Molecular Mechanisms of White Spot Syndrome Virus Infection and Perspectives on Treatments

Abstract

Since its emergence in the 1990s, White Spot Disease (WSD) has had major economic and societal impact in the crustacean aquaculture sector. Over the years shrimp farming alone has experienced billion dollar losses through WSD. The disease is caused by the White Spot Syndrome Virus (WSSV), a large dsDNA virus and the only member of the Nimaviridae family. Susceptibility to WSSV in a wide range of crustacean hosts makes it a major risk factor in the translocation of live animals and in commodity products. Currently there are no effective treatments for this disease. Understanding the molecular basis of disease processes has contributed significantly to the treatment of many human and animal pathogens, and with a similar aim considerable efforts have been directed towards understanding host-pathogen molecular interactions for WSD. Work on the molecular mechanisms of pathogenesis in aquatic crustaceans has been restricted by a lack of sequenced and annotated genomes for host species. Nevertheless, some of the key host-pathogen interactions have been established: between viral envelope proteins and host cell receptors at initiation of infection, involvement of various immune system pathways in response to WSSV, and the roles of various host and virus miRNAs in mitigation or progression of disease. Despite these advances, many fundamental knowledge gaps remain; for example, the roles of the majority of WSSV proteins are still unknown. In this review we assess current knowledge of how WSSV infects and replicates in its host, and critique strategies for WSD treatment.

Keywords: White Spot Syndrome Virus; apoptosis; endocytosis; host–pathogen interactions; miRNA; stress responses; treatments; viral infection pathway.

Figure 1

White Spot Syndrome Virus (WSSV) infection of Litopenaeus vannamei. The infection progresses through different stages that can be seen in the nucleus via histology. (A) Early-stage infected cells display enlarged nuclei with marginalized chromatin and a homogenous eosinophilic central region. These then develop an intranuclear eosinophilic Cowdry A-type inclusion (*); this can be surrounded by a clear halo beneath the nuclear membrane (white arrow). Scale bar = 25 µm; (B) The eosinophilic inclusion usually expands to fill the nucleus (*). This inclusion becomes basophilic in staining and denser in color as the infection progresses (white arrow). Nuclei then disintegrate so that the content fuses with the cytoplasm (black arrow). Scale bar = 10 µm. H & E stain; (C) WSSV virions appear ovoid in shape and contain an electron-dense nucleocapsid (white arrow) within a trilaminar envelope (black arrow). Scale bar = 0.2 µm. Inset. Negatively stained WSSV nucleocapsid, showing the presence of cross-hatched or striated material that is structured as a series of stacked rings of subunits and is a key diagnostic feature of WSSV. Scale bar = 20 nm; (D) Presumptive nucleocapsid material within the nucleus prior to envelopment. This material is cross-hatched or striated in appearance and linear prior to its incorporation in the formation of mature WSSV particles. This linear nucleocapsid material is observed sporadically in the manufacture of the WSSV particles. Scale bar = 100 nm. Transmission electron microscopy images.

Figure 2

Overview of WSSV entry and environment interactions. Top panel: Viral entry into the host cell. WSSV proteins interact with host receptors, which leads to induction of Clathrin-mediated endocytosis. WSSV then travels through endosomes. During maturation the pH decreases, a cue for viruses to exit the endosomes. This stage probably involves an interaction between VP28 and Rab7. How WSSV passes through the nuclear envelope is unknown. Once in the nucleus, host transcription factors bind the WSSV genome (e.g., ie1) and initiate expression of viral genes. Bottom panel: Intracellular interactions between WSSV and the host cell. WSSV DNA replication requires host machinery (e.g., processivity factors) and to make these available WSSV can act to halt the cell cycle in the S-phase through E2F1. A high level of viral protein production can lead to ER stress, e.g., activation of unfolded protein response (UPR) pathways. Transcription factors of the UPR can activate expression of viral genes, which in turn may inhibit translation through eIF2. WSSV replication requires essential nutrients including iron. To prevent the host from withholding iron, WSSV can inhibit the binding of iron to Ferritin. WSSV can influence apoptosis signaling either through miRNA-mediated inhibition of initiator caspases or through viral proteins that inhibit effector caspase activity.