High expression of oleoyl-ACP hydrolase underpins life-threatening respiratory viral diseases

Xiaoxiao Jia; Jeremy Chase Crawford; Deborah Gebregzabher; Ebony A. Monson; Robert C. Mettelman; Yanmin Wan; Yanqin Ren; Janet Chou; Tanya Novak; Hayley A. McQuilten; Michele Clarke; Annabell Bachem; Isabelle J. Foo; Svenja Fritzlar; Julio Carrera Montoya; Alice M. Trenerry; Shuai Nie; Michael G. Leeming; Thi H.O. Nguyen; Lukasz Kedzierski; Dene R. Littler; Andrew Kueh; Tina Cardamone; Chinn Yi Wong; Luca Hensen; Aira Cabug; Jaime Gómez Laguna; Mona Agrawal; Tim Flerlage; David F. Boyd; Lee Ann Van de Velde; Jennifer R. Habel; Liyen Loh; Hui Fern Koay; Carolien E. van de Sandt; Igor E. Konstantinov; Stuart P. Berzins; Katie L. Flanagan; Linda M. Wakim; Marco J. Herold; Amanda M. Green; Heather S. Smallwood; Jamie Rossjohn; Ryan S. Thwaites; Christopher Chiu; Nichollas E. Scott; Jason M. Mackenzie; Sammy Bedoui; Patrick C. Reading; Sarah L. Londrigan; Karla J. Helbig; Adrienne G. Randolph; Paul G. Thomas; Jianqing Xu; Zhongfang Wang; Brendon Y. Chua; Katherine Kedzierska

doi:10.1016/j.cell.2024.07.026

High expression of oleoyl-ACP hydrolase underpins life-threatening respiratory viral diseases

Xiaoxiao Jia, Jeremy Chase Crawford, Deborah Gebregzabher, Ebony A. Monson, Robert C. Mettelman, Yanmin Wan, Yanqin Ren, Janet Chou, Tanya Novak, Hayley A. McQuilten, Michele Clarke, Annabell Bachem, Isabelle J. Foo, Svenja Fritzlar, Julio Carrera Montoya, Alice M. Trenerry, Shuai Nie, Michael G. Leeming, Thi H.O. Nguyen, Lukasz KedzierskiDene R. Littler, Andrew Kueh, Tina Cardamone, Chinn Yi Wong, Luca Hensen, Aira Cabug, Jaime Gómez Laguna, Mona Agrawal, Tim Flerlage, David F. Boyd, Lee Ann Van de Velde, Jennifer R. Habel, Liyen Loh, Hui Fern Koay, Carolien E. van de Sandt, Igor E. Konstantinov, Stuart P. Berzins, Katie L. Flanagan, Linda M. Wakim, Marco J. Herold, Amanda M. Green, Heather S. Smallwood, Jamie Rossjohn, Ryan S. Thwaites, Christopher Chiu, Nichollas E. Scott, Jason M. Mackenzie, Sammy Bedoui, Patrick C. Reading, Sarah L. Londrigan, Karla J. Helbig, Adrienne G. Randolph, Paul G. Thomas, Jianqing Xu, Zhongfang Wang, Brendon Y. Chua, Katherine Kedzierska

Houston Methodist

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

22 Scopus citations

Abstract

Respiratory infections cause significant morbidity and mortality, yet it is unclear why some individuals succumb to severe disease. In patients hospitalized with avian A(H7N9) influenza, we investigated early drivers underpinning fatal disease. Transcriptomics strongly linked oleoyl-acyl-carrier-protein (ACP) hydrolase (OLAH), an enzyme mediating fatty acid production, with fatal A(H7N9) early after hospital admission, persisting until death. Recovered patients had low OLAH expression throughout hospitalization. High OLAH levels were also detected in patients hospitalized with life-threatening seasonal influenza, COVID-19, respiratory syncytial virus (RSV), and multisystem inflammatory syndrome in children (MIS-C) but not during mild disease. In olah^−/− mice, lethal influenza infection led to survival and mild disease as well as reduced lung viral loads, tissue damage, infection-driven pulmonary cell infiltration, and inflammation. This was underpinned by differential lipid droplet dynamics as well as reduced viral replication and virus-induced inflammation in macrophages. Supplementation of oleic acid, the main product of OLAH, increased influenza replication in macrophages and their inflammatory potential. Our findings define how the expression of OLAH drives life-threatening viral disease.

