Category Archives: Guest Blogger

Guest Blogger

MicroRNA and mosquitos: Possible method for arbovirus restriction?

Contributed by Guest Blogger: C. Romero ’14

Recent research has shown that microRNA miR-275 in the Aedes aegypti mosquito is necessary for blood digestion and egg development. A. aegypti is the most common vector of arboviruses, or ARthropod-BOrne viruses, which include the dengue fever and yellow fever viruses that infect millions and kill thousands each year. Mosquitoes require vertebrate blood to produce eggs, making them good vectors for human diseases. Blood feeding and egg maturation occur in cycles, where blood feeding is required to trigger a step in the process of egg production. In A. aegypti, researchers from University of California, Riverside led by Alexander Raikhel found that miR-275 plays a critical role in this regulatory system.
MicroRNA is a relatively recent discovery, having been first identified in 1993. It appears as if their primary function is post-transcriptional regulation, in which microRNA sequences bind to complementary mRNA. The outcome has come to be known as translational repression or gene silencing, where mRNA is kept from reaching ribosomes and producing proteins, thus interrupting gene expression.
The researchers developed a RNA inhibitor specific to the microRNA molecule, known as an antagomir, to bind to miR-275 before it could silence its corresponding mRNA. By injecting female A. aegypti with this antagomir, blood digestion, fluid excretory function and egg production were all severely inhibited.
This discovery opens new doors to control of the spread of arboviruses, where removal of a single tiny molecule can limit the mosquito’s function at a fundamental level.
Many new questions arise from this research, some of which are already pending investigation by Raikhel’s UC Riverside team. The researchers plan on looking into the particular mRNA that miR-275 targets, and thus find the genes that regulate the blood-meal-mediated egg maturation cycle and see what role they play. Raikhel also plans on looking into the mechanism that underlies the activation of miR-275.
Further off, however, are considerations of how to bring this finding into the real world with a new mosquito control method. New innovations in microRNA research will surely bring us closer to harnessing its power, much as the scientific community has done in DNA genetics.

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Septic Tanks: urban breeding grounds for virus-carrying mosquitoes

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Contributed by Guest Blogger: L. Herrera-Torres ’14

Like in several other landforms in tropical regions, Puerto Rico is victim to seasonal increases in the Dengue fever and West Nile Virus, which are transmitted via the mosquitoes Aedes aegypti and Culex quiquefasciatus respectively. In order to test whether or not active septic tanks with raw sewage provide an adequate environment for the development of mosquitoes (particularly Aedes aegypti) and therefore aid in the spread of these diseases, a test was conducted in a southern municipality of Puerto Rico, called Salinas. In the community of Playa-Playita 89 septic tanks with varying structural integrity and water quality were sampled for the presence and abundance of mosquito larvae using floating funnel traps and 93 septic tanks were tested for the presence and abundance of adult mosquitoes using screened, plastic emergence traps.
Predictably, Culex quinquefasciatus, the vector of West Nile virus, which has been proven to thrive in polluted waters, was found in 74% of the septic tanks in larval form and in 97% in adult form. However, the results of vector for Dengue fever (the main focus of the experiment) were more surprising.
Previously Ae. Aegypti was known to be well adapted to urban areas and were often found in artificial containers, but it was still generally accepted that these larvae developed in clean water. However in 18% of the septic tanks sampled revealed that Ae. Aegypti was present in this water despite its contamination and had a positive association with the cracking of septic tank walls, uncapped tanks, and larger tank surface area. Similar results were found for Ae. Aegypti adults. 49% of the tanks showed both their presence and abundance as well as their positive correlation with cracking, uncapping, and septic water pH. The correlation between the amount of larvae collected from the septic tanks and the amount of adult mosquitoes recorded strongly insinuates that this environment is conducive to mosquito reproduction and development and is not just a resting place as others have suggested.
These findings led the researchers to believe that Ae. Aegypti can develop in sewage water and that septic tanks provide ideal conditions for mosquito productivity and can serve as potential to maintain dengue transmission during the dry season.

