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Genova, Italy

Madariaga M.G.,Infectious Diseases
American Journal of Medicine | Year: 2015

Ebola virus caused an epidemic of unprecedented extension in West Africa. There was concern that the outbreak would not be controlled for a prolonged period of time. Two cases of infected returning travelers have been reported in the US. One of the cases has been associated with secondary transmission and other infected subjects have been repatriated for treatment. This article reviews the etiology, pathogenesis, transmission, clinical manifestations, diagnosis, treatment, and prevention of the disease with emphasis on the identification and management in the US. © 2015 Elsevier Inc. Source

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Type 3 secretion systems (T3SSs) are used by several pathogenic bacterial species to deliver effector proteins, responsible for the effects of infection, into the target host cells. An MGH research team has discovered that interaction between structural proteins within the host cell called intermediate filaments and IpaC, a bacterial protein that forms the pore through the host cell membrane, is required for T3SSs to dock onto the pores and secrete effector proteins into the host cell. Credit: Goldberg Laboratory, Division of Infectious Diseases, Massachusetts General Hospital Researchers from the Massachusetts General Hospital (MGH) Division of Infectious Diseases are investigating the mechanism by which several important pathogenic species of bacteria deliver proteins into the cells of the organisms they are infecting. In a paper receiving advance online publication in Nature Microbiology, the team describes determining a key step in how the diarrheal pathogen Shigella injects proteins into target host cells. Their findings may apply to additional bacterial species, including Salmonella and those responsible for typhoid fever, bubonic plague and many hospital-acquired pneumonias. "Many bacterial pathogens establish infection by delivering effector proteins - which are responsible for many of the effects of infection - into cells. Therefore, delivery of effector proteins is a significant mediator of the impact of infection on human tissue," says Marcia Goldberg, MD, director of Research in the MGH Division of Infectious Diseases, senior and corresponding author of the report. "The most common mechanism used by a major group of bacteria is a specialized apparatus known as a type 3 secretion system, by which pathogens sitting outside the cell first make a pore in the cell membrane and then deliver effector proteins into the cell. Our data show that interaction between one of the pore proteins and another protein within the cell is required for this process to succeed." Also called injectisomes, type 3 secretion systems (T3SSs) consist of a base within the pathogen and a needle-like structure that detects contact with the target host cell and through which bacterial proteins associated with the system are secreted. Upon contact with human cells, T3SSs secrete two proteins that make up the pore in the target cell's membrane. After the pore is formed, the T3SS docks onto the pore to deliver bacterial proteins into the cell. Exactly how the pore is formed and the process by which the T3SS docks onto the pore have not been clearly understood, and the MGH team set out to investigate the mechanism behind the docking process. In a series of cellular experiments, they first determined that Shigella infection requires the presence of cytoskeletal proteins called intermediate filaments - in this case a protein called vimentin - within host cells. They then showed that vimentin was required for efficient delivery of effector proteins via the T3SS and that vimentin directly interacts with IpaC, one of the proteins that make up the pores in the host cell membrane. While vimentin is not involved in the formation of pores, the researchers showed it is required for efficient docking of Shigella T3SSs onto the pores in the host cell membrane and that docking induces the secretion of effector proteins into the host cell. While these experiments focused on the role of vimentin, the investigators also showed that all intermediate filaments normally present in cells infected by Shigella are required for infection by the pathogen. Additional experiments with strains of Salmonella and Yersinia, the families that include the typhoid fever and plague bacteria, confirmed that intermediate filaments were also required for the T3SSs used by those pathogens, suggesting similar mechanisms may apply to all pathogens using T3SSs. "We know that type 3 secretion systems are critical for the virulence of the bacterial pathogens that use them and their inactivation renders those pathogens non-virulent," says Brian Russo, PhD, a research fellow on Goldberg's team and lead author of the report. "Fundamental understanding of how the type 3 secretion system functions could lead to the discovery of novel therapies for these very important infectious diseases." Explore further: Researchers see activity of bacterial effector protein in molecular detail More information: Brian C. Russo et al. Intermediate filaments enable pathogen docking to trigger type 3 effector translocation, Nature Microbiology (2016). DOI: 10.1038/NMICROBIOL.2016.25

