Category Archives: Epidemics

Epidemics, Uncategorized, Vaccines

Goodbye Rinderpest, Hello Measles

Variola virus, the agent of smallpox, once held a lonely spot on the list of globally eradicated diseases. Now it is joined by rinderpest, the cattle plague. The OIE (Organization for Animal Health) declared the disease eradicated and the UN’s Food and Agriculture Organization (FAO) is expected to adopt a resolution in June declaring it eradicated. The disease affects cloven-hoofed animals and can have an extremely high mortality rate in some cattle and buffalo. It is also extremely contagious, so its rapid spread through livestock can have an obviously large impact on animal health, food production and livelihood of cattle farmers. Thanks to an intensive word-wide vaccination effort, rinderpest virus can now be added to the list of organisms we actually intended to make extinct.

Rinderpest is caused by rinderpest virus, a member of the Morbillivirus genus. Another member of that genus is measles virus. Oh, and there is a vaccine for that too. In fact North America was free of measles in 2002 and perhaps it was on track for global eradication. But not anymore.

My son recently turned one, so I took him to get his measles, mumps and rubella (MMR) vaccine, feeling confident that Im helping protect him from three pretty nasty viruses, and not giving him Autism. In fact, before he turned one, I’d been feeling a little anxious about getting him the vaccine soon enough. My email inbox keeps filling up with notices from ProMED mail (Program to Monitor Emerging Diseases) with news of various measles outbreaks across the globe.

There are outbreaks all over Europe, especially in France, the UK, Spain and Switzerland. The epidemic in France that started in 2008 has now reached over 14,000 people, with 9000 of those infections reported in the last 6 months. (France has a vaccination rate of about 60%. Vaccination rates in the UK bottomed out at 80% and are slowly on the rise again). Outbreaks in the USA and Canada have been small, the vaccination rates are higher but not high enough. Many of these can be tracked to travel of unvaccinated individuals to areas where measles is still endemic or flaring up. In Minnesota, an outbreak counting 21 people has sent 13 people to the hospital (an unusually high number). Of the 21 people, 8 were old enough to be vaccinated but weren’t, 7 were too young to be vaccinated, 1 was vaccinated and the status of the others is unknown.

The Minnesota outbreak emphasizes an important point: it is necessary to maintain a sufficiently high level of herd immunity to prevent outbreaks and protect those who can’t be vaccinated. For most diseases, vaccination rates need to be at or above 95% to prevent outbreaks, and may need to be even higher for measles. Virus transmission depends on the virus finding a susceptible host. If a population is primarily made up of immune individuals, the virus has a hard time maintaining a chain of transmission.

Vaccination is therefore not just a matter of personal health, but community health. Maintaining high herd immunity helps protect babies too young to be vaccinated by limiting the chances that they ever encounter the virus. Don’t just get your kids vaccinated to protect themselves, do it to protect us all.

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Epidemics, Evolution, Guest Blogger, Vaccines

Swine Flu: New and Improved!

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Contributed by guest blogger: Marni Hershbain ’11

Flu season is never enjoyable, but some seasons are certainly worse than others. The 2009 swine flu outbreak was particularly serious because the 2009 H1N1 strain was a novel virus, formed via the reassortment of swine, avian and human flu viruses. There were over 600,000 confirmed cases of H1N1 and over 18,449 deaths during the course of the pandemic. While this sounds pretty bad, it could have been much worse. The transmission efficiency of H1N1 was actually much lower than those of other pandemic strains, such as the 1918 H1N1 strain. Unfortunately, recent research demonstrates that this could change.

Flu strains are characterized by the hemagglutinin and neuraminidase found on their surfaces, hence names like H1N1. In order for the virus to infect a cell, hemagglutinin on the surface of the virus must bind to glycan receptors on the cell. Therefore, to explain the low transmission efficiency of 2009 H1N1, researchers looked to its hemagglutinin.
In most flu strains, the amino acids at positions 219 and 227 within the hemagglutinin are both hydrophobic or both charged. In 1918 H1N1 both are hydrophobic. However, the 2009 H1N1 strain has isolucine, a hydrophobic molecule, in position 219 and glutamic acid, a charged molecule, in position 227. Researchers hypothesized that lacking either hydrophobic or ionic interactions at these positions would disrupt the positioning of neighboring residues and decrease the hemagglutinin’s binding affinity. They further hypothesized that if they replaced isolucine with the charged amino acid lysine, stable inter-residue interactions would occur and binding affinity would increase.

