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).