ApoD mediates age-associated increase in vulnerability to influenza virus infection
Abstract
Influenza A virus (IAV) infection causes significantly greater morbidity and mortality in the elderly population, but the molecular mechanisms in the aging process responsible for severe infection remain unclear. In this study, we found that increased severity in IAV infection and reduced innate immune response correlated with extensive mitophagy in senescent human cells and in the lung of aged mice. Apolipoprotein D (ApoD) was identified as strongly elevated in the lungs and sera of aged human (>65 y old) and mouse (>21 mo old). ApoD was able to localize to mitochondria and interact, through its WXXI motif in the LC3B-Interacting Region domain, with LC3B to trigger mitophagy during IAV infection, in a PINK1 pathway independent manner, which attenuated type I interferon response and promoted virus replication. ApoD deficiency, on the other hand, protected older mice from severe influenza and improved survival. Likewise, depletion of senescent cells by ABT-263, a senolytic compound, in aged mice lowered ApoD level and restored innate immune antiviral response, limiting virus propagation and associated pulmonary damage. Thus, age-induced ApoD drives IAV-mediated mitophagy, and promotes virus replication and infection severity, and is therefore a promising target for inhibition to improve disease outcome in older patients.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (15)
Zhimin Jiang
Guangxi Key Laboratory of Drug Discovery and Optimization, School of Pharmacy
Wenliang Pan
National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory for Prevention and Control of Avian Influenza and Other Major Poultry Diseases of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University
Yu Chen
Dongliang Zhou
National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory for Prevention and Control of Avian Influenza and Other Major Poultry Diseases of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University
Shuning Ren
National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory for Prevention and Control of Avian Influenza and Other Major Poultry Diseases of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University
Qi Tong
National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory for Prevention and Control of Avian Influenza and Other Major Poultry Diseases of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University
Litao Liu
National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory for Prevention and Control of Avian Influenza and Other Major Poultry Diseases of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University
Honglei Sun
National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory for Prevention and Control of Avian Influenza and Other Major Poultry Diseases of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University
Yipeng Sun
Yuhai Bi
Dayan Wang
National Institute for Viral Disease Control and Prevention, Chinese National Influenza Center, Chinese Center for Disease Control and Prevention, Key Laboratory for Medical Virology
Lu Lu
Juan Pu
National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory for Prevention and Control of Avian Influenza and Other Major Poultry Diseases of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University
Kin-Chow Chang
School of Veterinary Medicine and Science, University of Nottingham
Jinhua Liu
National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory for Prevention and Control of Avian Influenza and Other Major Poultry Diseases of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University