Original language	English (US)
Pages (from-to)	4586-4604.e20
Journal	Cell
Volume	187
Issue number	17
DOIs	https://doi.org/10.1016/j.cell.2024.07.026
State	Published - Aug 22 2024

Keywords

fatal avian A/H7N9 influenza disease
influenza mouse model
life-threatening seasonal influenza
MIS-C
OLAH
olah-driven macrophage-mediated disease severity
olah mice
oleoyl-ACP hydrolase as key early driver of disease severity
SARS-CoV-2 and RSV

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2024.07.026

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Jia, X., Crawford, J. C., Gebregzabher, D., Monson, E. A., Mettelman, R. C., Wan, Y., Ren, Y., Chou, J., Novak, T., McQuilten, H. A., Clarke, M., Bachem, A., Foo, I. J., Fritzlar, S., Carrera Montoya, J., Trenerry, A. M., Nie, S., Leeming, M. G., Nguyen, T. H. O., ... Kedzierska, K. (2024). High expression of oleoyl-ACP hydrolase underpins life-threatening respiratory viral diseases. Cell, 187(17), 4586-4604.e20. https://doi.org/10.1016/j.cell.2024.07.026

Jia, X, Crawford, JC, Gebregzabher, D, Monson, EA, Mettelman, RC, Wan, Y, Ren, Y, Chou, J, Novak, T, McQuilten, HA, Clarke, M, Bachem, A, Foo, IJ, Fritzlar, S, Carrera Montoya, J, Trenerry, AM, Nie, S, Leeming, MG, Nguyen, THO, Kedzierski, L, Littler, DR, Kueh, A, Cardamone, T, Wong, CY, Hensen, L, Cabug, A, Laguna, JG, Agrawal, M, Flerlage, T, Boyd, DF, Van de Velde, LA, Habel, JR, Loh, L, Koay, HF, van de Sandt, CE, Konstantinov, IE, Berzins, SP, Flanagan, KL, Wakim, LM, Herold, MJ, Green, AM, Smallwood, HS, Rossjohn, J, Thwaites, RS, Chiu, C, Scott, NE, Mackenzie, JM, Bedoui, S, Reading, PC, Londrigan, SL, Helbig, KJ, Randolph, AG, Thomas, PG, Xu, J, Wang, Z, Chua, BY & Kedzierska, K 2024, 'High expression of oleoyl-ACP hydrolase underpins life-threatening respiratory viral diseases', Cell, vol. 187, no. 17, pp. 4586-4604.e20. https://doi.org/10.1016/j.cell.2024.07.026

@article{9c1f0773f20a415e955a4a2a3f1bcd2e,

title = "High expression of oleoyl-ACP hydrolase underpins life-threatening respiratory viral diseases",

abstract = "Respiratory infections cause significant morbidity and mortality, yet it is unclear why some individuals succumb to severe disease. In patients hospitalized with avian A(H7N9) influenza, we investigated early drivers underpinning fatal disease. Transcriptomics strongly linked oleoyl-acyl-carrier-protein (ACP) hydrolase (OLAH), an enzyme mediating fatty acid production, with fatal A(H7N9) early after hospital admission, persisting until death. Recovered patients had low OLAH expression throughout hospitalization. High OLAH levels were also detected in patients hospitalized with life-threatening seasonal influenza, COVID-19, respiratory syncytial virus (RSV), and multisystem inflammatory syndrome in children (MIS-C) but not during mild disease. In olah−/− mice, lethal influenza infection led to survival and mild disease as well as reduced lung viral loads, tissue damage, infection-driven pulmonary cell infiltration, and inflammation. This was underpinned by differential lipid droplet dynamics as well as reduced viral replication and virus-induced inflammation in macrophages. Supplementation of oleic acid, the main product of OLAH, increased influenza replication in macrophages and their inflammatory potential. Our findings define how the expression of OLAH drives life-threatening viral disease.",