When researchers compared the ability of wild type and isolucine→lysine mutant strains to bind to an array of glycans representing human binding sites, they found the binding ability of the mutant strain was 30 times greater. The mutant version also bound more intensely to receptors in human tracheal tissue. Researchers also infected ferrets (commonly used as models in human influenza studies) with either wild type or mutant virus. Only the ferrets infected with mutant virus spread the infection to all of the previously uninfected ferrets placed in close proximity to them.

The mutation of just one amino acid could greatly impact the transmission efficiency of 2009 H1N1. Flu viruses tend to mutate frequently, which is why a new vaccine needs to be developed every year. Predicting what these mutations will be is not an easy task, but mutations at the positions in this study will certainly be monitored closely.

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Epidemics, Guest Blogger, Immunology, Vaccines

A possible new HIV vaccine target?

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Contributed by guest blogger: Lydia Mendoza ’11

In 2009, it was estimated that 33.3 million people in the world were living with HIV/AIDS. Since the discovery of HIV, more than two decades ago, money has poured into research in the hopes that an effective vaccine might be developed. As of yet a vaccine remains elusive. One reason why it is so difficult to create a vaccine is because HIV is highly mutable and genetically diverse subtypes, or clades, have evolved. A vaccine needs to be able to offer protection from a range of HIV clades.

Normally viral vaccines are based upon neutralizing antibodies, which prevent infection of the host cell. The first attempts to develop neutralizing antibodies against HIV targeted gp120, which is known to play a role in HIV’s ability to enter and infect CD4 t-cells. These attempts have not been successful as of yet because of the gene’s high rate of mutations. However a recent paper has shown that the V3 loop of gp120 is a potential vaccine target.

The strand of protein known as the V3 loop was never thought to be an attractive vaccine target because it is not highly conserved. However, it appears to have conserved structural elements that are involved in interactions with coreceptors. To study whether V3 was a viable vaccine target, a human monoclonal antibody, HGN194 was used. HGN194 was isolated from memory B cells of a person infected with HIV-1 clade AG circulating recombianant form (CRF). HGN194 targets the V3 loop and has been previously shown to neutralize a broad range of neutralization-sensitive and resistant strains of HIV.

The study evaluated whether HGN194 was able to protect rhesus monkeys from an HIV model system. One group of monkeys was injected with HGN194 then they were challenged with a high dose of a clade C SHIV, which is a chimeric simian-human imunodeficiency virus encoding HIV envelope genes in a SIV backbone. The second group of monkeys was also given a high dose of SHIV but was not given the HGN194. The monkeys given the antibody were protected from SHIV infection, and those not given the antibody were infected. The researchers concluded that HGN194, isolated from an HIV-positive individual harboring a clade AG CFR, was able to confer complete cross-clade protection against clade C SHIV.

The antibody apparently latches onto the virus’s V3 loop and prevents the virus from invading cells. This does not mean that this antibody treatment technique is a vaccine for HIV. It does not create long-term protection because the antibodies do not remain active in the body for very long. This is only a first step. A vaccine target has been identified but now scientists must create an antigen that induces formation of an antibody similar in structure to HGN194. There is a lot of work left to be done but this finding hopefully brings researchers much closer to the development of a vaccine.

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Epidemics, Uncategorized

Hey, I wonder what’s in bat poop?

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I know you were thinking the same thing! Bats are suspected reservoirs for several zoonotic viruses that can cause significant disease in humans or other animals. These include the dreaded Ebola virus, Nipah virus (which causes outbreaks of encephalitis in South East Asia), Hendravirus (which causes disease in horses) and several others. So knowing what viruses are carried by bats will be important in understanding emerging zoonoses.

Several studies have identified a diverse array of viruses in bats, but using next-generation sequencing it is now possible to investigate the population of viruses carried in bats to a much deeper level. In a study published last summer, guano from bats in California and Texas was collected by placing plastic sheets below the bat roosts. The individual roosts were occupied by as many as four different bat species, so the guano collected was a mix from the different inhabitants. To isolate viral DNA and RNA, the samples were filtered to remove cells then treated with nucleases to destroy any free DNA or RNA, leaving only encapsidated viral genetic material.

In the sequenced “virome” or population of viruses in the samples, only 51-39% of the sequences(depending on collection site) had matches to genbank sequences. So once again, viromic sequencing shows us how little we know about the viral world. Of those sequences that matched known sequences, most were insect and plant viruses. The bats are insectivores and the insects are herbivores, so you can see the viral populations from each link in the food chain. Only a very small proportion of the virome was of bacteriophage origin, much less than other viromic studies in humans and horses, although its not clear why there would be such a difference. Among mammalian viruses, which made up less thatn 10% of the sequences, there were adenoviruses, coronaviruses, parvoviruses, circoviruses, astrovirsues, picornaviruses and even poxviruses. Most of these sequences only matched less than 60% to known mammalian viruses however, so its unlikely that they pose a zoonotic threat.

