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.

Can Depression Stifle Response to a Common Vaccine?

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Can Depression Stifle Response to a Common Vaccine?

            A paper was recently published that investigates how patients suffering from major depression may respond to a specific vaccine. The authors studied the connection between this mental health disorder and the immune response to the varicella zoster virus vaccine. The varicella virus is more commonly known as virus that causes the chickenpox. It is an interesting virus because following infection; it remains inactive in the infected individual’s sensory neurons. In other words, if you are infected with this virus it essentially hangs around in your body and can re-infect you at a later time. If this re-infection does proceed via reactivation and replication, then it can lead to Herpes zoster (HZ), otherwise known as shingles. Shingles is a fairly well known syndrome that is characterized by a painful skin rash with blisters. Each year, there are more than a million new cases of shingles each year. The main risk factor for developing this type of viral infection is age. The incidence and severity of shingles increases with age.

As of yet, the main other identified risk factor is a low level of VZV-specific T cell-mediated immunity. VZV-specific T cell-mediated immunity is basically a measurement of how ready your immune system is to responding to varicella reactivation. A “higher” level of this immunity means your body is more capable of fighting off the dreaded shingles infection. Post-varicella infection, your body is able to develop and maintain this immunity. So although the virus that causes shingles may be hanging around in your neurons, waiting to attack, your body’s natural defenses are often ready to fight back.

Fighting Fire with Fire

To some it may seem counterintuitive to use an infection to cure a disease. Surprisingly enough, this is exactly what researchers have been doing using oncolytic virus therapy.  Oncolytic viruses are naturally occurring or engineered viruses that selectively target cancer cells by identifying common cancer characteristics such as defective immune responses or abnormalities in cellular signaling pathways. Once viruses infect the cancer cells, they replicate within the cell and eventually kill it.  As such, the infectious qualities of oncolytic viruses are becoming increasingly useful tools during cancer treatment. 

Past studies have shown great potential for oncolytic therapy using vesicular stomatitis virus, (VSV) -- a negative-strand RNA virus that generally infects insects, cattle, horses and pigs (1).  VSV has proven to be particularly conducive to oncolytic virus therapy as a result of its small easily manipulated genome and relative innocuity in humans (2). So far, VSV vectors have been used for immunization against HIV and influenza (2,3).  Additionally, testing has occurred that suggests that there is also potential of VSV as a recombinant cancer vaccine vector (4). 

Despite the high hopes for the use of VSV as oncolytic cancer treatment, a recent 2012 study suggests that human pancreatic ductal adenocarcinoma (PDA) cells do not consistently permit VSV infection (5).  In some cases, PDA cells retained all resistance and were still able to activate functional interferon (IFN) responses. As a result, the study of the interferons – proteins released by host cells to interrupt viral replication – and their association with oncolytic VSV infection is of great interest to researchers.

A Step Towards Curing Drug Resistant Flu

This Is What’s Up:

Simple viral inhibitors have long been the best hope for treating the Flu, but recent research has brought to light that there could be other methods.

There are many steps in the virus life cycle that you can target a drug at: attachment, entry, protein production, genome replication, and exit from the cell. Oseltamivir is a fairly well known antiretroviral drug used to combat the flu. This drug targets and inhibits the viral neuraminidase, which is a protein on the surface of the virus particle that is necessary for assembled viral particles to leave host cells. In other words, without this protein functioning, the virus is trapped inside the cells it’s in, and your immune system can quickly hunt it down and take it out.

While neuraminidase inhibition has worked well in the past, there are some disadvantages to using antiviral drugs such as these. Viruses replicate themselves thousands, if not millions of times a day, and they are pretty sloppy about it. This large number of “offspring” and high mutation rate creates a large pool of genetic variation for natural selection to act on, and thus allows viruses to evolve much faster than most organisms. As a result, viruses such as the flu can develop resistance to medications in relatively short amounts of time. In this case, certain flu strains have gained resistance to drugs such as oseltamivir. There are other antiviral drugs that target different steps in the virus life cycle, but it is only a matter of time before another strain develops resistance to them too.

This is a real public heath issue!

For this reason, many labs have been looking into more effective methods of inhibiting viral replication. Based on previous research, Aoki et al. began looking into methods of inhibiting the neuraminidase receptor on the flu virus that the virus could not evolve an immunity to.

So What’s New?