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Researchers are using the app to track free-roaming dogs that have been vaccinated against rabies. Monitoring them in this way has enabled vets to vaccinate 70 per cent of the dog population in the City of Ranchi - the threshold needed to minimise the risk that the disease is passed to people. Adopting the approach more widely could help to eliminate rabies from people and animals, the researchers say. Teams vaccinated more than 6000 dogs in 18 districts of the city of Ranchi, India. They surveyed the number of marked, vaccinated and unmarked, unvaccinated dogs to monitor the proportion of animals that had received the vaccine. A bespoke smartphone app - called the Mission Rabies app - was developed for researchers to instantly upload information about the animals vaccinated, including their exact location. In areas where coverage fell below 70 per cent, catching teams were re-deployed to vaccinate more dogs until the target was achieved. The study was led by Mission Rabies in collaboration with researchers from the Royal (Dick) School of Veterinary Studies at the University of Edinburgh. Rabies remains a global problem that leads to the suffering and premature deaths of over 50,000 people and many times more dogs each year. The disease has been eliminated from many countries through mass vaccination of the dog population. However, rabies elimination remains challenging in countries where the majority of dogs are allowed to roam freely. Previous research has shown that vaccinating just 70 per cent of the dog population is enough to cut the risk of rabies infections in people. Dr Richard Mellanby, a Wellcome Trust Clinical Fellow at the Royal (Dick) School of Veterinary Studies, said: "We have shown that mobile technology can help to monitor the efforts of large scale vaccination of free roaming dogs in real time This allows us to identify areas where vaccination needs to be increased to meet the 70 per cent threshold and cut the risk of the disease being passed to people." The study is published in the journal BMC Infectious Diseases. It was funded by the Dogs Trust with additional resources provided by Ranchi Municipal Council. All vaccines used in the project were donated by MSD Animal Health. Explore further: Within reach of Australia: Rabies is now present only 350 kilometres from northern Australia More information: Andrew D. Gibson et al. Vaccinate-assess-move method of mass canine rabies vaccination utilising mobile technology data collection in Ranchi, India, BMC Infectious Diseases (2015). DOI: 10.1186/s12879-015-1320-2

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The 2014 outbreak of Ebola virus, which caused more than 11,000 deaths in West Africa, has been brought to heel, but the need for effective Ebola treatments remains urgent. The drugmaker Gilead Sciences just launched a mid-stage study of GS-5734, an antiviral, that, if proven effective, could be a crucial weapon against future flare-ups of Ebola. The Phase II clinical trial in Liberia will test whether the Gilead compound can clear viral RNA that has hunkered down in areas of the body—the eyes, testes, and spinal column, for example—that immune cells have trouble reaching. In rare cases, that reservoir of genetic material causes the Ebola virus to come roaring back months after a person is believed to be cured. It also can be passed on to sexual partners. The National Institute of Allergy & Infectious Diseases, a sponsor of the trial, will recruit 60 to 120 men who are already enrolled in a study of the long-term health of Ebola survivors. The volunteers will be given either GS-5734 or a placebo once daily for five days and then monitored over the next six months to measure the compound’s effect on the viral load. GS-5734 is a monophosphoramidate prodrug of an adenosine analog that was discovered through a collaboration among Gilead, the Centers for Disease Control & Prevention, and the U.S. Army Medical Research Institute of Infectious Diseases. Discovered in 2014, the compound already has been shown to wipe out signs of the virus in monkeys. It also has been tested for safety in healthy humans. Gilead previously stated that the combination of the Phase II study, monkey data, and healthy human data could be enough to ask for U.S. regulatory approval for GS-5734. Given the urgency with which GS-5734 is moving forward, Gilead has made a major investment in manufacturing. According to Tomas Cihlar, vice president of biology, the company has made enough of the drug to treat 1,000 people infected with Ebola for up to two weeks and is in the process of making thousands more doses. GS-5734 also has shown activity against the Zika virus, but it is far more effective against Ebola, Cihlar notes. As such, Gilead is currently screening its library of antivirals for potential Zika treatments.