As researchers continue to sequence viral populations, we keep seeing mostly novel sequences, something that has decreased in bacterial and eukaryotic sequencing. That tells us we have a lot more sequencing to do if we want to understand global viral diversity. In bats however, the major question is not so much about the diversity but the threat of zoonoses. It will be interesting to see the guanome of bats in areas where zoonoses are a real problem, and I wonder if this will be a technique useful to monitor the threat of emergent diseases as the cost of high throughput sequencing continues to drop.

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Epidemics, Evolution, Immunology

Virus and Parasite Unite

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Contributed by Guest Blogger: Joseph Zaino ‘11

Recent research has found a unique relationship between the intracellular parasite, Leishmania, and it’s corresponding Leishmania RNA virus-1 (LRV1). Ives et. al. concluded that Leishmania parasites, in the presences of LRV1, suppressed the host immune response and strengthened the pathogen’s persistence. Leishmania infects the human immune system by attacking macrophages. The parasite causes the infection known as leishmaniasis, which is typically transmitted by sand files. This is a serious infection, affecting an estimated 12 million people in the Mediterranean basin, Africa, the Middle East, Asia, Central and South America. The strain of parasite investigated by this study was mucocutaneous leishmaniasis (MCL). MCL destroys the soft tissues of the face and nasopharyngeal regions, as well as damages host immune responses.

Leishmania parasites are dependent on proinflammatory protein mediators called Toll-like receptors (TLRs). TLRs are found in intracellular vesicles of the macrophage- presumably the same vesicles that host Leishmania. Ives et. al. confirmed that TLR3-TRIF dependent pathways are essential for macrophage infection by Leishmania. The unusual part is that TLRs usually help the mammalian immune system to eliminate pathogens. Specifically, TLR-3 recognizes the double stranded RNA of many viruses that are released from dead parasites, unable to survive within their host. Observations found that between virally infected and non-virally infected Leishmania, the virally infected ones were more likely to successfully infect a host. Similarly, metastasizing parasites had greater levels of the LRVI virus than non-metastasizing parasites. The authors verified this finding by treating macrophages with purified LRVI, and observing the same phenotypic infection as the viral-infected Leishmania. Further models concluded that when TLR3 is deleted from macrophages, parasitic persistence was diminished.

This apparent mutualism seems to benefit both Leishmania and the virus by allowing a more successful rate of host infection. Many Leishmania species have lost RNAi interference pathways, allowing viruses to inhibit and replicate within them. In this case, the virally infected parasite is more persistent against macrophages, and more damaging to the mammalian immune system. Thus, it is advantageous for the parasite to coexist with the LRV1 virus. If severe MCL infections are contingent on LRV1 for infection, then future research can perhaps focus on this relationship in order to better understand and cure leishmaniasis.

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Epidemics, Guest Blogger

Chicken Anemia Virus and its Similarities to Human Anelloviruses

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Contributed by Guest Blogger: Maggie Rasnake ’11

When a virus is not known to be associated with any disease, it is called an orphan virus. Human anelloviruses, like torque teno virus (TTV) and torque teno mini virus (TTMV), are orphan viruses because they do not have known symptoms. TTV was first discovered in a patient with liver disease. However, no definite link between liver disease and the virus has been shown. Anelloviruses are genetically similar to an avian virus called chicken anemia virus (or CAV). CAV has had a large, economic impact on the poultry industry. Unlike TTV, it is known to have symptoms, but it can have a long lag-time between infection and the development of disease.

Both CAV and TTV have similar, single-stranded, circular DNA and have highly variable sections of the genome. It is believed that they evolved from a plant virus. Researchers realized that much of what they learned about CAV could be applied to TTV and vice versa. For example, when they realized that TTV had more than just three proteins encoded by its three open reading frames, they found that the same was true for CAV. When CAV was found to replicate in the bone marrow, it was discovered that a great deal of TTV replication occurs in the bone marrow as well.

CAV is associated with developmental problems for fetuses and young chickens. The virus is less understood in adult chickens, but when chickens have CAV, they are much more likely to suffer from other diseases and have higher mortality rates. Similarly, in infected humans, the viral load of TTV is higher when the individual has other infections. In addition to liver disease, levels of TTV tend to be higher in those with respiratory infections, kidney disease, HPV, and certain cancers, among others. TTV may enhance the pathogenic effects of other pathogens. High levels of TTV are found in individuals with HIV, but it is not known if TTV simply reflects the immune system’s status or if it contributes to the damage. An effective medium for studying TTV has not yet been established. The authors suggest that the virus might be better studied in a novel primate cell line transformed by an oncogenic virus.

