Abstract
Recent advances in electron microscopy and tomography have revealed distinct virus-induced endoplasmic reticulum (ER) structures unique for dengue virus (DV) and other flaviviruses in cell culture models, including hepatocytes. These altered ultrastructures serve as sites for viral replication. In this study, we used transmission electron microscopy to investigate whether such structures were present in the liver of fatal dengue hemorrhagic fever (DHF) autopsy cases. In parallel, electron microscopic examination of suckling mouse brains experimentally infected with DV was performed as an in vivo model of acute DV infection. Typical features of ER changes containing abundance of replicative virions were observed in neurons and microglia of DV-infected suckling mouse brains (SMB). This indicated that the in vivo DV infection could induce similar viral replication structures as previously described in the in vitro DV-infected cell model. Nevertheless, liver tissues from autopsy of patients who died of DHF showed scant changes of ER membrane structures and rare particles of virions in hepatocytes, despite overwhelming evidence for the presence of viral antigens and RNA–indicating active virus replication. Instead hepatocytes contained an abundance of steatotic vesicles and structural damages. This lack of structural changes indicative of virus replication in human hepatocytes is discussed.
Highlights
Dengue viruses (DV) are mosquito-borne single-stranded RNA viruses within the family Flaviviridae
The structural features include: membrane invaginations into the endoplasmic reticulum (ER) lumen forming intra luminal vesicles (Ve) of ~90 nm which accumulate as vesicle packets (VP) and collections of convoluted membrane structures (CM) and membrane tubules (T) [4,5]
Using light microscopic and immunohistochemistry techniques, we have identified three major organs, i.e., liver, spleen and lymph nodes, that had significant levels of DV- RNA and – antigens, as well as histopathological changes
Summary
Dengue viruses (DV) are mosquito-borne single-stranded RNA viruses within the family Flaviviridae. Each new structure provides a particular function: Ve serves as a site for the “viral replicating complex” and a protected environment against host innate immune reactions to newly synthesized double stranded RNA [5,6], while CM is a site for RNA translation and viral protein processing [5,7]. The pattern of these cytoplasmic changes is found to be unique amongst closely related viruses within the same genera infecting mammalian and insect cells in vitro [5,6].
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