From friend to foe: How benign bacteria evolve to virulent pathogens

Contact: Isabel Gordo igordo@igc.gulbenkian.pt 351-214-407-915 Public Library of Science

Bacteria can evolve rapidly to adapt to environmental change. When the “environment” is the immune response of an infected host, this evolution can turn harmless bacteria into life-threatening pathogens. A study published on December 12 in PLOS Pathogens provides insight into how this happens.

Isabel Gordo and colleagues from the Instituto Gulbenkian de Ciencia in Oeira, Portugal, have for the first time devised an experimental system to observe and study the evolution of bacteria in response to encounters with cells of the mammalian immune system. They found that in less than 500 bacterial generations (or 30 days), the bacteria became more resistant to being killed by immune cells and acquired the ability to cause disease in mice. Continue reading “From friend to foe: How benign bacteria evolve to virulent pathogens”

More HIV ‘cured’: first a baby, now 14 adults

 

A drug-free life beckons for some people with HIV <i>(Image: Bruce Forster/Getty)</i>A drug-free life beckons for some people with HIV (Image: Bruce Forster/Getty)

Two weeks after the revelation that a baby has been “cured” of HIV, reports suggest that a similar treatment can cure some adults too. Early treatment seems crucial, but does not guarantee success.

Asier Sáez-Cirión of the Pasteur Institute’s unit for regulation of retroviral infections in Paris analysed 70 people with HIV who had been treated with antiretroviral drugs (ARVs) between 35 days and 10 weeks after infection – much sooner than people are normally treated.

All of the participants’ drug regimes had been interrupted for one reason or another. For example, some people had made a personal choice to stop taking the drugs, others had been part of a trial of different drug protocols.

Most of the 70 people relapsed when their treatment was interrupted, with the virus rebounding rapidly to pre-treatment levels. But 14 of them – four women and 10 men – were able to stay off of ARVs without relapsing, having taken the drugs for an average of three years.

The 14 adults still have traces of HIV in their blood, but at such low levels that their body can naturally keep it in check without drugs.

Drugless years

On average, the 14 adults have been off medication for seven years. One has gone 10-and-a-half years without drugs. “It’s not eradication, but they can clearly live without pills for a very long period of time,” says Sáez-Cirión.

Last week, a baby was reported to have been “functionally cured” of HIV after receiving a three-drug regime of ARVs almost immediately after birth. Sáez-Cirión warns that rapid treatment doesn’t work for everyone, but the new study reinforces the conclusion that early intervention is important.

“There are three benefits to early treatment,” says Sáez-Cirión. “It limits the reservoir of HIV that can persist, limits the diversity of the virus and preserves the immune response to the virus that keeps it in check.”

Further analysis confirmed that the 14 adults were not “super-controllers” – the 1 per cent of the population that are naturally resistant to HIV – since they lack the necessary protective genes. Also, natural controllers rapidly suppress their infections, whereas these 14 mostly had severe symptoms which led to their early treatment. “Paradoxically, doing badly helped them do better later,” says Sáez-Cirión.

Rapid response

The researchers are trying to identify additional factors that could explain why early intervention only works on some people, hopefully extending the scope for more functional cures.

“This whole area is fascinating, and we’ve been looking very closely at issues of early initiation of treatment, and the potential for functional cures,” says Andrew Ball, senior adviser on HIV/AIDS strategy at the World Health Organization in Geneva.

“The big challenge is identifying people very early in their infection,” says Ball, adding that many people resist testing because of the stigma and potential discrimination. “There’s a good rationale for being tested early, and the latest results may give some encouragement to do that,” he says.

Journal reference: PLoS Pathogens, DOI: 10.1371/journal.ppat.1003211

http://www.newscientist.com/article/dn23276-more-hiv-cured-first-a-baby-now-14-adults.html

 

New strain of virulent airborne fungi, unique to Oregon, is set to spread

2010 study posted for filing

Contact: Mary Jane Gore mary.gore@duke.edu 919-660-1309 Duke University Medical Center

DURHAM, N.C. – A newly discovered strain of an airborne fungus has caused several deaths in Oregon and seems poised to move into California and other adjacent areas, according to scientists at Duke University Medical Center.