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Shotgun Approach to Keeping Viruses Off

Contributed by Guest Blogger: J. Moon ’14

The amount of human resources to develop therapeutics on a single-pathogen basis is limited. A single-pathogen approach is made more impractical with the ever increasing number of viral pathogens. But there are alternatives to this approach: broad-spectrum antivirals that target various groups of viral pathogens. Recent studies have found that LJ001, a broad-spectrum small molecule antiviral , is effective against numerous lipid enveloped viruses including Influnza A, filoviruses, poxviruses, areanviruses, bunyaviruses, paramyxoviruses,flaviviruses, and HIV-1. Against nonenveloped viruses, however, LJ001 has no effect.
The LJ001 antiviral acts by attaching to the membranes of both the cell and virus and inhibits virus-cell fusion. The antiviral begins by injecting itself into the lipid bilayer of the cell. But it is only activated upon contact with the other antiviral on the virus. Once activated, the molecule damages the lipid membrane of the virus. This damage to the lipid membrane results in loss of fluidity/rigidity that is necessary to undergo fusion into the cell. Since viral membranes do not have the ability to repair themselves, the viral membrane is deactivated by the LJ001 antiviral. Therefore, LJ001 is effective against various enveloped virus groups including the previously mentioned.
One of the first experiments was to see the comparative effects of the antiviral on viruses. The experiment consisted of testing enveloped and nonenveloped cells. The conclusion reached after data collection was that the LJ001 antiviral has no effect on nonenveloped viruses. Experiments were also conducted to determine whether or not the LJ001 antiviral was acting on the virus or on the cell. This included the introduction of the antiviral to the cell culture before and after attachment of the virions to cells. Results showed high infection rates near 100% for the cell cultures introduced to the antiviral after the virus attachment whereas infection rates for the cell cultures pre-treated with the antiviral were near zero. Experiments were also conducted with the antiviral being applied to a wide variety of large-scale lipid enveloped viruses. These results showed that there are varying degrees of effectiveness across different viruses. The conclusions reached on these observations are that LJ001 affects only non-enveloped viruses on varying degrees of effectiveness and that the LJ001 deactivates virions and prohibits virus-cell fusion.
What impact does this have on these enveloped virus groups? Although the lipid membrane of a virus remains fairly static from generation to generation, is it likely or possible that these viruses will somehow develop mechanisms to counter the effect of the antiviral? What are some possibilities?

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Locking Viruses into Endosomes – An Advancement in Influenza Therapeutics

Contributed by Guest Blogger: E. Cesanek ’13

Enveloped viruses have developed a clever technique to enter host cells and release viral genome into the cell for replication. In order to enter the cell, a virus particle takes advantage of the endosomal transport system, in which large particles bud into the cell after being enclosed by a section of the cell’s lipid membrane. Then, the acidic environment of the endosome provides the cellular energy needed to fuse the viral membrane. This process requires energy because it involves changing the conformation of the viral membrane to bend it towards the lipid membrane enclosing it. Clearly, membrane fusion is an essential part of the viral life cycle as it is the only way viral genome can be released into the host cell.
As a result, lots of recent research has been directed at identifying molecules that effectively inhibit membrane fusion. A crystallography study has helped to elucidate the mechanism by which tert-butyl hydroquinone (TBHQ), a small molecular compound that binds to influenza HA envelope protein, inhibits membrane fusion and reduces viral infectivity. Unfortunately, TBHQ only works on influenza group 2 subtypes (e.g., H3 or H14), which have a special hydrophobic binding pocket for the molecule. Once there, TBHQ works as a kind of “molecular glue,” stabilizing the structural conformation of the HA envelope protein. As a result, the amount of energy required for membrane fusion is increased to the point that HA is unresponsive to the acidic environment of the endosome.
The findings of this study may provide a framework for structural design of effective membrane fusion inhibitors for use as therapeutics against enveloped viruses. Molecular compounds that are structurally similar to TBHQ are both easier to synthesize and have more drug-like chemical properties than other types of membrane fusion inhibitors (e.g., enfurvirtide, an HIV-1 membrane fusion inhibitor).
However, it is important to remember that the TBHQ binding site is only one possibility for such conformation-locking molecules. Further research should explore alternative sites, and also explore the problem of viral resistance developing against TBHQ inhibition of membrane fusion.

