Protein Disulfide Isomerase Inhibitor Suppresses Viral Replication and Production during Antibody-Dependent Enhancement of Dengue Virus Infection in Human Monocytic Cells

• Published in: Viruses Vol. 11; no. 2; p. 155
• Main Authors: Rawarak, Nantapon, Suttitheptumrong, Aroonroong, Reamtong, Onrapak, Boonnak, Kobporn, Pattanakitsakul, Sa-Nga
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 13.02.2019; MDPI
• Subjects: Antibodies; Antibodies, Viral; Antibody-Dependent Enhancement; Cell division; Cell Line; Dengue fever; Dengue hemorrhagic fever; Dengue Virus - drug effects; Dengue Virus - physiology; dengue virus infection; Disulfide bonds; Down-Regulation; Ebola virus; Enzyme Inhibitors - pharmacology; human monocytic cells; Humans; Infections; Infectivity; Life cycles; Mass spectroscopy; Monocytes; Monocytes - immunology; Monocytes - virology; Pathogenesis; Phosphoproteins; Phosphoproteins - immunology; Protein biosynthesis; protein disulfide isomerase inhibitor; Protein disulfide-isomerase; Protein Disulfide-Isomerases - antagonists & inhibitors; Proteins; Secondary infection; Signal Transduction; Tandem Mass Spectrometry; U937 Cells; Up-Regulation; Viral infections; viral replication and production; Virions; Virus Replication - drug effects; Viruses; Hawaii; United States > US; dengue virus infection; antibody-dependent enhancement; protein disulfide isomerase inhibitor; viral replication and production; human monocytic cells
• ISSN: 1999-4915; 1999-4915
• DOI: 10.3390/v11020155

One of several mechanisms that leads to the development of dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) is called antibody-dependent enhancement (ADE). Monocytes can be infected by the ADE phenomenon, which occurs in dengue secondary infection. This study aimed to investigate the proteins involved in ADE of DENV infection in the human monocytic cell line U937. The phosphoproteins were used to perform and analyze for protein expression using mass spectrometry (GeLC-MS/MS). The differential phosphoproteins revealed 1131 altered proteins compared between isotype- and DENV-specific antibody-treated monocytes. The altered proteins revealed 558 upregulated proteins and 573 downregulated proteins. Protein disulfide isomerase (PDI), which is an enzyme that had a high-ranking fold change and that catalyzes the formation, breakage, and rearrangement of disulfide bonds within a protein molecule, was selected for further study. PDI was found to be important for dengue virus infectivity during the ADE model. The effect of PDI inhibition was also shown to be involved in the early stage of life cycle by time-of-drug-addition assay. These results suggest that PDI is important for protein translation and virion assembly of dengue virus during infection in human monocytes, and it may play a significant role as a chaperone to stabilize dengue protein synthesis.