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A research team led by University of Arkansas chemist Jingyi Chen and University of Arkansas for Medical Sciences microbiologist Mark Smeltzer has developed an alternative therapeutic approach to fighting antibiotic-resistant infections. The novel method uses a targeted, light-activated nanodrug consisting of antibiotic-loaded nanoconstructs, which are nanoscale cages made of gold and coated with polydopamine. The antibiotic is loaded into the polydopamine coating. The gold nanocages convert laser irradiation to heat, resulting in the photothermal effect and simultaneously releasing the antibiotic from the polydopamine coating. “We believe that this approach could facilitate the effective treatment of infections caused by antibiotic-resistant bacteria, including those associated with bacterial biofilms, which are involved in a wide variety of bacterial infections,” says Chen, assistant professor in the Department of Chemistry and Biochemistry in the J. William Fulbright College of Arts and Sciences. Microbial resistance to antibiotics has become a growing public health concern in hospitals and the community at large, so much so that the Infectious Diseases Society of America has designated six bacterial species as “ESKAPE pathogens” — Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species. This designation reflects the limited availability of antibiotics that can be used to treat infections caused by these species. “It is also estimated that 80 percent of all bacterial infections involve formation of a biofilm, and all of these infections share the common characteristic of intrinsic resistance to conventional antibiotic therapy,” says Smeltzer, professor in the Department of Microbiology and Immunology at UAMS and director of the Center for Microbial Pathogenesis and Host Inflammatory Responses. “Intrinsic resistance refers to the fact that bacteria within a biofilm exhibit a therapeutically relevant level of resistance to essentially all antibiotics.” Researchers in Smeltzer’s laboratory study the ESKAPE pathogen Staphylococcus aureus. They focus on how the pathogen causes biofilm-associated bone infection and infections associated with orthopaedic implants. But, as Smeltzer explains, there are many other examples in infections — intravenous catheters and vascular grafts, for example — caused by Staphylococcus aureus. The team used Staphylococcus aureus as the proof-of-principle pathogen to demonstrate the potency of their nanodrug. The combination of achieving a photothermal effect and controlled release of antibiotics directly at the site of infection was achieved by laser irradiation at levels within the current safety standard for use in humans. The therapeutic effects of this approach were validated using planktonic bacterial cultures — bacterial cells that are free-floating rather than contained with a biofilm — of both methicillin-sensitive and methicillin-resistant Staphylococcus aureus strains. However, the method was subsequently shown to be effective even in the context of an intrinsically resistant biofilm. “The even better news is that the technology we developed would be readily adaptable to other bacterial pathogens that cause such infections, including the other ESKAPE pathogens,” Smeltzer says. The researchers’ work was recently published in ACS Infectious Diseases, a publication of the American Chemical Society (ACS) and “the first journal to highlight chemistry and its role in the multidisciplinary and collaborative field of infectious disease research.” Participating in the research were first authors Daniel Meeker, an M.D./Ph.D. student in Smeltzer’s lab, and Samir Jenkins, who obtained his doctoral degree in the Chen lab and is now a postdoctoral fellow at UAMS. Other participants included Karen Beenken, senior researcher in Smeltzer’s lab; Allister Loughran at UAMS; Timothy Muldoon, assistant professor of biomedical engineering at the U of A; Amy Powless, doctoral student in biomedical engineering at the U of A; Emily Miller, a U of A undergraduate and Honors College student; Vladimir Zharov, director of the Arkansas Nanomedicine Center at the UAMS Winthrop P. Rockefeller Cancer Institute and professor of otolaryngology, head and neck surgery at UAMS; and Ekaterina Galanzha, associate research professor of otolaryngology, head and neck surgery at UAMS.

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