“This novel fungus is worrisome because it appears to be a threat to otherwise healthy people,” said Edmond Byrnes III, a graduate student in the Duke Department of Molecular Genetics and Microbiology. “Typically, we see this fungal disease associated with transplant recipients and HIV-infected patients, but that is not what we are seeing.” Byrnes and other Duke co-authors work in the laboratory of senior author Joseph Heitman, M.D., Ph.D., and chair of the Department of Molecular Genetics and Microbiology.

Their new work on the emergence and virulence of the new genotypes of Cryptococcus gattii fungi in the United States was published online in PLoS Pathogens on April 22.

The mortality rate for recent C. gattii cases in the Pacific Northwest is running at approximately 25 percent out of 21 cases analyzed in the United States, compared to a mortality rate of 8.7 percent out of 218 cases in British Columbia, Canada, the researchers said. Most have a more complicated clinical course than people infected with the more common Cryptococcus neoformans.

Because the strain is so virulent when it infects some humans and animals, the researchers are calling for greater awareness and vigilance. Testing involves culturing the fungus and then sequencing its DNA to learn whether it is the virulent or more benign strain, which could affect treatment plans.

Some strains of C. gattii are not more virulent than C. neoformans, for example, but doctors need to know what type they are dealing with, Byrnes said. Using molecular techniques, the geneticists uncovered clues that showed the Oregon-only fungal type most likely arose recently, in addition to an outbreak of C. gattii that began in Canada in 1999 that has now spread into Washington and Oregon.

Symptoms can appear two to several months after exposure, and may include a cough lasting weeks, sharp chest pain, shortness of breath, headache (related to meningitis), fever, nighttime sweats and weight loss. In animals the symptoms are a runny nose, breathing problems, nervous system problems and raised bumps under the skin. While C. gattii can be treated, it cannot be prevented; there is no vaccine.

The new type of Cryptococcus gattii reproduces both sexually and asexually. The more virulent strain may have genetically recombined with related but less harmful strains. This novel genotype is highly virulent compared with similar isolates of Cryptococcus that are not causing disease outbreaks.

The researchers found that the novel genotype (VGIIc) is now a major source of Cryptococcus gattii illness in Oregon. Because C. gattii types had been found in tropical areas before, co-lead author Wenjun Li, M.D., Ph.D., of Duke Molecular Genetics and Microbiology, speculates that environmental changes may be responsible for the evolution and emergence of this pathogen.

Determining the exact origin of the VGIIc type is difficult, and sampling thus far has failed to turn up isolates in Oregon soil, water or trees.

“We are trying to put together the evolutionary story of where these types come from by closely studying the genetics of all samples possible,” said Yonathan Lewit, a research associate also in Duke Molecular Genetics and Microbiology. He said that cell components called mitochondria may play a role in the increased virulence of certain types.

VGIIc, the new Oregon strain, has yielded dozens of isolates in many specimens, including from domesticated animals: cats, dogs, an alpaca and a sheep. “Most of those are nonmigratory animals,” Byrnes said, explaining that the animals probably didn’t bring the pathogen from some other region, and most likely acquired it locally.

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Other authors include Hansong Ma, Kerstin Voelz and Robin May of the Department of Molecular Pathobiology at the University of Birmingham, United Kingdom; Ping Ren and Vishnu Chaturvedi of the Mycology Laboratory at Wadsworth Center in Albany, N.Y.; Dee Carter of the Department of Molecular and Microbial Biosciences, the University of Sydney, Australia; and Robert Bildfell of the Department of Biomedical Sciences, Oregon State University, Corvallis.

This work was supported by National Institutes of Health/National Institute of Allergy and Infectious Diseases grants.