keywords = "fatal avian A/H7N9 influenza disease, influenza mouse model, life-threatening seasonal influenza, MIS-C, OLAH, olah-driven macrophage-mediated disease severity, olah mice, oleoyl-ACP hydrolase as key early driver of disease severity, SARS-CoV-2 and RSV",

author = "Xiaoxiao Jia and Crawford, \{Jeremy Chase\} and Deborah Gebregzabher and Monson, \{Ebony A.\} and Mettelman, \{Robert C.\} and Yanmin Wan and Yanqin Ren and Janet Chou and Tanya Novak and McQuilten, \{Hayley A.\} and Michele Clarke and Annabell Bachem and Foo, \{Isabelle J.\} and Svenja Fritzlar and \{Carrera Montoya\}, Julio and Trenerry, \{Alice M.\} and Shuai Nie and Leeming, \{Michael G.\} and Nguyen, \{Thi H.O.\} and Lukasz Kedzierski and Littler, \{Dene R.\} and Andrew Kueh and Tina Cardamone and Wong, \{Chinn Yi\} and Luca Hensen and Aira Cabug and Laguna, \{Jaime G{\'o}mez\} and Mona Agrawal and Tim Flerlage and Boyd, \{David F.\} and \{Van de Velde\}, \{Lee Ann\} and Habel, \{Jennifer R.\} and Liyen Loh and Koay, \{Hui Fern\} and \{van de Sandt\}, \{Carolien E.\} and Konstantinov, \{Igor E.\} and Berzins, \{Stuart P.\} and Flanagan, \{Katie L.\} and Wakim, \{Linda M.\} and Herold, \{Marco J.\} and Green, \{Amanda M.\} and Smallwood, \{Heather S.\} and Jamie Rossjohn and Thwaites, \{Ryan S.\} and Christopher Chiu and Scott, \{Nichollas E.\} and Mackenzie, \{Jason M.\} and Sammy Bedoui and Reading, \{Patrick C.\} and Londrigan, \{Sarah L.\} and Helbig, \{Karla J.\} and Randolph, \{Adrienne G.\} and Thomas, \{Paul G.\} and Jianqing Xu and Zhongfang Wang and Chua, \{Brendon Y.\} and Katherine Kedzierska",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s)",

year = "2024",

month = aug,

day = "22",

doi = "10.1016/j.cell.2024.07.026",

language = "English (US)",

volume = "187",

pages = "4586--4604.e20",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

number = "17",

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TY - JOUR

T1 - High expression of oleoyl-ACP hydrolase underpins life-threatening respiratory viral diseases

AU - Jia, Xiaoxiao

AU - Crawford, Jeremy Chase

AU - Gebregzabher, Deborah

AU - Monson, Ebony A.

AU - Mettelman, Robert C.

AU - Wan, Yanmin

AU - Ren, Yanqin

AU - Chou, Janet

AU - Novak, Tanya

AU - McQuilten, Hayley A.

AU - Clarke, Michele

AU - Bachem, Annabell

AU - Foo, Isabelle J.

AU - Fritzlar, Svenja

AU - Carrera Montoya, Julio

AU - Trenerry, Alice M.

AU - Nie, Shuai

AU - Leeming, Michael G.

AU - Nguyen, Thi H.O.

AU - Kedzierski, Lukasz

AU - Littler, Dene R.

AU - Kueh, Andrew

AU - Cardamone, Tina

AU - Wong, Chinn Yi

AU - Hensen, Luca

AU - Cabug, Aira

AU - Laguna, Jaime Gómez

AU - Agrawal, Mona

AU - Flerlage, Tim

AU - Boyd, David F.

AU - Van de Velde, Lee Ann

AU - Habel, Jennifer R.

AU - Loh, Liyen

AU - Koay, Hui Fern

AU - van de Sandt, Carolien E.

