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Abstract
BackgroundDengue 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 FindingsWe 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/SignificanceOur 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.
Highlights
Dengue disease is a severe health problem in tropical or subtropical areas of the world [1,2]
We investigated the induction of autophagy by antibodyenhanced Dengue virus (DENV) infection of pre-basophil-like KU812 cells and immature mast cell-like HMC-1 cells
We found that antibody-enhanced DENV infection of KU812 cells increased autophagosome formation as observed by electron microscopy (Figure 1E, arrowhead)
Summary
Dengue disease is a severe health problem in tropical or subtropical areas of the world [1,2]. ADE of DENV infection occurs when heterotypic, sub-neutralizing antibodies derived from a previous infection enhance viral uptake through the interaction between virus-antibody complexes and Fcc receptors on Fcc receptor-bearing cells, monocytes, macrophages and basophil/mast cells [14,15,16,17,18,19]. Basophil/mast cells expressing Fc receptors play an important role in a wide variety of inflammatory reactions and in host defense against pathogens These cells selectively produce and secrete numerous factors including chemokines, cytokines, lipid mediators, and granule-associated products [20]. The pathogenic mechanisms underlying severe DENV disease remain unclear, one of the possible contributing factors is antibodydependent 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. Recent reports showed that DENV induces autophagy, the relationship between antibody-enhanced DENV infection and autophagy is not clear
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