Genetic sleuthing uncovers deadly new virus in Africa: ‘Bas-Congo’ virus

Contact: Jason Socrates Bardi jason.bardi@ucsf.edu 415-502-4608 University of California – San Francisco

Global research effort identifies ‘Bas-Congo’ virus as the cause of  small, isolated outbreak in 2009

IMAGE:Charles Chiu, MD, PhD

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An isolated outbreak of a deadly disease known as acute hemorrhagic fever, which killed two people and left one gravely ill in the Democratic Republic of Congo in the summer of 2009, was probably caused by a novel virus scientists have never seen before.

Described this week in the open-access journal PLoS Pathogens, the new microbe has been named Bas-Congo virus (BASV) after the province in the southwest corner of the Congo where the three people lived.

It was discovered by an international research consortium that included the University of California, San Francisco (UCSF) and University of California, Davis (UCD), Global Viral, the Centre International de Recherches Médicales de Franceville in Gabon, the Institut National de Recherche Biomédicale, Kinshasa in the Democratic Republic of the Congo, Metabiota and others.

“Known viruses, such as Ebola, HIV and influenza, represent just the tip of the microbial iceberg,” said Joseph Fair, PhD, a co-author and vice president of Metabiota. “Identifying deadly unknown viruses, such as Bas-Congo virus, gives us a leg up in controlling future outbreaks.”

“These are the only three cases known to have occurred, although there could be additional outbreaks from this virus in the future,” said Charles Chiu, MD, PhD, an assistant professor of laboratory medicine at UCSF and director of the UCSF-Abbott Viral Diagnostics and Discovery Center, who spearheaded the UCSF effort to identify the virus. Chiu and his team continue to work on new diagnostics to detect the virus so that health officials in Congo and elsewhere can quickly identify it should it emerge again.

One odd characteristic of the Bas-Congo virus, Chiu said, is that while a number of other viruses in Africa also cause deadly outbreaks of acute hemorrhagic fever—Ebola virus, Lassa virus and Crimean-Congo Hemorrhagic Fever virus to name a few —the new virus is unlike any of them.

Genetically it is more closely related to the types of viruses that cause rabies, which are known to infect people with a very different sort of disease—a neurological illness that is uniformly fatal if untreated but may take months to develop.

An antibody test developed in this study was applied to the one patient who survived and to others who had come into contact with him. It suggested that the disease may be spread from person to person but likely originated from some other source, such as an insect or rodent.

IMAGE:This is an electron microscope image of a typical rhabdovirus.

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The identity of this animal “reservoir” and the precise mode of transmission for the virus remain unclear and are currently being investigated by Metabiota and the central African members of the consortium through the PREDICT Project of USAID’s Emerging Pandemic Threats Program.

How the New Virus Emerged

In the summer of 2009, a 15-year old boy in a small rural community called Mangala village suddenly fell ill and developed a bleeding nose, bleeding gums and bloody vomit. He rapidly worsened, dying within three days of the first signs of illness.

A week later, a 13-year old girl who attended the same school and lived in the same neighborhood as the boy came down with a similar, serious illness. She declined just as rapidly and also died within three days. One week after that, the male nurse who cared for this girl began showing the same symptoms, and he was transferred to a hospital in Boma, a nearby port city that sits along the Congo River upstream from Africa’s Atlantic coast.

Members of the consortium, who had initiated a project to diagnose unusual cases of severe hemorrhagic fever, obtained blood samples collected from the nurse by the Congolese doctors and sent them to the laboratory of Eric Leroy, PhD, doctor of veterinary medicine at the Centre International de Recherches Médicales de Franceville in Gabon. There the samples were tested for traces of any known virus, but nothing was found. The Metabiota scientists then solicited the expertise of Chiu at UCSF and Eric Delwart at the Blood Systems Research Institute (BSRI) in San Francisco to aid in the diagnosis.

The researchers ultimately identified a completely new virus as the cause of the mysterious illness through a powerful strategy for identifying novel pathogens known as “deep sequencing,” in which millions of DNA sequences are generated from a clinical sample and then pieced together using computer algorithms combined with human analysis.

Distinct Attributes of Bas-Congo

The Bas-Congo virus belongs to a family of viruses known as the rhabdoviruses, a large family of viruses that infect plants, insects and mammals, including humans. The most famous member of this family is the virus that causes rabies. But even among the rhabdoviruses, Bas-Congo is something of an outlier, being very genetically distinct from other members of the family.