AU - Konstantinov, Igor E.

AU - Berzins, Stuart P.

AU - Flanagan, Katie L.

AU - Wakim, Linda M.

AU - Herold, Marco J.

AU - Green, Amanda M.

AU - Smallwood, Heather S.

AU - Rossjohn, Jamie

AU - Thwaites, Ryan S.

AU - Chiu, Christopher

AU - Scott, Nichollas E.

AU - Mackenzie, Jason M.

AU - Bedoui, Sammy

AU - Reading, Patrick C.

AU - Londrigan, Sarah L.

AU - Helbig, Karla J.

AU - Randolph, Adrienne G.

AU - Thomas, Paul G.

AU - Xu, Jianqing

AU - Wang, Zhongfang

AU - Chua, Brendon Y.

AU - Kedzierska, Katherine

PY - 2024/8/22

Y1 - 2024/8/22

N2 - Respiratory infections cause significant morbidity and mortality, yet it is unclear why some individuals succumb to severe disease. In patients hospitalized with avian A(H7N9) influenza, we investigated early drivers underpinning fatal disease. Transcriptomics strongly linked oleoyl-acyl-carrier-protein (ACP) hydrolase (OLAH), an enzyme mediating fatty acid production, with fatal A(H7N9) early after hospital admission, persisting until death. Recovered patients had low OLAH expression throughout hospitalization. High OLAH levels were also detected in patients hospitalized with life-threatening seasonal influenza, COVID-19, respiratory syncytial virus (RSV), and multisystem inflammatory syndrome in children (MIS-C) but not during mild disease. In olah−/− mice, lethal influenza infection led to survival and mild disease as well as reduced lung viral loads, tissue damage, infection-driven pulmonary cell infiltration, and inflammation. This was underpinned by differential lipid droplet dynamics as well as reduced viral replication and virus-induced inflammation in macrophages. Supplementation of oleic acid, the main product of OLAH, increased influenza replication in macrophages and their inflammatory potential. Our findings define how the expression of OLAH drives life-threatening viral disease.

AB - Respiratory infections cause significant morbidity and mortality, yet it is unclear why some individuals succumb to severe disease. In patients hospitalized with avian A(H7N9) influenza, we investigated early drivers underpinning fatal disease. Transcriptomics strongly linked oleoyl-acyl-carrier-protein (ACP) hydrolase (OLAH), an enzyme mediating fatty acid production, with fatal A(H7N9) early after hospital admission, persisting until death. Recovered patients had low OLAH expression throughout hospitalization. High OLAH levels were also detected in patients hospitalized with life-threatening seasonal influenza, COVID-19, respiratory syncytial virus (RSV), and multisystem inflammatory syndrome in children (MIS-C) but not during mild disease. In olah−/− mice, lethal influenza infection led to survival and mild disease as well as reduced lung viral loads, tissue damage, infection-driven pulmonary cell infiltration, and inflammation. This was underpinned by differential lipid droplet dynamics as well as reduced viral replication and virus-induced inflammation in macrophages. Supplementation of oleic acid, the main product of OLAH, increased influenza replication in macrophages and their inflammatory potential. Our findings define how the expression of OLAH drives life-threatening viral disease.

KW - fatal avian A/H7N9 influenza disease

KW - influenza mouse model

KW - life-threatening seasonal influenza

KW - MIS-C

KW - OLAH

KW - olah-driven macrophage-mediated disease severity

KW - olah mice

KW - oleoyl-ACP hydrolase as key early driver of disease severity

KW - SARS-CoV-2 and RSV

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UR - https://www.scopus.com/inward/citedby.url?scp=85202217790&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2024.07.026

DO - 10.1016/j.cell.2024.07.026

M3 - Article

C2 - 39137778

AN - SCOPUS:85202217790

SN - 0092-8674

VL - 187

SP - 4586-4604.e20

JO - Cell

JF - Cell

IS - 17

ER -

High expression of oleoyl-ACP hydrolase underpins life-threatening respiratory viral diseases

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