HPV Vaccine Highly Effective Against Multiple Cancer-Causing Strains

WASHINGTON, DC February 13, 2015 -- According to a multinational clinical trial involving nearly 20,000 young women, the human papilloma virus vaccine, Cervarix, not only has the potential to prevent cervical cancer, but was effective against other common cancer-causing human papillomaviruses, aside from just the two HPV types, 16 and 18, which are responsible for about 70 percent of all cases. That effectiveness endured for the study’s entire follow-up, of up to four years. The research was published February 4 in Clinical and Vaccine Immunology, a journal of the American Society for Microbiology.

“The study confirms that targeting young adolescent girls before sexual debut for prophylactic HPV vaccination has a substantial impact on the incidence of high grade cervical abnormalities,” said corresponding author, Dan Apter, Director, The Sexual Health Clinic, Family Federation of Finland, Helsinki.

The vaccine was extremely effective in young women who had never been infected with HPV. It protected nearly all from HPV-16 and -18, and protected 50-100 percent against different grades of precancerous transformation of cervical cells caused by other strains of HPV, including up to 100 percent of those with the immediate precursor grade to cancer. The women were followed for up to four years post-vaccination.

The vaccine was distinctly more effective among ages 15-17 than ages18-25, underscoring the value of vaccinating young adolescents, said Apter. The lower efficacy in the oldest age group may result from a larger proportion of women in that age group having had persistent infections at the time of vaccination, he said.

The study is the final report from the Papilloma Trial Against Cancer in Young Adults (PATRICIA), a multinational clinical trial encompassing 14 countries in Europe, the Asia-Pacific region, North America, and Latin America, and it confirms previous reports in this trial. The over-all trial constituted the basis for approval of the Cervarix vaccine in Europe and the United States.

While the trial did not investigate the vaccine’s efficacy in males, sexually transmitted HPV causes anogenital and head and neck cancers in both males and females. HPV-related head and neck cancers now number around 8,400 in the US, annually. “The more adolescents are vaccinated, the closer we will be to eradicating high risk HPV viruses,” said Apter. “So I think boys should also be vaccinated.”

“Cervical cancer is the fourth most common cancer among women, with estimates from 2012 indicating that there are 528,000 new cases and 266,000 deaths each year worldwide, with the majority of cases occurring in developing countries,” said Apter. In the US, about 12,000 new cases, and 4,000 deaths occur annually, according to the SEER database of the National Cancer Institute. “It is now established that having a persistent infection with HPV is a necessary cause of cervical cancer,” said Apter.

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The American Society for Microbiology is the largest single life science society, composed of over 39,000 scientists and health professionals. ASM's mission is to advance the microbiological sciences as a vehicle for understanding life processes and to apply and communicate this knowledge for the improvement of health and environmental and economic well-being worldwide.

Could Proteins From Frog Skin Be a Source Of A New Class of Antibiotics?

2005 WASHINGTON, DC - FEBRUARY 11, 2015 -- With minor tinkering, a peptide—a tiny protein—from the skin of  a frog could be fashioned into a novel antibiotic that would lack the toxic byproducts of some more conventional  drugs. More importantly, such peptides would represent a new class of antibiotics, at a time when new classes are  sorely needed as resistance rises among existing classes. The research was published online, 26 January 2015,  in Antimicrobial Agents and Chemotherapy, a journal of the American Society for Microbiology.

 Frog skin is a mucus membrane—the same type of tissue that lines the oral cavity and the rest of the  gastrointestinal tract. As such, it’s potentially quite vulnerable to infection; yet frogs are remarkably resistant, said  principal investigator David Craik, Ph.D., a professor in the Institute for Molecular Bioscience, the University of  Queensland, Australia. “Their skin is known to secrete peptides with antimicrobial activity and we wanted to  explore them as potential antibiotics for human use. However, although those peptides make great leads for drug  discovery, they are often not stable enough to be used as drugs.”

 Craik found that the sequences of peptides from the frog Rana sevosa (also known as the gopher frog), closely resemble a cyclic peptide produced in sunflower seeds that he had studied earlier, which he said is exceptionally stable. That stability, and the interest the pharmaceutical industry had already expressed in peptides’ potential as a new class of drugs, led him to study the frog peptides.

The research showed that the frog peptides, which lacked the sunflower peptide’s cyclic structure, also lacked its stability. The problem is that non-cyclic peptides are vulnerable to proteases, digesive enzymes which are designed to cleave the ends of peptides. “A cyclic peptide has no loose ends to be clipped by proteases,” said Craik.

