Tissue selectivity of West Nile virus infection

A recent study reveals insight into how West Nile virus is able to infect spleen but not liver tissue.

           West Nile virus (WNV) is most commonly transmitted to humans by mosquitoes that pickup the virus from infected birds. Originally identified in Africa in 1937, WNV is now a problem in the U.S since it spread to New York in the summer of 1999.³ Although infection isn’t always serious, when it is the virus can be very harmful. As a neurotropic virus it has the ability to infect nerve cells and the neurologic effects of infection can be permanent or deadly^2,3,4. About 1 in 150 people will develop a severe illness as a result of the infection². Since the initial outbreak in the U.S. the virus is still spreading around the country via mosquitoes². To get an idea for numbers, about 30,000 people have been reported sick from WNV in U.S. since 1999.  Not every infection is severe because our bodies have mechanism to fight off the virus.

            Upon infection with West Nile virus, the virus is localized into particular tissues within our body, while other tissues remain “protected” from infection.  In humans, WNV infection is restricted to the skin, draining lymph node, spleen and central nervous system tissues like the brain and spinal cord. WNV does not infect the liver. We still haven’t quite figured out what controls whether WNV can infect one type of tissue over another. What are the differences between these tissues that cause a difference in the ability of WNV to infect? Are there cell factors present in the liver that restrict infection by WNV? These are the types of questions that researchers at University of Washington School of Medicine gave some answers to in a recent study published in February 2013.

            In order to address the question of what controls tissue tropism, we’ll we need to take a closer look at processes not visible by the naked eye. Previous research has established pathways inherent in our cells that are involved in fighting off virus infection. For instance there are receptors in our cells that recognize viral mRNA as foreign which initiates a response in order to fight off the virus. There are two major signaling pathways in our cells identified in previous research as important in this response. One is called RIG-1 and it recognizes viral RNA as a non-self pathogen. Once viral RNA is recognized, this eventually activates a secondary pathway involving proteins called interferons (IFN) that drive transcription to activate an anti-viral response.

             Research studies have found that there are some cases of infection, although rare, in peripheral organs like the liver¹. Since WNV has the capability to infect liver cells in rare cases, this suggests that maybe those liver cells lacked the restriction factors normally present to block virus infection. Researchers at Washington School of Medicine investigated if the two pathways that are already well established by previous research to be involved in general restriction of virus infection (RIG-1 and IFN)^5,6 also control what tissue types WNV can infect. They used mouse models to mimic WNV infection in humans. In both humans and mice, WNV infections are limited to the same tissues. They found that RIG-1 and IFN pathways did indeed regulate tissue specific responses to West Nile virus!

            So what’s different between spleen and liver cells that allows WNV to infect spleen cells? That’s exactly the question that researchers in this study were delving into. They found that if you block the RIG-1 and/or IFN pathways then upon exposure to WNV the liver cells become permissive to WNV. This indicated that these two signaling pathways (RIG-1 and IFN) are involved in restricting WNV from infecting certain tissue types. For infection of the spleen, which is a tissue that usually gets infected by WNV, it took about 4 days for the amount of virus to build up to significant levels. Once the RIG-1 and/or IFN pathways were blocked, the virus was able to infect spleen cells much earlier suggesting that these pathways have a function in spleen cells to restrict early stages of viral replication.

            Now these pathways have many genes involved with them, so the network of what is going on is very complex. Therefore the researchers took a systems biology approach in order to investigate what genes are being differentially expressed in spleen versus the liver tissue that impacts WNV infectivity. They were able to categorize hundreds of genes which were differentially expressed between spleen and liver tissue in response to viral infection. Their systems biology approach confirmed previous findings of restriction factors that block WNV virus infection, and also found new ones! The new genes identified can now be  investigated for furthur research. Once we get a better handle on what is going on in our bodies to fight off West Nile virus, we will have a better chance at stopping virus infection. So until further research, watch out for those mosquitoes!

Primary Article:

1) Suthar MS, Brassil MM, Blahnik G, McMillan A, Ramos HJ, Proll SC, Belisle SE, Katze MG, Gale M (2013) A Systems Biology Approach Reveals that Tissue Tropism to West Nile Virus is regulated by Antiviral Genes and Innate Immune Cellular Processes. PLOS pathogens. Vol 9:2.

Supplementary Sources:

  

2) http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0004457/

3) http://www.cdc.gov/ncidod/dvbid/westnile/index.htm

4) Samuel MA,  Diamond MS (2006) Pathogenesis of West Nile Virus Infection: a Balance between Virulence, Innate and Adaptive Immunity, and Viral Evasion. J Virol. 80: 9349-9360.

5) Ramos HJ, Gale  M, Jr. (2011) RIG-1 like receptors and their signaling crosstalk in the regulation of antiviral immunity. Curr Opin Virol 1: 167-176. Schoggins JW, Wilson SJ, 6) Panis M, Murphy MY, Jones CT, Bieniasz P, Rice CM ( 2011). A diverse range of gene products are effectors of the type I interferon antiviral response. Nature. 472: 481-485.