What’s most unusual about this virus, though, said Chiu, is what it does to people.

IMAGE:This is an image of collecting samples in the Jungles of Boma in 2009 after the outbreak. Courtesy: Metabiota

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No other rhabdoviruses are known to cause the acute, rapid and deadly hemorrhagic fever seen in the three cases in the Congo. Rabies, for instance, can be a deadly disease if untreated, but the course of rabies in humans is nothing like the rapid and deadly onset seen with the Bas-Congo virus. There is some precedent, however, for hemorrhagic disease from rhabdoviruses in the animal kingdom: fish rhabdoviruses are known to cause hemorrhagic septicemia—acute bleeding and death—in affected fish.

The third patient had enormous amounts of BASV in his bloodstream just two days after he fell ill—more than a million copies in every milliliter of blood.

The BASV sequence was also used to design an antibody test for the virus, an effort led by Graham Simmons at the BSRI, another member of the consortium. Antibodies are blood immune proteins produced in response to an infection. The antibody test allowed the researchers to screen both the third patient with acute hemorrhagic fever and other people who had come into contact with the third patient, including the nurse who cared for him in the Boma hospital. High levels of BASV-specific antibodies were found in the third patient, establishing that he indeed had been infected with Bas-Congo virus.  The same antibodies were also found in the second nurse, even though he never actually became sick.

“What this suggests is that the disease may be transmissible from person to person—though it’s most likely to have originated from some other source,” said Nathan Wolfe, PhD, founder and chairman of Global Viral, and a co-author on the paper. “The fact that it belongs to a family of viruses known to infect a wide variety of mammals, insects and other animals means that it may perpetually exist in insect or other ‘host’ species and was accidentally passed to humans through insect bites or some other means.”

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The article, “A Novel Rhabdovirus Associated with Acute Hemorrhagic Fever in Central Africa” by Gilda Grard, Joseph N. Fair, Deanna Lee, Elizabeth Slikas, Imke Steffen, Jean-Jacques Muyembe, Taylor Sittler, Narayanan Veeraraghavan, J. Graham Ruby, Chunlin Wang, Maria Makuwa, Prime Mulembakani, Robert B. Tesh, Jonna Mazet, Anne Rimoin, Travis Taylor, Bradley S. Schneider, Graham Simmons, Eric Delwart, Nathan D. Wolfe, Charles Y. Chiu, and Eric M. Leroy appears in the September 27, 2012 issue of the journal PLOS Pathogens. (http://dx.doi.org/10.1371/journal.ppat.1002924)

The research consortium includes San Francisco-based Global Viral, Metabiota, UCSF, BSRI, as well as researchers with the Centre International de Recherches Médicales de Franceville in Gabon; the Institut de Recherche pour le Développement in Montpellier, France; the Institut National de Recherche Biomédicale, Kinshasa in the Democratic Republic of the Congo, the University of Texas Medical Branch in Galveston, TX; the University of California, Davis; the University of California, Los Angeles; Stanford University; and the Howard Hughes Medical Center.

This work was funded by support from Google.org, the Skoll Foundation, the government of Gabon, Total-Fina-Elf Gabon, and the Ministère des Affaires Etrangères et Européennes de la France, the U.S. Department of Defense Armed Forces Health Surveillance Center, Division of Global Emerging Infections, Surveillance Operations (AFHSC GEIS) and the Defense Threat Reduction Agency Cooperative Biological Engagement Program (DTRA-CBEP), and the U.S. Agency for International Development (USAID) Emerging Pandemic Threats Program, PREDICT project. Additional funding was provided by the National Institutes of Health provided via grant numbers R01-HL083254, R01-HL105770, R56-AI089532, and R01-HL105704 and by an Abbott Viral Discovery Award.

* Global Viral was previously known as Global Viral Forecasting Initiative.

**Metabiota was previously known as Global Viral Forecasting Inc. The contents of this release are the responsibility of the authors and do not necessarily reflect the views of USAID or the United States Government and its agencies.

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