So Craik et al. joined the two ends of some frog peptides and left others linear, and tested both versions in a mouse model of wound infection. The linear peptides had powerful activity againstStaphylococcus aureus, a leading cause of skin and soft tissue infections, which many patients acquire in hospital. “However, the re-engineered cyclic molecules lost some of their antibiotic potency,” said Craik. “We need to do further work to generate molecules with both potency and stability.”

Even though this is not the first time researchers have investigated the use of frog skin peptides as drugs, Craik says this peptide is a relatively small one and easy to synthesize, the latter having been a problem in some previous such efforts. Additionally, the small size means that it is less likely than larger peptides to generate immune reactions against itself.

A further, more general advantage of cyclic peptides as drugs is that unlike many conventional drugs, their breakdown products, amino acids, the building blocks from which proteins are made, are harmless.

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The American Society for Microbiology is the largest single life science society, composed of over 39,000 scientists and health professionals. ASM's mission is to advance the microbiological sciences as a vehicle for understanding life processes and to apply and communicate this knowledge for the improvement of health and environmental and economic well-being worldwide.

Ebola, Marburg Viruses Edit Genetic Material During Infection

WASHINGTON, DC – November 4, 2014 – Filoviruses like Ebola “edit” genetic material as they invade their hosts, according to a study published this week in mBio®, the online open-access journal of the American Society for Microbiology. The work, by researchers at the Icahn School of Medicine at Mount Sinai, the Galveston National Laboratory, and the J. Craig Venter Institute, could lead to a better understanding of these viruses, paving the way for new treatments down the road.


Using a laboratory technique called deep sequencing, investigators set out to investigate filovirus replication and transcription, processes involved in the virus life cycle. They studied the same Ebola virus species currently responsible for an outbreak in West Africa, and also analyzed a related filovirus, Marburg virus, that caused a large outbreak in Angola in 2005 and recently emerged in Uganda. The scientists infected both a monkey and human cell line with both viruses, and analyzed the genetic material produced by each virus, called RNA.


Their results highlight regions in Ebola and Marburg virus RNAs where the polymerase of the virus (a protein that synthesizes the viral RNA) stutters at specific locations, adding extra nucleotides (molecules that form the building blocks of genetic material like DNA and RNA), thereby “editing” the new RNAs. The study found new features at a described RNA editing site in the Ebola glycoprotein RNA, which makes the protein that coats the surface of the virus. Their work also identified less frequent but similar types of editing events in other Ebola and Marburg virus genes – the first time this has been demonstrated.


Because of these messenger RNA modifications, Ebola and Marburg are potentially making proteins “that we previously didn’t realize,” said Christopher F. Basler, PhD, senior study author and professor of microbiology at Mount Sinai.


“The bottom line is we know these changes occur but we don’t yet know what it really means in the biology of the virus,” Basler said. There are many aspects of how the viruses replicate that aren’t yet understood, he said, “so we need a complete description of how they grow to develop new strategies used to treat the infections.”


The study also illustrated how the filoviruses express their genes, and deep sequencing identified all seven messenger RNAs within six hours of infection.


“Our study suggests that the Ebola virus is making forms of proteins previously undescribed,” said lead author Reed Shabman, PhD, an assistant professor at the J. Craig Venter Institute in Rockville, Md. Shabman was at Mount Sinai when the study was initiated. “Understanding the products of these viruses is critical to understanding how to target them.”


In addition, he said, proteins produced by the glycoprotein editing site are associated with virulence in animals, “so it’s of great interest to understand how that protein is made, and in as much detail as possible.”


“We infer that this probably contributes to how the virus grows in a person or an animal,” Basler said.


Further study is needed to determine the biological significance of these findings and how these processes are regulated, Basler said.


The study was supported by the National Institutes of Health and the J. Craig Venter Institute. The article can be accessed freely online at http://mbio.asm.org/content/5/6/e02011-14.

Engineered for Tolerance, Bacteria Pump Out Higher Quantity of Renewable Gasoline

WASHINGTON, DC—November 4, 2014—An international team of bioengineers has boosted the ability of bacteria to produce isopentenol, a compound with desirable gasoline properties. The finding, published in mBio®, the online open-access journal of the American Society for Microbiology, is a significant step toward developing a bacterial strain that can yield industrial quantities of renewable bio-gasoline.

