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

Abstract

BACKGROUND:

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.

METHODOLOGY/PRINCIPAL FINDINGS:

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.

CONCLUSIONS/SIGNIFICANCE:

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.

• Authors: Yi-Ting Fang, Shu-Wen Wan, Yi-Tien Lu, Ju-Han Yao, Chiou-Feng Lin, Li-Jin Hsu, Michael G Brown, Jean S Marshall, Robert Anderson, Yee-Shin Lin
• Journal: PloS one (PLoS One) Vol. 9 Issue 10 Pg. e110655 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 25329914 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Viral
• Viral Envelope Proteins

Topics

• Antibodies, Viral (immunology)
• Antibody-Dependent Enhancement (immunology)
• Autophagy (immunology)
• Basophils (immunology)
• Cell Line
• Dengue (immunology, virology)
• Dengue Virus (immunology, pathogenicity)
• Humans
• Mast Cells (immunology, virology)
• Viral Envelope Proteins (immunology)