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Epidemics, Guest Blogger

The Relationship Between Diabetes and Enteroviruses

Contributed by Guest Blogger: Charlie Gray ‘11

Enteroviruses are a genus of positive sense, single-stranded RNA viruses which include poliovirus, coxsackie A & B, echovirus, and enterovirus. These viruses can cause a variety of symptoms ranging from the common cold and conjunctivitis to paralytic poliomyelitis. Researchers have also found an association between enteroviruses and type 1 diabetes, a disease whose incidence has increased over the past 25 years at an annual rate of 3%, a rate that cannot be explained simply by genetics.

In a recently published paper, Wing-Chi G Yeung and his colleagues conduct a systematic review of controlled studies that use molecular virological methods in an effort to compile what is currently known about the association between enteroviruses and type 1 diabetes, and to aggregate their results. Their meta-analysis included 34 papers, 30 of which used reverse transcriptase PCR or in situ hybridization to detect the enterovirus RNA; the other four used immunostaining for the enterovirus capsid protein, vp1, on autopsy pancreas specimens. Although the studies varied in age distribution, most investigated children and adolescents (i.e. less than 16).

Yeung and his colleagues found a strong association between enterovirus infection and diabetes, with a 9 fold increase in the risk of infection in diabetic individuals. They conclude that their meta-analysis of these previous observational studies do provide support to the growing collection of findings that individuals with type 1 diabetes have increased odds of suffering from an enterovirus infection.

Despite Yeung et al.’s findings, there was quite a bit of variation in the designs and methods used in the various studies that the authors analyzed. Only 10 of the 34 studies matched for three or more potential confounding factors such as age, genetic risk, geographical location and sampling time. In addition, the studies varied greatly in the site selection from which they collected samples (e.g., serum, stool, throat swabs). Enteroviruses invade cells and replicate at mucosal surfaces; therefore, detection rates could be significantly higher in samples that were obtained from the gastrointestinal tract.

Although this paper does provide evidence for a diabetes-enterovirus link, it does leave several questions for future research. It is unclear how strong the association between enterovirus infection and diabetes is, and if the other factors such as geographic location and genetics may influence the observation of enterovirus infection and diabetes. For example, previous studies have examined varying HLA (a gene encoding an important immune system protein) genotypes and how certain genotypes can modify the association between enterovirus infection and diabetes; however, those results have provided conflicting evidence. Therefore, further study is needed to determine how these confounding factors affect one another and the enterovirus-diabetes link.

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Epidemics, Guest Blogger

The Role of Social Networks in H1N1 Transmission Within a School

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Contributed by Guest Blogger: Aaron Grober ’11

The H1N1 subtype of the Influenza type A virus, known colloquially as “swine flu,” was the most common cause of human influenza infection in 2009, and remained a major concern in sparking a pandemic throughout the 2009/2010 flu season.

This recent paper examines the role of grade, class, and social network in transmission of this virus in a school setting. Taking a closer look at the actual transmission pattern of this novel subtype of influenza is critical in developing models to better predict and combat pandemic spread. In the case of this school, closure due to outbreak did not significantly affect transmission among students, indicating that it may have occurred too late to be effective, stressing the importance of more exact models. The study encompassed 370 students from 295 households, surrounding an H1N1 pandemic that occurred in a Pennsylvania elementary school in April and May 2009.

The researchers found that the structuring of the school into grades and classes significantly affected the probability of transmission: 3.5% between students within a class, five times less than that between students of the same grade but different class, and five times less than that between students of different grades.

The researchers took an in-depth look at fourth-graders. They note that children are four times more likely to play with members of the same sex, and found that this behavior had a significant impact on disease transmission; the onset of epidemic transmission occurred among boys significantly before that of female classmates. In addition, they found no significant difference between recorded playmate transmission rates, and the expected proportion for if being a playmate was not a risk factor. The researchers used class seating charts to determine if proximity to an infected individual affects the risk of transmission; as it turns out, they found that sitting next to an infected individual did not significantly affect one’s risk.

In addition to school structure, the researchers looked at spread within households. The probability of a child to adult transmission within a household depended significantly on the household size, where probability of spreading the disease is much lower in larger households than smaller ones. The predominant means of adult infection was from outside the home.