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Crop Virus Bamboozles Vectors

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Contributed by Guest Blogger: H. Tran ‘14

A virus’s ability to replicate is largely dependent on the health of its host; a virus cannot proliferate in an immobile or dead organism. For this reason, viruses have a vested interest in doing as little damage as possible to ensure easy transmission. Vector-borne pathogen transmission between plants is seemingly ideal for viruses as particles can move freely from one diseased host to another potential host. However, infected plants do not typically attract vectors in the first place, as they don’t promise healthy feeding. One common crop virus is able to sidestep this obstacle by causing its diseased host to release a greater number of vector-attractants without sacrificing virulence.
It was recently discovered that the widespread plant pathogen cucumber mosaic virus elevates the release of host volatiles, or odorous chemicals, that attract vectors. Researchers measured the rates of aphid population growth on and emigration from healthy and infected plants. It was discovered that aphids were initially more attracted to the infected plants than to the healthy plants. However, the aphids dispersed rapidly from the diseased hosts after feeding. This form of transmission is known as non-persistent transmission because rather than long-term feeding and colonizing on the plants (persistent), the vectors are repelled by the inferior quality and move on to other plants (non-persistent). This type of transmission is advantageous for CMV as it facilitates easy transmission from one host to another.
It is known that the non-persistent nature of CMV transmission encourages quicker spreading between host and uninfected plants. It remains unclear, however, whether the elevated level of volatile emission is a result of an adaptation to hosts for the purpose of manipulating vectors or simply an accidental by-product of infection. In either case, the phenotypic change resulting in higher levels of volatile release has the capacity to significantly alter ecology, agriculture and human health. Damaged crops are less nutritious and unmarketable, making CMV a vastly undesirable pathogen.
Which is a more probable explanation for the deceptive mechanism by which the virus enhances host-vector interaction: manipulative adaptation or coincidentally advantageous evolution? What does your conclusion tell us about the evolution of this virus, or viruses in general? Knowing what was recently discovered about CMV, can anything be done to prevent the cultivation of diseased crops?

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Social Spread of HIV

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Contributed by Guest Blogger: T. McKinnon ’14

In the mid-1980’s, businesspeople were crossing the Tanzania/Uganda border, and caught a disease. This disease spread through all of Tanzania after 2 years, and this is the birth of the HIV/AIDS epidemic. The question that was being asked in this research is how rampant HIV is in two differing economic classes, the “rich” and the “poor,” and in which is it more prevalent. The model created by studying the transmission of this disease through differing socio-economic classes is to see the impact HIV/AIDS has on one economic class versus another, and whether transmission is easier, harder, faster, etc. in different social classes.
The experiment conducted worked like this: a total population of individual is accounted for, divided into susceptibles, infectives (infectious), pre-AIDS and AIDS patients. These people are then divided into pre-AIDS hospitalized patients and AIDS patients seeking no hospitalization, because this is common in lower economic classes. From then, the spread and rate of infection of HIV and the spread of AIDS is measured among these separate groups, whether it is initial infection or development into full blown AIDS.
Through extensive experimentation, HIV/AIDS was found to be more prevalent among wealthier populations, but it spreads faster among the lower classes. I find it very interesting that this disease is not more prevalent and spreads faster in the lower classes. In the upper class, people can more readily afford the treatments and medications than people living in lower classes with less money.
The researchers acknowledged that this experiment was by no means exhaustive. I would like this experiment to expand to how race and sexuality interact with social class in the spread and prevalence of HIV/AIDS or if race has anything to do with it, both separately and together. I also would like to know how level of sexual activity among social class propagates HIV spread, and if the members of the upper class were more or less sexually active, or participated in more unsafe sexual practices than those of the lower class, or if it was the other way around.

