Hypoxia enhances antibody-dependent dengue virus infection.
Dengue virus (DENV) has been found to replicate in lymphoid organs such as the lymph nodes, spleen, and liver in post-mortem analysis. These organs are known to have low oxygen levels (~0.5-4.5% O2) due to the vascular anatomy. However, how physiologically low levels of oxygen affect DENV infection via hypoxia-induced changes in the immune response remains unknown. Here, we show that monocytes adapted to 3% O2show greater susceptibility to antibody-dependent enhancement of DENV infection. Low oxygen level induces HIF1α-dependent upregulation of fragment crystallizable gamma receptor IIA (FcγRIIA) as well as HIF1α-independent alterations in membrane ether lipid concentrations. The increased FcγRIIA expression operates synergistically with altered membrane composition, possibly through increase membrane fluidity, to increase uptake of DENV immune complexes for enhanced infection. Our findings thus indicate that the increased viral burden associated with secondary DENV infection is antibody-dependent but hypoxia-induced and suggest a role for targeting hypoxia-induced factors for anti-dengue therapy.
Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore.
Esther Shuyi
ES
Gan
Department of Biochemistry, National University of Singapore, Singapore, Singapore.
Wei Fun
WF
Cheong
Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore.
Kuan Rong
KR
Chan
Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore.
Eugenia Ziying
0000-0003-2187-7058
EZ
Ong
Program in Cardiovascular & Metabolic Disorders and Centre for Computational Biology, Duke-NUS Medical School, Singapore, Singapore.
Xiaoran
X
Chai
Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore.
Hwee Cheng
HC
Tan
Program in Cardiovascular & Metabolic Disorders and Centre for Computational Biology, Duke-NUS Medical School, Singapore, Singapore.
Sujoy
S
Ghosh
Department of Biochemistry, National University of Singapore, Singapore, Singapore.
Markus R
MR
Wenk
Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore engeong.ooi@duke-nus.edu.sg.|Department of Microbiology and Immunology, National University of Singapore, Singapore, Singapore.|Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore.|Infectious Diseases Interdisciplinary Research Group, Singapore MIT Alliance Research and Technology CREATE Campus, Singapore, Singapore.
Eng Eong
0000-0002-0520-1544
EE
Ooi
D000914:Antibodies, Viral / Q000378:metabolism*; D019067:Antibody-Dependent Enhancement; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D003715:Dengue / Q000473:pathology*; D003716:Dengue Virus / Q000254:growth & development*; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D050356:Lipid Metabolism; D009000:Monocytes / Q000821:virology*; D017452:Receptors, IgG / Q000378:metabolism
D000914:Antibodies, Viral; C080568:Fc gamma receptor IIA; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017452:Receptors, IgG
Fc receptors; antibody‐dependent enhancement; cellular lipids; dengue; hypoxia