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Goodbye nasty virus. Love, your spleen


What's that big brown bag - packed full of red blood cells - for in the upper left of your chest? Sure you can live without it but why's it there in the first place and what's it doing for you? You wouldn't just be carrying round that extra 175g (for an 'average' person) just for nothing would you? While it has been known that loss of your spleen, or asplenia has some pretty strange effects, such as an increase in some blood cells, lessened response to vaccinations and an increased risk of serious infections, we haven't exactly known why. That is until now, when a German team - publishing in Nature Immunology a few weeks back - uncovered an unrecognised role for a certain kind of immune cell that specifically hides out in your spleen.

Actually a number of years ago you might have heard something very like this story when researchers found that the spleen could aid in the regeneration of damaged tissue but this is something different. This is the second time that the spleen's function has been revolutionised.

You are continuously being bombarded by potentially dangerous molecules, microbes and other organisms who would really like to use you to further their own evolutionary lineage. This is why a system to specifically recognise these organisms and physically remove them and protect you from future attacks has been selected for over millennia. This is one of the reasons why you have a spleen.


Your spleen is basically one big immune organ - much like a giant lymph node. It has two jobs to do, one: to remove old dysfunctional red blood cells and replenish them, and another: to clean up after your body's immune defence by removing antibody-bound bacteria and physically sending out regeneration-promoting monocytes to help heal damaged disease. But what this Nature Immunology paper shows is that the spleen is actually at the very centre of this immune response and is involved in the rapid and massive production of antiviral T cells.  To understand how we have to first understand mammalian immunity.

Our bodies recognise antigens (proteins, nucleic acids or fats - specific to, say a dangerous virus) and mount a response in the form of antibody-producing B cells or infected cell-killing T cells. In order to kickstart this kind of response we need to select for those cells that recognise the dangerous antigens only and not bits and pieces of proteins from your own body. We do not want an auto-immune reaction. To do this certain immune cells pick up parts of organisms and physically bring them into close contact with these B and T cells in places like lymph nodes and the spleen (see dendritic cells and macrophages). Here we begin to ramp up the numbers of those cells that can recognise that antigen (and hence the dangerous virus) and they are sent off towards the site of infection, e.g the brain or the skin.

Here comes the apparent paradox. We want to remove the source of the antigen from your body, i.e we want to destroy the virus and infected cells. But to do so and kick-start your immune response we actually require physical antigen. So on one hand we have to ensure that the virus doesn't replicate too much and therefore cause disease but we must also ensure that it replicates enough so as we can respond immunologically. It's thought that we need around 200,000 antigen peptides to start your immune system. The more antigen we have the better the immune response. How does your body deal with this situation? Well turns out it's your spleen that steps up to the job.

VSV grows only in the spleen of infected mice. Remove macrophages with Clodronate at it grows everywhere and all mice die. Clearly macrophages are important in antiviral defence, but how?
This German-led paper comes from a group trying to explain why one cell type - macrophages (see above) - were so necessary to protect against a viral infection. For example, when they injected a large amount of the virus (a mouse adapted Vesicular Stromatitis Virus - or VSV) directly into the bloodstream of the mice these macrophages removed the vast majority of it from circulation within 10 minutes. Macrophages really like to grad up and eat nasty organisms like viruses and bacteria - and they are found throughout your body. Yet when they depleted the same mice of those very cells, the virus hung around for over an hour, spread to organs like the brain and caused all the mice to die within a couple of days. However, with normal mice the virus was found to still replicate in the spleens of the mice yet caused no disease and in no where else did they find virus. All this work suggested that macrophages in all organs captured the virus and prevented it from growing any more but not so in the spleen. The spleen appeared to be very special, it was actually letting the virus grow, but why?

VSV antigen in green (seen inside the spleen) colocalises with CD169+ cells (macrophages) during infection. However, remove Usp18 and no or little replication (antigen) is seen in liver. 
By investigating this phenonomon in more detail the group found that the macrophages found inside your spleen (CD169+ metallophillic macrophages to be precise) are quite different from the macrophages found elsewhere in your body (explaining their apparent special powers): they appear to be adapted to specifically promote viral replication due to the upregaulation of one gene inparticular, USP18. This gene inhibits the interferon response from dampening and preventing virus replication. These cells would capture any virus floating around in your blood, bring it into the cell and actively allow it to grow, thus rapidly increasing the amount of antigen available to the T cells in the spleen. But why would your body allow a clearly very dangerous pathogen to replicate - isn't this cunterintuitive?

No virus replication (UV inactivated) means no protection
The answer to this mystery came from one observation: the immune response against the virus was severely blunted when you prevented it from replicating. When you shone UV light on to inactivate the virus, antibody levels and T cell activity weren't as good as when the virus could grow normally. When you removed the Usp18 gene, it seemed to mimic what happened with the inactivated virus. There was clearly a relationship between virus growth and immune response specifically involving those cells with Usp18 up-regulated in the spleen. When you came back in and challenged the mice with the virus, only those mice who had previously been infected with the replicating virus or who had Usp18, survived.

This work although in mice suggests that in order for us to develop an effective immune response (T cells in this case) we need the spleen and it's macrophages, specifically those ones with Usp18. All your other macrophages aren't up to the job. However, it does not rule out the role of other interferon inhibitory proteins allowing virus replication in those macrophages and it even suggests that other cells expressing Usp18 (like dendritic cells) may allow viral replication and immune system activation.

This work also gives us a mechanism to explain why vaccines that can replicate (and hence maybe grow in your spleen) are much more effective than those that cannot. And finally it may show us how some virus take advantage of our immune system for their own gain - something which the authors fail to mention. For example, measles and HIV utilise dendritic cells to spread from entry points (lung and genital tract respectively) to lymph tissue. One question is how come some viruses (in this case VSV but also influenza) clearly replicate in cells like these but they are prevented from going any further. Why and how does measles and HIV spread once they reach the lymph tissue? I bet to understand it fully we will need to compare how viruses like VSV and measles interact differently with dendritic cells and macrophages. We need to answer the question: what is stopping VSV from getting further than the macrophages in the spleen.

ResearchBlogging.orgHonke, N., Shaabani, N., Cadeddu, G., Sorg, U., Zhang, D., Trilling, M., Klingel, K., Sauter, M., Kandolf, R., Gailus, N., van Rooijen, N., Burkart, C., Baldus, S., Grusdat, M., Löhning, M., Hengel, H., Pfeffer, K., Tanaka, M., Häussinger, D., Recher, M., Lang, P., & Lang, K. (2011). Enforced viral replication activates adaptive immunity and is essential for the control of a cytopathic virus Nature Immunology, 13 (1), 51-57 DOI: 10.1038/ni.2169



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