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Adenovirus-36 and Obesity

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Contributed by Guest Blogger: S. Bekele ’14

Obesity is an extremely serious problem, especially in the United States. Excessive weight gain can lead to many health problems, such as diabetes, heart failure, and cancer. Most people think that this is due to overeating and living a sedentary life, but new research suggests that a virus, specifically adenovirus-36, could be one of the causes of obesity. Perhaps obesity is not an overweight person’s fault, it could be simply due to an infection by a virus.
In order to find an association between adenovirus-36 and obesity, researchers in a recent study took blood samples of obese and non-obese subjects. They examined the blood serum to see if it contained antibodies for the adenovirus-36. Their BMI, cholesterol, triglyceride levels and percent body fat were also noted. After all the obese subjects’ data were gathered together, it was found that 30% had adenovirus-36 antibodies, while among the non-obese subjects, 11% had these antibodies. Also what was interesting to note was that obese and non-obese subjects with Ad-36 had lower levels of cholesterol and triglycerides, which were higher for those without the antibodies. Other types of adenovirus antibodies were viewed such as Ad-2, Ad-31 and Ad-37. There were no differences in BMI among obese and non-obese subjects; it appears that Ad-36 is the only strain of adenovirus that is associated with obesity.
From the data, it was shown that obese patients were three times higher to have Ad-36 antibodies. The researchers explained this by suggesting that those that are obese are more likely to be infected with adenovirus-36, since they may have have impaired immune function. Ad-36’s role in obesity is unknown, but researchers came up with a few ideas. For example, Ad-36 may affect fat cells which would in turn lead to an increase in the number and size of those fat cells, thus causing obesity.
The association found between this virus and obesity sparks many interesting questions. Is it truly possible that we can blame a virus (at least partially) for obesity? If we were all vaccinated for adenovirus-36, would there be a great reduction in the number of obese people, especially in the United States? If we begin to understand the effects of this virus, perhaps we can examine how big a role it plays in obesity.

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Millions of Viruses and Only One Drug

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Contributed by Guest Blogger: M. Carraher ’14

A former leader of the Pentagon considers, “Mother Nature among the worst terrorists.” Throughout modern time, the threat of a virus pandemic has seemed more likely, and more deadly than a nuclear war. Swine flu, HIV, and SARS have all frightened average citizens and leading microbiologists into a frenzy. The biggest threats have been the viruses that were least expected. If you don’t see them coming, how can you protect against a deadly outbreak? The general strategy for antivirals is “one bug, one drug”. However, any small mutation of the virus might render the drug useless. Research is currently being poured into developments of a broader range of antivirals. The current hypothesis is that certain proteins inside cells are vital for virus replication. But what if those cellular proteins aren’t necessarily vital for host life? A promising target is the TSG101 protein, which is involved in the transport of viruses out of a cell. A small-molecule drug has been developed to inhibit that interaction between the protein and virus. Researchers have identified more than 30 viruses that rely on this protein, so the drug does protect over a broader range infections. One hundred percent of Ebola-infected mice survive if exposed to the drug, a day after infection. Eighty percent survive if treated two days post infection, and 40% live four days after infection. The early test results seem promising for a strong, broad ranged antiviral drug, that does not hurt the host.
The most promising broad spectrum antiviral targets the host instead of the virus. Healthy cell membranes express a substance called phosphatidylserine on their inner surfaces. When under stress from a viral infection, this substance ends up on the outer surface. All viral infections seem to exhibit this behavior, making it a key target for drugs. An antibody called bavituximab has been developed, which binds to the phosphatidylserine. Once bound, the immune system should clearly recognize the infected cell and destroy, thus limiting viral replication. This method was tested on guinea pigs exposed to a Pichinde virus. Half the animals treated with bavituximab survived, compared 100% death for the control group, not injected with the antibody.
The antibody is currently being tested for a broader range of viruses, such as HIV, hepatitis, and influenza. So far, all infected cells express this molecule on the outside of their membranes, as compared to healthy cells, which maintain the molecule within the cell. This antibody could potentially protect against all known viruses, and some unknown as well, considering all viruses are believed to exhibit this behavior. However, viruses do evolve. Could they evolve to become immune to the antibody at some point? Further testing with humans is also needed to determine any potential side-effects. But, this is one step closer to a universal antiviral.