These unique findings shed light on the extremely complex transmission pattern within structured populations. The biggest factors for transmission within school are grade and class, but not seating arrangement, sex, but not playmate transmission. A number of obvious questions remain: Why does sharing a class, but not a desk-space affect transmission? Why is one more likely to transmit the disease in a smaller household than a larger one? This study is an extremely insightful epidemiological tool to help explain transmission, but our knowledge of how this virus spreads remains incomplete; it seems that the flu is far more complex than we imagined.

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Epidemics, Guest Blogger

Feeling tired all the time? You might have a virus.

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Update (Janyary 2012): Two studies identifying XMRV in CFS patients have been retracted, including the original paper that proposed the association. The current, best supported evidence, in this area suggests that the association was actually due to contamination. There appears to be strong scientific agreement that CFS is not related to infection with this virus.

Contributed by Guest Blogger: Nicole Krenitsky ’11

Patients with Chronic Fatigue Syndrome (CFS) perked up when a paper published in Science in 2009 linked the symptom-defined illness to xenotropic murine leukemia virus-related virus (XMRV). XMRV, also connected to prostate cancer, is positive sense, single-stranded RNA retrovirus of the class murine leukemia viruses (MLV). Four subsequent studies failed to find any MLV-related viruses in CFS patients or controls. Then in 2010, a paper published in PNAS reinvigorated the debate. The study did not specifically find XMRV but did find MLV-related viruses in the blood cells of CFS patients tested. Yet one month later, the CDC published report, stating that they had not found any MLV-related viruses in their own study of CFS patients.

Reasons for the inconsistent results are presently unknown. One hypothesis is that the PCR could have picked up mouse DNA or mouse viruses, contaminating the tests and producing false positives. Another involves the samples of participants; CFS is diagnosed solely based on symptoms and clinical case definitions such as the one published by the CDC do not differentiate well between CFS and depression, resulting in overdiagnosis. A study conducted by Ian Lipkin is underway and seeks to standardize sampling and analysis methods and use a larger sample size to settle the controversy.

Relating CFS to a virus has far-reaching consequences for patients and for public health. Antiretrovirals used to treat HIV have been shown to inhibit XMRV replication in vitro and some CFS patients have already begun ART following the 2009 Science publication. The AABB and the American Red Cross, erring on the side of caution, have banned patients with CFS from donating blood erring on the side of caution. If CFS is caused by MLV-related viruses, the blood supply would be tainted the syndrome passed to transfusion recipients.

One million Americans are affected by CFS and experience sleep disorders, cognitive difficulties, chronic muscle pain and headaches. Many dismiss the disorder as psychosomatic and doubt its legitimacy as an illness. In addition to diagnostic testing and finding clinical treatment or a cure for CFS, a link to a virus would give CFS scientific credibility. Mary Schweitzer, historian and CFS sufferer explains, “Patients are hopeful that now the disease itself might be treated seriously, that they’ll be treated seriously, and that there might be some solution.”

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Epidemics, Uncategorized

Frank Fenner 1914-2010

It is with great sadness that I report the death of one of my science heroes, Frank Fenner. One of the key people involved in the eradication of smallpox, he was also a prolific researcher in poxvivrology, and discoverer of the virus I study, ectromelia virus. Although I never met him, I have read many of his papers and they have influenced my own research and interests.

Here is the text of the email I received this morning, from Julio Lincio:

“Frank John Fenner AC, CMG, MBE, FRS, FAA (born 21 December 1914,died 22 November 2010) was an Australian scientist with a distinguished career in the field of virology. His two greatest achievements are cited as overseeing the eradication of smallpox during his term as Chairman of the Global Commission for the Certification of Smallpox Eradication, and the control of Australia’s rabbit plague through the introduction of myxoma virus.

Professor Fenner was Director of the John Curtin School from 1967 to 1973. During this time he was also Chairman of the Global Commission for the Certification of Smallpox Eradication. In 1973 Professor Fenner was appointed to set up the new Centre for Resource and Environmental Studies at the Australian National University (ANU). He held the position of Director until 1979.

Professor Fenner has been elected a fellow of numerous faculties and academies, including Foundation Fellow of the Australian Academy of Science (1954), Fellow of the Royal Society (1958), and Foreign Associate of the United States National Academy of Sciences (1977).

During his career Professor Fenner received many awards. Among these are the Britannica Australia Award for Medicine (1967), the Australia and New Zealand Association for the Advancement of Science Medal (1980), the World Health Organization Medal (1988), the Japan Prize (1988), the Senior Australian Achiever of the Year (1999), the Albert Einstein World Award for Science (2000), and the Prime Minister’s Science Prize (2002).

A man of decisive scientific action and strong opinions, Professor
Fenner’s last interview with The Australian is extremely thought provoking and can be found here

A summary of Frank’s remarkable career can be found here”

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