New Compound Protects 100 Percent of Ferrets, Mice, from H5N1

 


(colorized transmission electron micrograph of Avian influenza A H5N1 viruses)

Since 2003, the H5N1 influenza virus, more commonly known as the bird flu, has been responsible for the deaths of millions of chickens and ducks and has infected more than 650 people, leading to a 60 percent mortality rate for the latter. Luckily, this virus has yet to achieve human-to-human transmission, but a small number of mutations could change that, resulting in a pandemic. Now a team of investigators from St. Jude Children’s Research Hospital, Stanford University Medical Center, and MacroGenics have developed an antibody which has proven 100 percent protective against the virus in two species of animal models. The research is published ahead of print February 11, in the Journal of Virology, a publication of the American Society for Microbiology.

Antivirals have been potential sources of protection, but they are hampered by the propensity of viruses to rapidly mutate, which often results in resistance. “We have seen this in H5N1 viruses,” said corresponding author Richard Webby, PhD, a Member in the Infectious Diseases Department at St. Jude Children’s Research Hospital, Memphis, TN, and Director of the World Health Organization (WHO) Collaborating Center for Studies on the Ecology of Influenza Viruses in Lower Animals and Birds.

Vaccines, Webby said, must be developed to match each flu virus, something which would likely take at least six months following the emergence of a pandemic. Additionally, vaccines are somewhat ineffective in the elderly and immunocompromised individuals.

The investigators turned to antibodies, which target antigens on viruses as specifically as keys to locks, thus disabling them. Regardless, mutations can render antibodies ineffective. “Our solution was to make a ‘dual-specific’ antibody by combining two different antibodies that attach strongly to H5N1 viruses into a single antibody-like molecule,” said Webby. That, he said, should make it much harder for resistance to emerge. The new compound is called FcDART, for Fc (the type of fusion protein) Dual-Affinity ReTargeting molecule.

A single, low dose of the FcDART provided complete protection against lethal H5N1 viruses in laboratory models of influenza. “This dose could be given one day before infection—for example, to protect healthcare providers—or up to three days after,” said Webby.

“Laboratory models are rough approximations of what might happen in humans,” said first author Mark Zanin, a post-doctoral fellow in Webby’s lab at St. Jude. “We did see complete protection against H5N1 in ferrets, which have long been used as a model for human flu, so we are confident in our results.”

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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.

What We Know and Don’t Know About Ebola Virus Transmission in Humans

MINNEAPOLIS/ST. PAUL - February 19, 2015 – A new comprehensive analysis from the Center for Infectious Disease Research and Policy (CIDRAP) at the University of Minnesota, involving leading International Ebola researchers, examines what is known about transmission of the Ebola virus and cautions that the public health community should not rule out the possibility of respiratory transmission. Prior to the current Ebola epidemic in West Africa there have been only 24 reported Ebola outbreaks with approximately 2,400 cases reported over the previous 39 years. Evidence suggests that direct patient contact and contact with infectious body fluids are the primary modes for Ebola virus transmission, however, this evidence is based on a limited number of studies.

The analysis was published today in mBio®, the online open-access journal of the American Society for Microbiology.

The analysis further examines what we already know about the transmission of the Ebola virus and what we need to learn about its transmission. Due to the limitations of current data on Ebola virus cases, the role of aerosol transmission remains unclear. Transmission potentially occurs via virus-laden aerosols generated through the emission of body fluids during vomiting, diarrhea or coughing. It is advised that more studies are needed to better understand aerosol transmission in spreading the disease.

“Available evidence demonstrates that direct patient contact and contact with infectious body fluids are the primary modes for Ebola virus transmission, but this is based on a limited number of studies,” said Michael Osterholm, Ph.D., MPH, McKnight Presidential Endowed Chair in Public Health and director of CIDRAP and lead author of the analysis. “In our comprehensive review, we address what we know and what we don’t know about Ebola virus transmission. We also hypothesize that based on the best scientific evidence, Ebola viruses have the potential to be respiratory pathogens with primary respiratory spread.”

The Center for Infectious Disease Research and Policy (CIDRAP), founded in 2001, is a global leader in addressing public health preparedness and emerging infectious disease response. Part of the Academic Health Center at the University of Minnesota, CIDRAP works to prevent illness and death from targeted infectious disease threats through research and the translation of scientific information into real-world, practical applications, policies, and solutions. For more information, visit www.cidrap.umn.edu.

Media Contact:
Aleea Khan (akhan@asmusa.org)

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.

Mutant Bacteria That Keep On Growing

WASHINGTON, DC – February 17, 2015 - The typical Escherichia coli, the laboratory rat of microbiology, is a tiny 1-2 thousandths of a millimeter long. Now, by blocking cell division, two researchers at Concordia University in Montreal have grown E. coli that stretch three quarters of a millimeter. That’s up to 750 times their normal length. The research has potential applications in nanoscale industry, and may lead to a better understanding of how pathogens work. The study is published ahead of print on February 17 in the Journal of Bacteriology, a journal of the American Society for Microbiology.

Normally, an E. coli grows until its length doubles, and then it divides. Many previous studies had shown that if cell division were blocked, the bacterium would grow still longer. However, such cells would presumably die within a few hours, said first author Ziad El-Hajj, a post-doctoral fellow, because the mutations that blocked cell division also interfered with some other aspect of physiology that was necessary for a cell’s survival. “Our hypothesis was if the block in cell division were so specific that it would not affect any of the cell’s other processes, the cells would simply keep elongating,” he said.

Once they isolated a viable mutant where, presumably, physiological processes besides cell division were unaffected, that’s what happened. El-Hajj noted that even the longest mutant cells had no subdivisions and all the normal cellular material was spread along the microbe’s entire length. Remarkably, he said, when they allowed the cells to resume cell division, prior to dividing anew, the cells formed loops at multiple points along their length, and then divided at or near these loops.

The investigators have not yet figured out why this mutant is unable to divide. “We know that they have reduced levels of a protein called FtsZ, which is almost ubiquitous in bacteria and is essential for their division,” said El-Hajj. “Why it is reduced remains uncertain.”

New industrial tubes, that straddle the interface of biology, materials science, and nanotechnology could be made from the cell walls of the hyper-elongated E. coli, said El-Hajj, noting that such technology was already being developed on a much shorter scale. Franziska Lederer of the Helmholtz-Zentrum Dresden-Rossendorf, Germany has already demonstrated the use of “filamentous” E. coli cell structures, which range up to 50-70 micrometers, to create conductive metallic wires, which he writes could be used in electronic devices, or as novel catalysts.

El-Hajj also suggests that such tubes might be used as gene therapy delivery devices. Additionally, he speculates that creating such lengthy bacteria might be useful for achieving a greater understanding of pathogenic species. The advantage: using tiny needles—perhaps made from elongated E. coli—one could extract enough cytoplasm to study it in isolation from membrane materials, in order to illuminate their biochemistry. Currently, there is no way to separate cytoplasm from membrane that offers certainty of purity.

“Ironically, the research originally focused on a different topic, an E. coli strain that failed to make a compound that is essential to all types of cells,” said El-Hajj. The strain unexpectedly lacked another compound, the amino acid methionine, and so in order to understand why, El-Hajj and coauthor Elaine B. Newman, Distinguished Professor Emeritus, Biology, created many mutants that did not require methionine, said El-Hajj. “One shocked us when we saw that it made extremely long cells, and we decided to focus on the biology of long E. coli.”

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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.

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