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Exosomes Signaling Surroundings

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Contributed by Guest Blogger: E. Raganit ’14

Epstein-Barr virus (EBV), also known as Human Herpes virus 4, greatly influences the development of many cancers. Latent membrane protein 1 (LMP1) was found to be an important oncogene of EBV in that it has transforming properties. Exosomes, vesicles that are secreted to aid in the transfer of proteins, mRNAs, and microRNAs to neighbor cells, have just recently been discovered as a mechanism that may be manipulated by both cancer cells and virus-infected cells. They are found in many biological fluids, including blood and urine. It was also recently concluded that viruses may use the exosome pathway to evade the immune system.
In a study done by the Lineberger Comprehensive Cancer Center and the Department of Microbiology-Immunology of the University of North Carolina, the group of scientists wished to test the effects of LMP1 on the exosome composition. The group harvested cells from the nasopharyngeal cell (NPC) C666 cell line that retained EBV, but also had low levels of LMP1 and compared it to both a C666 line that strongly expressed LMP1 exosomes (C666-LMP1) and a C666 control (C666-pBabe). Both the C666 and the C666-LMP1 exsosomes contained epidermal growth factor receptors.
In a test to determine if LMP1 had the ability to activate signaling pathways, the scientists exposed human umbilical vein endothelial cells (HUVECs) to exosomes. Results showed that the C666-pBabe exosomes were capable of activating the signaling pathways, but the C666-LMP1 exosomes induced activation in higher levels. This led to the conclusion that LMP1 increased the release of the epidermal growth factor receptor into exosomes, causing the activation of the ERK pathways. Findings also showed that EBV virus used the exosomal system in order to secrete molecules and viral-encoded proteins.
With the knowledge that through these exosome pathways, viruses may escape the immune system with the LMP1 activating biological channels, is it possible to create some sort of drug that halts all LMP1 processes in the hopes that the Epstein-Barr virus will not be able to continue transforming cells into tumor cells? Is it possible for the immune system to enter the exosome pathways in order to stop the EBV from further spreading?

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An Ironic Defense Against Influenza

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Contributed by Guest Blogger: M. Steinschneider ’14

The influenza virus’s unique, 8 fragments genomic structure makes the virus quite fast to evolve, and therefore very difficult to vaccinate against. New techniques for protection against the virus are thus desirable. A 2008 study by Dimmock et. al has identified a naturally existing sequence of defective influenza A RNA, named 244 RNA. Their study suggests that defective, 244 RNA viruses protect against H1N1, as well as other strains of the influenza A virus. This holds interesting implications for the prevention and treatment of influenza, perhaps providing an alternative to vaccination.
Experiments conducted in the study support Dommick’s conclusion that the 244 RNA virus protects against functional strains of influenza A. For instance, a group infected with the 244 RNA carrying virus was then infected with a human H3N2 strain, and then compared to a control group that was infected with the same H3N2, but not given the protecting virus. While the control group lost weight and demonstrated other signs of illness, the group given the protecting virus remained healthy.
The mechanism suggested by Dimmock et. al is that the 244 RNA protecting virus infects cells in the respiratory tract, an important target for the influenza Virus. Since influenza A viruses infecting the same cell are capable of swapping genetic information, due to their unique genomic arrangement, other influenza viruses introduced into the host will take on the defective RNA. The packaging process does not favor the functioning RNA sequence over the defective 244 RNA, so the 244 RNA is favored if it proportionally outweighs the functional RNA sequence.
Although this seems highly promising for fighting influenza, it does lead to several questions. For instance, is it possible that the protecting virus could mutate at some point? If this were to happen, it may cease to be benign. There is also the chance that Influenza A may mutate to have a mechanism for favoring the correct RNA during genetic swapping. Still, 244 RNA seems to be an effective and creative approach to protecting against influenza, by turning the virus’s strength (genetic flexibility in multi-infected cells) against it.

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