High expression of oleoyl-ACP hydrolase underpins life-threatening respiratory viral diseases
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<sup>-/-</sup> 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.
Authors
- Stuart P. Berzins (ORCID: https://orcid.org/0000-0003-0713-1882)
- Mona Agrawal (ORCID: https://orcid.org/0009-0006-4659-2373)
- Brendon Y. Chua (ORCID: https://orcid.org/0000-0001-5654-1293)
- Tanya Novak (ORCID: https://orcid.org/0000-0002-7115-7545)
- Jianqing Xu (ORCID: https://orcid.org/0000-0003-0896-9273)
- Paul Glyndwr Thomas (ORCID: https://orcid.org/0000-0001-7955-0256)
- Katherine Kedzierska (ORCID: https://orcid.org/0000-0001-6141-335X)
- Karla J. Helbig (ORCID: https://orcid.org/0000-0001-6306-2821)
- Jennifer R. Habel (ORCID: https://orcid.org/0000-0003-0380-1527)
- Julio Carrera Montoya (ORCID: https://orcid.org/0000-0002-2503-5643)
- Michael G. Leeming (ORCID: https://orcid.org/0000-0001-8981-0701)
- Zhongfang Wang (ORCID: https://orcid.org/0000-0003-3236-5170)
- Aira F. Cabug
- Christopher Chiu (ORCID: https://orcid.org/0000-0003-0914-920X)
- Tim Flerlage
- Thi H. O. Nguyen (ORCID: https://orcid.org/0000-0002-9294-7693)
- Igor E. Konstantinov (ORCID: https://orcid.org/0000-0002-9981-1123)
- Svenja Fritzlar (ORCID: https://orcid.org/0000-0003-3407-1758)
- Hui‐Fern Koay (ORCID: https://orcid.org/0000-0002-3236-9609)
- Łukasz Kedzierski (ORCID: https://orcid.org/0000-0003-0203-1057)
- Janet Chou (ORCID: https://orcid.org/0000-0002-4610-2657)
- Nichollas E. Scott (ORCID: https://orcid.org/0000-0003-2556-8316)
- Lee-Ann Van de Velde (ORCID: https://orcid.org/0009-0000-6205-1151)
- Linda M. Wakim (ORCID: https://orcid.org/0000-0003-1752-9579)
- Ebony A. Monson (ORCID: https://orcid.org/0000-0001-5632-9575)
- Isabelle J. H. Foo (ORCID: https://orcid.org/0000-0002-4465-7245)
- Jeremy Chase Crawford (ORCID: https://orcid.org/0000-0003-4096-6048)
- Tina Cardamone
- Alice M. Trenerry (ORCID: https://orcid.org/0000-0002-8424-4250)
- Katie L. Flanagan (ORCID: https://orcid.org/0000-0002-1575-1953)
- Hayley A. McQuilten (ORCID: https://orcid.org/0000-0002-7089-5300)
- Andrew J. Kueh (ORCID: https://orcid.org/0009-0005-9596-1422)
- Luca Hensen (ORCID: https://orcid.org/0000-0001-8467-8537)
- Heather S. Smallwood (ORCID: https://orcid.org/0000-0001-5711-5771)
- Sarah L. Londrigan (ORCID: https://orcid.org/0000-0003-0989-4971)
- Shuai Nie (ORCID: https://orcid.org/0000-0002-6425-972X)
- David F. Boyd (ORCID: https://orcid.org/0000-0003-1383-4939)
- Annabell Bachem (ORCID: https://orcid.org/0000-0002-0047-2097)
- Ryan S. Thwaites (ORCID: https://orcid.org/0000-0003-3052-2793)
- Sammy Bedoui (ORCID: https://orcid.org/0000-0002-7443-0543)
- Patrick C. Reading (ORCID: https://orcid.org/0000-0002-8860-5308)
- Dene R. Littler (ORCID: https://orcid.org/0000-0001-5904-1905)
- Liyen Loh (ORCID: https://orcid.org/0000-0002-1676-0579)
- Adrienne G. Randolph (ORCID: https://orcid.org/0000-0002-3084-3071)
- Carolien E. van de Sandt (ORCID: https://orcid.org/0000-0002-4155-7433)
- Marco J. Herold (ORCID: https://orcid.org/0000-0001-7539-7581)
- Jason M. Mackenzie (ORCID: https://orcid.org/0000-0001-6613-8350)
- Jamie Rossjohn (ORCID: https://orcid.org/0000-0002-2020-7522)
- Robert C. Mettelman (ORCID: https://orcid.org/0000-0002-3527-5616)
- Yanqin Ren (ORCID: https://orcid.org/0000-0002-8054-0001)
- Yanmin Wan (ORCID: https://orcid.org/0000-0001-5027-9423)
- Amanda Green (ORCID: https://orcid.org/0009-0006-2250-2687)
- Deborah Gebregzabher (ORCID: https://orcid.org/0009-0001-0844-260X)
- Michele V. Clarke
- Chinn Yi Wong
- Xiaoxiao Jia
Institutions
- Boston Children's Hospital (US)
- University of Tasmania (AU)
- St. Jude Children's Research Hospital (US)
- Royal Children's Hospital (AU)
- Shanghai Medical College of Fudan University (CN)
- Harvard University (US)
- Federation University (AU)
- University of Tennessee Health Science Center (US)
- The University of Melbourne (AU)
- University of California, Santa Cruz (US)
- Walter and Eliza Hall Institute of Medical Research (AU)
- La Trobe University (AU)
- Launceston General Hospital (AU)
- Australian Regenerative Medicine Institute (AU)
- Clifford Craig Foundation (AU)
- Peter Doherty Institute (AU)
- Shanghai Public Health Clinical Center (CN)
- Center for Pain and the Brain (US)
- State Key Laboratory of Respiratory Disease (CN)
- Olivia Newton-John Cancer Wellness & Research Centre (AU)
- Institute of Infection and Immunity (CA)
- Imperial College London (GB)
- University of Córdoba (ES)
- Monash University (AU)
- Cardiff University (GB)
- RMIT University (AU)
- Guangzhou Medical University (CN)
Publication Details
- Journal
- Cell
- Published
- 2024-08-01
- DOI
- https://doi.org/10.1016/j.cell.2024.07.026
- Citations
- 22
- Primary Topic
- Influenza Virus Research Studies
- Type
- article
- Field-Weighted Citation Impact
- 8.51