I seem to keep saying this but it's good to have in mind: viruses are obligate intracellular parasites. They infect cells and this is what allows them to replicate and persist (and evolve) in the environment. What cells these viruses infect helps dictate how they infect and importantly, how they cause disease. The process of causing disease is known as pathogenesis and is the subject of this post. Knowing what cells a virus infects - and how they infect the cells - provides an understanding of basic virus biology and may influence the development of new antiviral treatments and vaccine design and implementation. Of course this isn't the only factor influencing viral infection, pathogenesis and transmission but it's a pretty major one and it's one factor that I have articulated interest in during and after my formative PhD years.
I have always felt (probably simplistically) that a virus actively chooses what cells to infect. Viruses evolve and adapt to particular host factors that allow it to enter, replicate in and assemble new infectious particles, which carry on the infectious cycle. On the scale of a human body, a virus might have adapted to infect epithelial cells lining your respiratory tract to allow initial infection, it might infect lymphocytes allowing modulation of systemic immunity, which may also provide the virus with access to tissues around the body that can lead to a large boost in replication facilitating virus excretion and transmission. Each one of these steps,in my head, the virus has chosen to infect. But what if a virus chooses not to infect a certain cell type, or at least limit replication. This is something I have not considered before. That was until I read this paper out recently. Not open access sadly:
To recap the paper, which has a particular pop. Sci title, (which I don't particularly like) but it's an interesting enough paper anyway. This group was interested in what stopped their favourite positive-sense RNA virus (North American eastern equine encephalitis virus, or EEEV, an rare infection limited to North America) from replicating in one certain cell type, myeloid dendritic cells. These cells are very important for antiviral immunity and act to coordinate our antiviral response to pathogens. Thus their biology affects protection from infection, disease progression and ultimately survival. They do this by sensing components of viruses or their replication and signalling to other cells that they have found an intruder. This signalling takes the form of an increase in interferon production and likely secretion of pro inflammatory proteins, designed to promote anti pathogen responses following infection. As myeloid dendritic cells pose a significant barrier to infection viruses have evolved multiple strategies to interact with and manipulate this cell type. Many viruses infect this cell type (for one example see this) and from within the cell influence it's behaviour but what EEEV does is a bit different. It simply avoids ever entering these cell types. And how it achieves this was the aim of this paper.
|electron micrograph of EEEV virus particles (red) inside host cells|
What they found was that EEEV harbours sequences that are recognised by myeloid specific miRNAs, in particular miR-142-3p. This miRNA bound to viral genomes and prevented critical translation and subsequent replication and infection. Deletion of the region within the viral genome alleviated this restriction in replication in culture and addition of the region to other RNAs restricted their expression. There is also a mouse model for EEEV pathogenesis and when mice were infected with wild type or miR-142-3p binding region-deleted viruses they noticed a striking difference on infection and pathogenesis. Deletion of miR binding led to a decrease in virulence associated with increased replication in lymph nodes (as you might expect from a virus with little myeloid restriction) and secretion if interferons.
Now this is cool but it's not all simple. This region is also required for replication in mosquitoes (the vector species for EEEV). This is not thought to be mediated by a miR-142-3p interaction, presumably because it is not present in the insect genome. What is also difficult about this work is that they base their conclusions on whole-sale deletion of the miR-binding region and not targeted nucleotide substitutions, which could rule out any other functions this region might have, for example in RNA secondary structure or protein-RNA interactions. Until these experiments are done I think that the complete role of this region in the EEEV genome will not be cleared up. However, the interaction of miR-142-3p and the virus genome appears solid and with some interesting consequences.
These data show that EEEV contains an RNA sequence within its genome that directly limits its replication in these important cells in order to influence pathogenesis by physically interacting with host miRNAs. And, importantly, the virus doesn't really care - it actually likes it that way. It actively uses this 'negative tropism' to modulate the hosts immune response towards it, favouring its own replication and immune subversion. Uncovering secrets of viruses like this is fascinating and can have an impact on human health. Importantly it may lead to engineered vaccines for viruses, especially EEEV. Imagine an EEEV that replicated in myeloid cells, triggering an antiviral response in infected hosts that would limit disease but produce long-term protection? This work is put in context when you consider than influenza viruses that cannot express their genes in myeloid cells (antigen presenting cells specifically) by engineering of miR-142 into its genome (in the tenOever lab) do not stimulate an antiviral IFN response. Taken together with this work on EEEV, the myeloid cell/miR-142/pathogen axis looks like an interesting target when considering the link between infection, disease and rational vaccine design. But like any gene product that is involved in lots of aspects of host biology like miR-142 be wary when extrapolating from cell cultures and mice.