Previous research by Suzuki et al. suggested that a molecule called anthraquinone has the ability to degrade proteins in the presence of long wavelength ultra violet light. With this in mind, Aoki et al. made an anthraquinone-sialic acid hybrid protein. Sialic acid is a receptor that neuraminidase binds to. Whether or not a flu virus has gained drug resistance, it still must bind to sialic acid to perform its functions in the cell. In this hybrid protein, the sialic acid section targets the anthraquinone to the virus, where it can then be activated with UV light to degrade the neuraminidase it is attached to.

Cool… right!?

After performing several SDS-Page experiments (these look for the presence/absence of a protein), the authors found that in a test tube, when neuraminidase is mixed with the anthraquinone-sialic acid hybrid protein and then irradiated with UV light, there are significantly diminished amounts of neuraminidase. They also made sure that there was no neuraminidase degradation by either the hybrid or the light alone–it had to be the combination that was causing the effect seen.

Keeping the Defenses Quiet

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Plants and animals alike fall sick when infected by something pathogenic: viruses, bacteria, oomycetes, and more. Thankfully, higher-order eukaryotes have evolved multiple ways to stop many of these bugs from “taking over”. However, these mini critters don’t give up quite so easily, and have a few clever tricks of their own to combat the host immune system. This paper investigates the strategy of RNA silencing suppressors, a counter defense utilized by the Phytophthora microbial plant pathogens.

            Before discussing the paper, however, why bother to study this topic? First of all, humans rely on plants for everyday life. If one understands the ways this group of notorious crop pathogens causes plant sickness, we will have an edge in curbing the economical and physical damage caused by these microbes to the supply of food worldwide. For example, in Ireland, the potato famine was caused by

 Phytophthora infes­tans; since 1845, the pest causes endemic loss of crop of up to 50% seven out of ten years (1). More importantly, however, we will have a model that may be extrapolated to other critical plant species and even animals when trying to tailor specific cures for diseases in the future. As with all science, understanding a little piece of the puzzle has multifaceted usefulness, because often this piece can help us solve the puzzles in other plants and animals. This paper successfully characterizes factors in Phytophthora plant pathogens that contribute to its successful virulence in the hopes of demonstrating that further characterizations of factors in relevant organisms will help in finding effective cures.

            One method by which a host may prevent, or at least lessen, the infection of pathogens, especially against RNA viruses, is to encode for miRNAs or siRNAs; small-RNAs that work to degrade the genetic material of the invading species (2). But what happens when Phytophthora creates something called an effector, a factor boosting virus fitness (3) where the small-RNA defense mechanism is actually disabled? You get successful infection of the invading species, or at least enhanced succeptibility. In a series of clever experiments, Qiao et al. characterized PSR1 and PSR2, miRNA/siRNA interfering proteins of pathogens belonging to the Phytophthora genus.

Measles Vaccine Virus: A New Weapon against Cancer?

When viruses come to mind, most people tend to think of their threats against human health.  However, scientists are rapidly discovering a new branch of medicine: oncolytics.  Oncolytics is the use of viruses to kill cancerous cells, while leaving the surrounding healthy tissue unaffected.  Certain forms of cancer are ideal for oncolytic research, due to their location and lack of viable treatment.  A sarcoma is a certain type of cancer that comes from mesenchymal tissue (1).  Sarcomas can be divided into two categories: soft-tissue or bone (1).  While certain types of surgeries can cure sarcoma, other forms are inoperable, and difficult to treat with surgery, chemotherapy, or radiation (1).  Thus, sarcomas are optimal for experimental oncolytic research.

            In a recent study published by the Journal of Virology, German scientists from the University Hospital Tubingen investigated the effectiveness of the measles vaccine virus (MeV) in treatment of eight types of sarcoma cell lines: HT1080 (human fibrosarcoma), A673 (extraosseous Ewing sarcoma), SRH (sclerosing spindle cell rhabdomyosarcoma), BR and ZF (alveolar rhabdomyosarcoma), SCOS (osteosarcoma), CCS (clear cell sarcoma), and ST (dedifferentiated leiomyosarcoma).  Researchers chose to focus on MeV due to its previous oncolytic potential in several types of cancers, such as ovarian carcinoma (2), lymphoma (3), and glioblastoma (4).  Typically, oncolytic viruses are equipped with “suicide genes,” which can produce localized chemotherapy in an infected cell (5).  In this experiment, the researchers armed MeV with super cytosine deaminase (SCD), which converts 5-fluorocytosine (5-FC) into 5-FU, a type of clinical chemotherapy, thus producing MeV-SCD (6).