Bringing Structure to Biology
Waves of Trouble
The image for December in our 2018 calendar depicts Hepatitis A virus and a common route of human infection with the virus, shellfish from polluted water.
Hepatitis A virus infects ∼1.4 million people annually (WHO, 2016) and, although there is a vaccine, there are no licensed therapeutic drugs.
The natural host of Hepatitis A virus are vertebrates, including humans, in whom it causes hepatitis. Hepatitis A virus belongs to the family of picornaviruses, so called because of their small RNA genome. The virus is easily transmitted through consumption of water or food contaminated by faeces. It targets cells in the liver called hepatocytes. In these cells, it affects the metabolism of bilirubin (the bile pigment that is also a product of haem catabolism), which therefore remains in the liver and the bloodstream. The high levels of bilirubin in the bloodstream cause the most typical symptom of hepatitis, jaundice (icterus), a yellowish or greenish pigmentation of the skin and whites of the eyes.
The Hepatitis A virus contains only viral RNA and viral proteins, but this is all that the virus needs to infect cells and hijack the host translation system to make more viral molecules. The entry of the virus into the host cell is achieved by its recognition of a host cell and attachment to its surface, triggering the cell to internalise the virus. Right after entry, the RNA genome of the virus functions as mRNA that encodes the viral proteins, including RNA-dependent RNA polymerase (RdRP). RdRp transcribes complementary strands of RNA, and uses them as templates to produce more RNA strands. The virus uses the host cell machinery to replicate itself into multiple copies, often exhausting all the resources within the host cell. This often leads to cell death, resulting in the symptoms of hepatitis.
In the PDB database, you can find structures of Hepatitis A virus solved by both X-ray and CryoEM methods. The X-ray structure 4QPG and CryoEM structure 5WTF represent the empty viral particles, having only the proteins which make up the capsid. PDB entry 4QPI, solved by X-ray diffraction, and CryoEM structures 5WTH and 5WTE are of the mature virus, meaning the viral particle also contained RNA genome, but in the study the RNA genome could not be modelled. Moreover, 5WTE is complexed with the antigen-binding fragment (FAB) of an antibody, revealing atomic details of antibody binding and receptor recognition on the viral surface that provides new opportunities for therapeutic intervention.
Very little detail is known about the mechanisms of how the virus reaches the liver, binds to the host cell surface, enters cells and releases its RNA. Any structural knowledge about the attachment and entry mechanism of virus and/or release of viral RNA in host cells would help in development of new drugs to inhibit viral infection.
The structure solved by CryoEM (PDB entry 5WTH) was used as a template for the December artwork in our calendar. The image (batik on silk) by Doy Vongsuriya from Impington Village College represents the Hepatitis A virus, coloured in yellow, reflecting the jaundice caused by the infection. The blue waves display a source of the infection, the shellfish from the polluted water which can be a very common source of the infection if it is not sufficiently cooked.