Guest Blogger

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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Guest Blogger

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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Guest Blogger

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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Guest Blogger

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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Guest Blogger

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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Guest Blogger

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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Guest Blogger

Creating Synthetic HIV Vaccines

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Contributed by Guest Blogger: A. Lee ’14

HIV is particularly virulent due to its specific attack of host immune cells and disruption of their normal function. The human body needs helper T-lymphocytes (HTL), which coordinate and activate other immune cells, and cytotoxic T-lymphocytes (CTL), which attack infected cells, to work cooperatively to defeat illness. HIV attacks HTL and through its high sequence mutation rate evades the body’s attempts to identify a parts of it for counterattack, called epitopes; these constant, minute changes in the virus also makes vaccine development difficult. However, recent technological advances have allowed immunologists to circumvent this problem through study of HIV’s amino acid sequence, or its structural makeup.
Researchers have identified key epitopes of major HIV subtypes, recognizable by HTL and CTL, and combined them into two vaccines, a synthetic protein structure to activate HTL (called EP-1043) and a plasmid (DNA segment, EP HIV-1090) to activate CTL. EP-1043 was created by cutting the DNA sequence of the 18 epitopes into overlapping sequences, fusing that with insect and viral sequences to ensure viability in a bacterium, and using this sequence in a non-deadly virus to force a bacteria to create the protein. The EP-1090 DNA sequence was created using a similar process of combining epitopes into overlapping sequences and replicating them using a process called PCR (no similar process exists for replicating proteins). Importantly, EP-1043’s protein epitopes are joined by weak bonds, meant to break and spread the epitopes through the body. Because the protein aggregates (becomes useless) at blood pH, it is packaged in aluminum hydroxide (Alhydrogel) and aluminum phosphate gels, which dissolve later.
Effectiveness of the virus was measured 39-42 days after infection by measuring cytokine (cytokines are secretions of infected cells causing immune reaction) and by measuring reproduction of splenocytes (spleen immune cells). Though EP-1090 was ineffective, EP-1043 was significantly effective in causing immune. Despite the low toxicology of the vaccine, and the fact that a true vaccine for HIV would require CTL and HTL epitope response from singular cells, this is an important step towards combating HIV.
One wonders, then, what more complex methods can be used to amalgamate epitopes for vaccines, and what method immunologists will use to create true HIV vaccines, if at all possible. This method can be used for other, less complex viruses, but does this relatively non-specific, general epitope flood lessen the necessary specific response? Can the body handle such a large, sudden appearance of viral material?

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Guest Blogger

Cross-Species Transmission in Rabies

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Contributed by Guest Blogger: D. Patel ’14

Deadly human diseases including HIV Aids, swine flu and rabies are infectious diseases where the viruses have jumped from one animal species into another and now infect humans too. This is a phenomenon known as cross-species transmission (CST). Understanding this process is the key to predicting and preventing future outbreaks.
The scientists who researched CST and wrote this paper made a groundbreaking discovery into how viruses jump from host to host. They used and thought of rabies as an ideal system because it occurs across the country, affects many different host species, and is known to mutate frequently. Although cases of rabies in humans are rare in the U.S., bats are a common source of infection. Hence, the study was based on and narrowed down to CST events among different bat species.
To determine the rate of CST, a large dataset containing hundreds of rabies viruses from 23 North American bat species was used. Population genetics tools were used to quantify how many CST events were expected to occur from any infected individual and the cases were verified by genotyping both the viruses and the bats.
The study showed that depending on the species involved, a single infected bat may infect between 0 and 1.9 members of a different species; and that, on average, CST occurs only once for every 72.8 transmissions within the same species. This means that the majority of viruses from cross-species infections were tightly nested among genetically similar bat species.
It is a long-held belief that CST depends on virus mutation and contact of the host with other species. However, this study showed that CST may have more to do with host similarity. The similarity in the defenses of closely related species may favor virus exchange by making it easier for natural selection to favor a virus’ ability to infect new hosts.
Whether other factors (like evolution of viruses) are enough to overcome the genetic differences between hosts remains questionable. However, the basic knowledge gained through the study is key to developing new intervention strategies for diseases that can jump from wildlife to humans.

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Guest Blogger

Redefining the HPV-32 Detection Gold Standard

Contributed by Guest Blogger: R. Hendricks ’13

A recent study focuses on HPV-32, which is frequently associated with focal-epithelial-hyperplasia (FEH), which is a wart-like growth in the mucous tissues of the mouth. Detection of HPV-32 is currently labor-intensive and insensitive, so this work was focussed on testing an experimental polymerase chain reaction (PCR) assay, or measurement of the virus in a sample, to determine if it was more sensitive and user-friendly than the current gold standard method (MY09/11 amplification and dot blot hybridization).
The experimental assay was specific for the HPV-32 L1 gene, so the experimenters used samples of the HPV-32 gene from HPV-positive subjects and tested sensitivity of the current dot-blot assay by applying it to the sample and seeing how many copies of the gene it could detect and amplify. They then did the same procedure with the experimental assay, which correctly identified many more genes as HPV-32 positive. Specifically, the dot-blot assay detected HPV-32 in 24 oral samples. All but one were also identified by the HPV-32 L1 PCR, which identified an additional 78 samples. Reproducibility was also assessed, by retesting 111 samples, 57 of which were HPV-32-positive. The researchers found that 94.6% of the samples were reproducible.
The HPV-32 specific PCR system targeting the L1 gene produced significantly greater sensitivity in identifying HPV-32. It is also highly reproducible and less labor-intensive, and is therefore the new gold standard.
Follow-up experiments, such as one that targeted a different gene of HPV-32 (the E6/E7 region) were carried out to ensure that the increased sensitivity was a result of the robustness of the experimental assay. A potential next step in this research could be to target other specific genes with a similar PCR assay, to see if the robustness will remain.

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Immunology, Molecular Virology

Curing infected cells instead of killing them

Once a cell is infected, our immune system clears the infection not by targeting the virus, but by simply killing the infected cell.  Antibodies are also an important part of our defense against viral infections, but their function is limited to targeting viruses floating around outside the cell.  It is believed the once the virus enters the cell, it’s safe from antibodies.  But a recent study suggests that this may not be true; it seems that antibodies can eliminate viruses from inside cells too.  This is particularly groundbreaking because this may be a mechanism to cure infected cells, rather than just killing them.

Researchers identified a protein called TRIM21 that binds antibodies, but it was localized to the cell’s cytoplasm.  Why would it be there, when antibodies are secreted?  It seems that sometimes viruses can enter a cell with antibodies bound to it.  While some antibodies are neutralizing, meaning that they prevent attachment to the receptor, others are not.  If the virus is coated with these non-neutralizing antibodies, it can still enter, and it bring the antibodies in with it.  TRIM21 recognizes these internalized antibodies, with virions attached to them, and then targets it for destruction in a cellular blender called the proteasome. In an appropriately named “fate of capsid” experiment, the researchers showed that antibody bound adenovirus capsid proteins were being degraded as soon as 2 hours after infection and that the degradation required both the proteasome and TRIM21.  So the virus is being destroyed quickly, before it gets the chance to replicate.

As always, this study introduces many new questions.  They used adenovirus, which causes mild respiratory infections, but does the mechanism extend to other non-enveloped viruses? Can this mechanism be used to improve existing vaccines or develop new ones? How important is this mechanism in the overall response to viral infection?  Have viruses evolved mechanisms to block TRIM21?

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Teaching and Research on the Microbial World in the Liberal Arts

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