The metabolic engineering steps to produce short-chain alcohol solvents like isopentenol in the laboratory bacteria Escherichia coli have been worked on extensively by many research groups, explains Aindrila Mukhopadhyay, director of host engineering at the Joint BioEnergy Institute in Emeryville, California and senior author on the study.

“Biofuels are one tool in the array of alternative energy solutions that can be used in our infrastructure immediately,” she says. Sustainably produced fuel compounds can be added directly into gasoline blends used today to offset reliance on fossil fuels and also lower the net carbon emissions from vehicles.

“But the solvent-like compounds inhibit microbial growth and that was an aspect that we realized would come up sooner rather than later,” says Mukhopadhyay, who holds a joint appointment at Lawrence Berkeley National Laboratory. “We wanted to look at that aspect with a systems biology approach — could we engineer bacteria to also tolerate the solvent it is producing?”

Improving tolerance is key to moving production toward levels that are industrially relevant. Industrial production requires a robust strain that can stably produce for longer periods of time and withstand the accumulation of the solvent-like biofuel.

To address this challenge, the team, which also included researchers from Nanyang Technological University in Singapore, National University of Singapore, and the University of California, Berkeley, treated a non-producing E. coli strain with isopentenol by adding it to the culture. As the bacteria responded to the solvent-stressor, the team measured which genes were shifted up or down by looking at messenger RNA transcripts across the entire genome.

They chose 40 genes that the bacteria cranked up in response to isopentenol—presumably because their actions helped mitigate the toxicity in some way. Next, they overexpressed each one in a bacterial strain actively producing isopentenol to see which ones might improve the strain’s growth.

Of the eight genes that rescued growth, two stood out as promising—MetR, a biosynthesis regulator, that improved isopentenol production by 55%, and MdlB, a transporter, that improved production by 12%. If the researchers bumped up the levels of the MdlB transporter protein inside the cells even further, they saw production improve by as much as 60% over the original strain.

“Finding a transporter really appealed to us because it has the potential to export the final solvent product out of the cell,” says Mukhopadhyay. “And in this case, once enough alcohol gets outside the cell, it might phase separate and not even be accessible to the organism anymore.” In other words, the biofuel would separate away to sit atop the watery broth the bacteria live in.

As an added bonus, the MdlB protein is a good candidate for directed evolution experiments that could improve the performance and specificity of the transporter for shuttling isopentenol out as quickly as possible. Combining a more efficient transporter with other genes that improved tolerance might produce a strain that can generate bio-gasoline for the gas pump in the near future.

This research was supported by the U.S. Department of Energy and the National Research Foundation of Singapore. The article can be found online at http://mbio.asm.org/content/5/6/e01932-14.

STUDY SUGGESTS GUT BACTERIA MAY PLAY A ROLE IN LUPUS SYMPTOMS IN MICE

WASHINGTON, DC – October 20, 2014 (updated February 2, 2015) --  Researchers found that Lactobacillus species, a bacteria commonly seen in yogurt cultures, when present in the guts of mice, mitigate lupus symptoms, while Lachnospiraceae, a type of Clostridia, correlate with the worsening of these symptoms. This research was published ahead of print in the journal Applied and Environmental Microbiology.

In the study, investigators found that mice with lupus had higher levels of Lachnospiraceae (a type of Clostridia), and lower levels of Lactobacillus compared to mice in the control group. They also compared male and female mice, and found that these differences were present only in females.

They also monitored the gut microbiota over time in both the lupus and control mice, and found that in the former, Clostridia increased in both early and late stages of the disease.

"Our results suggest that the same investigation should be performed in human subjects with lupus," says principal investigator Xin Luo of Virginia Tech, Blacksburg, VA.

In further experiments, the investigators treated the symptoms in the lupus mice with either retinoic acid alone or vitamin A plus retinoic acid. The latter worsened the symptoms—surprisingly, Luo says, because it had been expected to reduce them—and in those mice, Clostridia increased, while Lactobacillus declined. Retinoic acid alone improved the symptoms, with opposite population changes in the gut bacteria.

"We were inspired in part to perform this research by a study on type 1 diabetes, which found that that disease is dependent on gut microbiota," says Zhang. "Like type 1 diabetes, lupus is an autoimmune disease that is even more prevalent [than type 1 diabetes] in women."

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Applied and Environmental Microbiology is a publication of the American Society for Microbiology (ASM). The ASM is the largest single life science society, composed of over 39,000 scientists and health professionals. Its mission is to advance the microbiological sciences as a vehicle for understanding life processes and to apply and communicate this knowledge for the improvement of health and environmental and economic well-being worldwide.

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