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Cells can trap viruses in protein cage to stop their spread

Cells can trap viruses in protein cage to stop their spread

Researchers at The Francis Crick Institute in London have discovered that cells can trap viruses in a protein cage to stop them from spreading to neighboring cells. The study, which will be published June 19 in the Journal of Cell Biology, reveals that the vaccinia virus can escape this trap by recruiting additional proteins to dismantle the cage and propel the virus out of the cell.

The vaccinia virus usually causes only mild symptoms in healthy adults and, because it is closely related to the smallpox virus, it is a key component of anti-smallpox vaccines. During vaccinia infections, the virus replicates in the cytoplasm of a host cell and then moves along the microtubule cytoskeleton to the plasma membrane, from where it can be released into the surrounding environment. Some of the viral particles remain attached to the plasma membrane and cause the cell’s actin cytoskeleton to assemble into “tails” that help the viruses move directly into adjacent cells.

Septins are a family of cytoskeletal proteins that control a variety of cellular processes by assembling into filaments and ring-shaped structures. In contrast to microtubules and actin, septins appear to suppress vaccinia infections, although which stage of the virus’ life cycle they affect is unknown.

“We have now found that septins exert their antiviral effect by forming cage-like structures around viral particles to suppress the release of vaccinia virus from infected cells,” explains Michael Way, a group leader at The Francis Crick Institute, who performed the work in conjunction with Julia Pfanzelter, also from The Francis Crick Institute, and Serge Mostowy from Imperial College London.

Way and colleagues found that septins assemble around newly formed vaccinia particles soon after they arrive at the plasma membrane. This septin cage inhibits the virus’ release and delays the assembly of the actin tail that can help the virus spread to neighboring cells.

The researchers discovered that the vaccinia virus can break out of this trap by recruiting several other host cell proteins. These host factors include a protein called dynamin that, working with actin assembly proteins known as formins, displaces the septin cage by inducing the formation of an actin tail. Inhibiting dynamin or formins prevented vaccinia virus particles from escaping the septin cage.

Septins have previously been shown to form inhibitory cages around bacterial pathogens such as Shigella. “Our study represents the first example where septins play an important, inhibitory role during virus spread,” says Way. “It will be interesting to see whether septins also suppress the release of other viruses, such as herpes virus, when they fuse with the plasma membrane.”

This article was published in Science Daily website dated ‘Jun. 18, 2018’

Antibody Protects Against Both Zika and Dengue, Mouse Study Shows

Antibody Protects Against Both Zika and Dengue, Mouse Study Shows

Brazil and other areas hardest hit by the Zika virus – which can cause babies to be born with abnormally small heads – are also home to dengue virus, which is spread by the same mosquito species.

A new study led by researchers at Washington University School of Medicine in St. Louis shows that an antibody that protects against dengue virus is also effective against Zika in mice.

Antibodies remain in the bloodstream for weeks, so one or a few doses of an antibody-based drug given over the course of a woman’s pregnancy potentially could protect her fetus from Zika, with the added benefit of protecting her from both Zika and dengue disease, the researchers said. Dengue causes high fever, severe headaches, and joint and muscle pain in children and adults but does not directly harm fetuses.

“We found that this antibody not only neutralizes the dengue virus but, in mice, protects both adults and fetuses from Zika disease,” said Michael S. Diamond, MD, PhD, the Herbert S. Gasser Professor of Medicine and the study’s senior author.

Since dengue and Zika are related viruses, the researchers reasoned that an antibody that prevents dengue disease may do the same for Zika. Diamond and graduate student Estefania Fernandez collaborated with Gavin Screaton, MD, DPhil, of Imperial College London, who had generated a panel of human anti-dengue antibodies years before.

The scientists infected nonpregnant adult mice with Zika virus and then administered one of the anti-dengue antibodies one, three or five days after infection. For comparison, another group of mice was infected with Zika virus and then given a placebo. Within three weeks of infection, more than 80 percent of the untreated mice had died, whereas all of the mice that received the anti-dengue antibody within three days of infection were still alive, and 40 percent of those that received the antibody five days after infection survived.

To find out whether the antibody also could protect fetuses from infection, the researchers infected female mice on the sixth day of their pregnancies with Zika virus and then administered a dose of antibody or a placebo one or three days later.

On the 13th day of gestation, the amount of Zika’s genetic material was 600,000 times lower in the placentas and 4,900 times lower in the fetal heads from the pregnant mice that were treated one day after infection, compared with mice that received the placebo. However, administering the antibody three days after infection was less effective: It reduced the amount of viral genetic material in the fetal heads nineteen fold and in the placentas twenty-threefold.

