Autophagy facilitates antibody-enhanced dengue virus infection in human pre-basophil/mast cells

• Published in: PloS one Vol. 9; no. 10; p. e110655
• Main Authors: Fang, Yi-Ting, Wan, Shu-Wen, Lu, Yi-Tien, Yao, Ju-Han, Lin, Chiou-Feng, Hsu, Li-Jin, Brown, Michael G, Marshall, Jean S, Anderson, Robert, Lin, Yee-Shin
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 16.10.2014; Public Library of Science (PLoS)
• Subjects: Antibodies; Antibodies, Viral - immunology; Antibody-Dependent Enhancement - immunology; Autophagy; Autophagy - immunology; Basophils - immunology; Cell death; Cell Line; Cytokines; Dengue; Dengue - immunology; Dengue - virology; Dengue fever; Dengue virus; Dengue Virus - immunology; Dengue Virus - pathogenicity; Disease control; Double-stranded RNA; Fatty acids; Fc receptors; Health aspects; Hemorrhage; Hemorrhagic disease; Humans; Immunology; Infection; Infections; Infectious diseases; Laboratories; Lipids; Localization; Macrophages; Mast cells; Mast Cells - immunology; Mast Cells - virology; Medicine and Health Sciences; Monocytes; Neutralizing; Pathogenesis; Patients; Phagocytosis; Phagosomes; Replication; Rodents; Vector-borne diseases; Viral diseases; Viral envelope proteins; Viral Envelope Proteins - immunology; Viral infections; Viruses; Thailand; Canada; Taiwan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0110655

Dengue virus (DENV) infection can cause severe hemorrhagic disease in humans. Although the pathogenic mechanisms underlying severe DENV disease remain unclear, one of the possible contributing factors is antibody-dependent enhancement (ADE) which occurs when sub-neutralizing antibodies derived from a previous DENV infection enhance viral infection through interaction between virus-antibody complexes and FcR-bearing cells, such as macrophages and basophil/mast cells. Although recent reports showed that DENV induces autophagy, the relationship between antibody-enhanced DENV infection and autophagy is not clear. We showed that sub-neutralizing antibodies derived from dengue patient sera enhanced DENV infection and autophagy in the KU812 pre-basophil-like cell line as well as the HMC-1 immature mast cell line. Antibody-enhanced DENV infection of KU812 cells increased the number of autophagosome vesicles, LC3 punctation, LC3-II accumulation, and p62 degradation over that seen in cells infected with DENV alone. The percentages of DENV envelope (E) protein-positive cells and LC3 puncta following antibody-enhanced DENV infection of KU812 cells were reduced by the autophagy inhibitor 3-MA. Antibody-enhanced DENV infection of HMC-1 cells showed co-localization of DENV E protein and dsRNA with autophagosomes, which was inhibited by 3-MA treatment. Furthermore, DENV infection and replication were reduced when KU812 cells were transfected with the autophagy-inhibiting Atg4BC74A mutant. Our results demonstrate a significant induction of autophagy in antibody-enhanced DENV infection of pre-basophil-like KU812 and immature mast cell-like HMC-1 cells. Also, autophagy plays an important role in DENV infection and replication in these cells. Given the importance of ADE and FcR-bearing cells such as monocytes, macrophages and basophil/mast cells in dengue disease, the results provide insights into dengue pathogenesis and therapeutic means of control.