitle><stitle>Nat Immunol</stitle><addtitle>Nat Immunol</addtitle><date>2020-07-01</date><risdate>2020</risdate><volume>21</volume><issue>7</issue><spage>746</spage><epage>755</epage><pages>746-755</pages><issn>1529-2908</issn><eissn>1529-2916</eissn><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.
Bensinger and colleagues show that interferons promote host cell resistance to bacterial cytolysins by decreasing cholesterol synthesis and promoting the esterification of cholesterol, which alters the availability of this pool of ‘free’ cholesterol needed for pore formation.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>32514064</pmid><doi>10.1038/s41590-020-0695-4</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0002-9657-4206</orcidid><orcidid>https://orcid.org/0000-0003-1259-0477</orcidid><orcidid>https://orcid.org/0000-0001-5519-6037</orcidid><orcidid>https://orcid.org/0000-0002-0184-4884</orcidid><orcidid>https://orcid.org/0000-0002-7030-8663</orcidid><orcidid>https://orcid.org/0000-0002-0599-0432</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Nature immunology, 2020-07, Vol.21 (7), p.746-755 |
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| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7778040 |
| source | MEDLINE; Nature; Alma/SFX Local Collection |
| subjects | 631/250/262 631/45/287 Animals Bacteria Bacteria - immunology Bacteria - metabolism Bacterial Infections - immunology Bacterial Proteins - administration & dosage Bacterial Proteins - immunology Bacterial Proteins - metabolism Bacterial Toxins - immunology Bacterial Toxins - metabolism Biological response modifiers Biomedical and Life Sciences Biomedicine Cell Membrane - metabolism Cell Membrane Permeability - immunology Cells, Cultured Cholesterol Cytolysins Disease Models, Animal Disease Susceptibility - immunology Esterification Female Host Microbial Interactions - immunology Humans Hydroxycholesterols - metabolism Immunology Infectious Diseases Interferon Interferons - isolation & purification Intravital Microscopy Leukocytes (neutrophilic) Lipid metabolism Macrophages Male Membranes Mice Mice, Transgenic Phagocytes Phagocytes - cytology Phagocytes - immunology Phagocytes - metabolism Physiological aspects Plasma membranes Primary Cell Culture Steroid Hydroxylases - genetics Steroid Hydroxylases - metabolism Streptolysins - administration & dosage Streptolysins - immunology Streptolysins - metabolism Toxins |
| title | Interferon-mediated reprogramming of membrane cholesterol to evade bacterial toxins |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-22T13%3A56%3A27IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Interferon-mediated%20reprogramming%20of%20membrane%20cholesterol%20to%20evade%20bacterial%20toxins&rft.jtitle=Nature%20immunology&rft.au=Zhou,%20Quan%20D.&rft.date=2020-07-01&rft.volume=21&rft.issue=7&rft.spage=746&rft.epage=755&rft.pages=746-755&rft.issn=1529-2908&rft.eissn=1529-2916&rft_id=info:doi/10.1038/s41590-020-0695-4&rft_dat=%3Cgale_pubme%3EA627539034%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2416036286&rft_id=info:pmid/32514064&rft_galeid=A627539034&rfr_iscdi=true |