These findings suggest that for the antibody to effectively protect fetuses from Zika infection, it must be administered soon after infection. Such a goal may be unrealistic clinically because women rarely know when they get infected.

However, giving women the antibody as soon as they know they are pregnant could provide them with a ready-made defense against the virus should they encounter it. Antibody-based drugs have been used for decades to provide temporary protection against infectious diseases such as rabies when there is no time to vaccinate or, as in the case of Zika, when there is no vaccine available.

The key to using this antibody as a preventive drug would be to make sure that antibody levels in a woman’s bloodstream stay high enough to protect her fetus for the duration of her pregnancy.

Diamond and colleagues are working on identifying how much antibody a pregnant woman would need to ensure that her fetus is protected from Zika. They also are exploring ways to extend the antibody’s half-life in the blood, to reduce the number of times it would need to be administered.

Having anti-dengue antibodies circulating in the bloodstream for months on end poses a risk, though, because antibodies that protect against one strain of dengue virus sometimes worsen symptoms if a person is infected by another dengue strain.

To avoid the possibility of accidentally aggravating an already very painful disease, the researchers mutated the antibody in four spots, making it impossible for the antibody to exacerbate dengue disease.

“We mutated the antibody so that it could not cause antibody enhancement of dengue infection, and it was still protective,” said Diamond, who is also a professor of pathology and immunology, and of molecular microbiology. “So now we have a version of the antibody that would be therapeutic against both viruses and safe for use in a dengue-endemic area, because it is unable to worsen disease.”

This article was published in bioscience technology website dated ‘Sep. 27, 2017’

Antibiotics often inappropriately prescribed for hospitalized kids, global study suggests

Antibiotics often inappropriately prescribed for hospitalized kids, global study suggests

Nearly a third of all antibiotics prescribed for hospitalized children globally were intended to prevent potential infections rather than to treat disease, according to the results of a worldwide survey published in the Journal of the Pediatric Infectious Diseases Society. A large proportion of these preventive, or prophylactic, prescriptions also were for broad-spectrum antibiotics or combinations of antibiotics, or were for prolonged periods, which can hasten the development of antibiotic-resistant bacteria and drug-resistant infections.

“This pattern and high rate of prophylactic prescribing indicates a clear overuse of antibiotics,” said study author Markus Hufnagel, DTM&H, of the University of Freiburg in Germany. “Hopefully, our study results will help to raise awareness among health professionals about appropriate prescribing of antibiotics in children,” Dr. Hufnagel said.

The study provides a snapshot of antibiotic prescriptions for 6,818 children who were inpatients at 226 pediatric hospitals in 41 countries, including four hospitals in the United States, during one day in 2012. There were 11,899 total prescriptions for antibiotics, and 28.6 percent of these were for prophylactic use, researchers found. Among hospitalized children who received at least one antibiotic prescription, 32.9 percent (2,242 children) were prescribed an antibiotic to prevent a potential infection rather than to treat a current one.

Of the antibiotics prescribed for prophylactic use, 26.6 percent were to prevent potential infections associated with an upcoming surgery, and the vast majority of these antibiotics were given for more than one day. The remaining 73.4 percent of the prophylactic prescriptions were intended to potentially prevent other types of infections. Approximately half (51.8 percent) of all preventive antibiotic prescriptions were for broad-spectrum antibiotics. In 36.7 percent of cases, two or more systemic antibiotics were prescribed at the same time.

These patterns contradict current recommendations for appropriate prophylactic antibiotic use. Guidelines often call for using narrow-spectrum antibiotics for shorter periods, in an effort to limit the development of antibiotic resistance. The study findings suggest clear targets for improving antibiotic prescribing in pediatric patients, according to the authors. These include reducing prolonged, preventive antibiotic use before surgery, limiting the use of broad-spectrum and combinations of antibiotics, and reducing antibiotic use, overall, for prophylactic rather than therapeutic use.

Additional education for clinicians and improved implementation of current guidelines for antibiotic use to prevent surgical infections are needed, Dr. Hufnagel said. More in-depth guidelines that address the use of prophylactic antibiotics for a broader range of medical conditions than current guidelines do are also needed, as well as efforts to communicate these guidelines to health care providers and to analyze how the recommendations are used.

This article was published in Science Daily dated ‘Mar. 22, 2018’