TY - JOUR
T1 - PMI-controlled mannose metabolism and glycosylation determines tissue tolerance and virus fitness
AU - Liang, Ronghui
AU - Ye, Zi Wei
AU - Qin, Zhenzhi
AU - Xie, Yubin
AU - Yang, Xiaomeng
AU - Sun, Haoran
AU - Du, Qiaohui
AU - Luo, Peng
AU - Tang, Kaiming
AU - Hu, Bodan
AU - Cao, Jianli
AU - Wong, Hoi Leong Xavier
AU - Ling, Guang-Sheng
AU - Chu, Hin
AU - Shen, Jiangang
AU - Yin, Feifei
AU - Jin, Dong Yan
AU - Chan, Jasper Fuk-Woo
AU - Yuen, Kwok-Yung
AU - Yuan, Shuofeng
N1 - This study was partly supported by the Health and Medical Research Fund (COVID1903010–Project 15, 20190732, and 21200562 to S.Y.) and the HMRF Fellowship Scheme (07210107 to S.Y.), the Food and Health Bureau, The Government of the Hong Kong Special Administrative Region; the National Natural Science Foundation of China/Research Grants Council Joint Research Scheme (N_HKU767/22 to S.Y.); the National Natural Science Foundation of China (32322087 and 32300134 to S.Y. and General Program 82272337 to J.F.-W.C.); Guangdong Natural Science Foundation (2023A1515012907 to S.Y.); Health@InnoHK, Innovation and Technology Commission, the Government of the Hong Kong Special Administrative Region (to K.-Y.Y.); the Collaborative Research Fund (C7060-21G to J.F.-W.C.) and Theme-Based Research Scheme (T11-709/21-N to D.-Y.J.) of the Research Grants Council, The Government of the Hong Kong Special Administrative Region; Programme of Enhancing Laboratory Surveillance and Investigation of Emerging Infectious Diseases and Antimicrobial Resistance for the Department of Health of the Hong Kong Special Administrative Region Government (to J.F.-W.C. and K.-Y.Y.); Emergency COVID-19 Project, Major Projects on Public Security, National Key Research and Development Program (2021YFC0866100) (to D.-Y.J., J.-F.W.C., and K.-Y.Y.); Sanming Project of Medicine in Shenzhen, China (SZSM201911014) (to K.-Y.Y.); the High Level-Hospital Program, Health Commission of Guangdong Province, China (to J.F.-W.C.); the research project of Hainan Academician Innovation Platform (YSPTZX202004) (to F.Y., J.F.-.W.C., and K.-Y.Y.); Emergency Collaborative Project of Guangzhou Laboratory (EKPG22-01) (to D.-Y.J., J.F.-W.C., and K.-Y.Y.); and the National Key R&D Program of China (projects 2021YFC0866100 and 2023YFC3041600 to D.-Y.J., J.F.-W.C., and K.-Y.Y.); and donations from the Shaw Foundation Hong Kong, Richard Yu and Carol Yu, Michael Seak-Kan Tong, May Tam Mak Mei Yin, Lee Wan Keung Charity Foundation Limited, Providence Foundation Limited (in memory of the late Lui Hac Minh), Hong Kong Sanatorium & Hospital, Hui Ming, Hui Hoy and Chow Sin Lan Charity Fund Limited, the Chen Wai Wai Vivien Foundation Limited, Chan Yin Chuen Memorial Charitable Foundation, Marina Man-Wai Lee, the Hong Kong Hainan Commercial Association South China Microbiology Research Fund, Perfect Shape Medical Limited, Kai Chong Tong, Tse Kam Ming Laurence, Foo Oi Foundation Limited, Betty Hing-Chu Lee, Ping Cham So, and Lo Ying Shek Chi Wai Foundation. The funding sources had no role in the study design, data collection, analysis, interpretation, or writing of the report.
PY - 2024/3/8
Y1 - 2024/3/8
N2 - Host survival depends on the elimination of virus and mitigation of tissue damage. Herein, we report the modulation of D-mannose flux rewires the virus-triggered immunometabolic response cascade and reduces tissue damage. Safe and inexpensive D-mannose can compete with glucose for the same transporter and hexokinase. Such competitions suppress glycolysis, reduce mitochondrial reactive-oxygen-species and succinate-mediated hypoxia-inducible factor-1α, and thus reduce virus-induced proinflammatory cytokine production. The combinatorial treatment by D-mannose and antiviral monotherapy exhibits in vivo synergy despite delayed antiviral treatment in mouse model of virus infections. Phosphomannose isomerase (PMI) knockout cells are viable, whereas addition of D-mannose to the PMI knockout cells blocks cell proliferation, indicating that PMI activity determines the beneficial effect of D-mannose. PMI inhibition suppress a panel of virus replication via affecting host and viral surface protein glycosylation. However, D-mannose does not suppress PMI activity or virus fitness. Taken together, PMI-centered therapeutic strategy clears virus infection while D-mannose treatment reprograms glycolysis for control of collateral damage.
AB - Host survival depends on the elimination of virus and mitigation of tissue damage. Herein, we report the modulation of D-mannose flux rewires the virus-triggered immunometabolic response cascade and reduces tissue damage. Safe and inexpensive D-mannose can compete with glucose for the same transporter and hexokinase. Such competitions suppress glycolysis, reduce mitochondrial reactive-oxygen-species and succinate-mediated hypoxia-inducible factor-1α, and thus reduce virus-induced proinflammatory cytokine production. The combinatorial treatment by D-mannose and antiviral monotherapy exhibits in vivo synergy despite delayed antiviral treatment in mouse model of virus infections. Phosphomannose isomerase (PMI) knockout cells are viable, whereas addition of D-mannose to the PMI knockout cells blocks cell proliferation, indicating that PMI activity determines the beneficial effect of D-mannose. PMI inhibition suppress a panel of virus replication via affecting host and viral surface protein glycosylation. However, D-mannose does not suppress PMI activity or virus fitness. Taken together, PMI-centered therapeutic strategy clears virus infection while D-mannose treatment reprograms glycolysis for control of collateral damage.
UR - http://www.scopus.com/inward/record.url?scp=85187117958&partnerID=8YFLogxK
U2 - 10.1038/s41467-024-46415-4
DO - 10.1038/s41467-024-46415-4
M3 - Journal article
SN - 2041-1723
VL - 15
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2144
ER -
