Researchers unveil evolution of bacterial genomes over course of single chronic infection

A team at Allegheny General Hospital documents first scientific evidence that bacteria alter their genetic makeup in real time to circumvent the host’s immune system

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PITTSBURGH—Researchers at Allegheny General Hospital have made what they consider "a landmark discovery" in the evolutionary nature of bacteria in chronic infectious disease, as the AGH team documents for the first time that bacteria engage in a process called horizontal gene transfer to evolve rapidly during the course of a single infection.

The team reported its results recently in the journal PLoS Pathogens.

According to Garth Ehrlich, scientific director of the AGH Center for Genomic Sciences and the paper's senior author, the result is a group of highly-related bacterial strains that are changing genetically so fast that it is likely nearly impossible for the host's immune system to effectively track and eradicate it.

"As far as we know, this is the first report documenting definitively that bacteria during a single chronic or persistent infection undergo multiple mutations so that during the course of infection a group of related, but still different, strains are produced," Ehrlich tells ddn. "The rate of change was much higher than we anticipated."

Ehrlich points out that the findings can have great implications for drug research and development as well as vaccine research.

"The one thing which is very clear to us now with the rate of recombination that is going on and the fact that that these constructions tend to be polyclonal, is that we are almost always dealing within a population of multiple resistances," he says.

As a result, scientists have to work to get ahead of the mutation rate of the organism.

"If you are treating with three antibiotics at once, and you one in 107 chance of developing resistance and you've got 109 or 1010 organisms, well you have a hundred or a thousand resistant organisms right off the bat," Ehrlich points out.

Ehrlich explains the research team has found that successful pathogens—such as viruses and certain parasitic organisms that are designed to mutate and confuse the immune system, and bacteria which cause the vast majority of chronic infectious disease in the United States—appear to be using a similar tactic.

"And they are doing so through a dynamic, real-time process of altering their genetic code that until now has not been understood and which is counter to conventional wisdom about the typical pace of species evolution," he adds.
Dr. Christopher Post, a pediatric ear/nose/throat specialist, medical director of the Center for Genomic Sciences and president of the Allegheny Singer Research Institute, points out that from a patient and public health perspective, the discovery could have significant implications.
"Bacterial infections are some of the most formidable and costly diseases that healthcare professionals confront on a daily basis in clinics and hospitals throughout the world," he explains. "This finding may prove to be a seminal event in our pursuit of more effective strategies for overcoming the primary challenges to preventing and treating such infections, including antibiotic resistance, chronic biofilm disease and bacterial species that readily adapt to vaccinations."
According to Post, bacterial infections have traditionally been studied under the assumption that a single genetic organism is at the heart of any single case of infection.

Post points out that over the past decade, he, Ehrlich and others at the Center for Genomic Sciences have helped pioneer the concept that many chronic infections do not fit this paradigm, but rather are the result of multiple strains or species of bacteria living together in highly structured and formidable communities, called biofilms.

"It is essentially a genomic chess match where bacteria through horizontal gene transfer are always staying one step ahead," Ehrlich explains.
In the course of studying biofilms, Post points out that the AGH team began documenting evidence that bacteria often incorporate DNA from neighboring bacteria into their own genomes.
Using advanced high-throughput bacterial DNA sequencing, Ehrlich and his colleagues in the current study investigated the tempo and relevance of horizontal gene transfer among nasopharyngeal strains of Streptococcus pneumoniae recovered from a child with chronic respiratory and middle ear infections. Specimens were collected during the child's clinic visits over a seven month period.
Commonly referred to as pneumococcus, Streptococcus pneumoniae is one of the world's most prevalent and deadly pathogens, associated with severe invasive diseases such as meningitis and bacteremia as well as common mucosal diseases such as pneumonia, sinusitis and otitis media.
Complete genome sequencing and comparative genomics were performed by the AGH team on multiple bacterial strains collected during the course of the child's pneumococcal infection.

Ehrlich points out that the team identified extensive gene transfer among multiple infecting strains of the bacteria.

"Comparing the original strain that started the infection with strains sequenced at its end, approximately 7.5 percent of the entire genome had changed," he says. "In just a seven month period of time, we documented a remarkable ongoing evolution of this species that appears to be precisely orchestrated to confound the host's immune surveillance."

The immune system works in a similar fashion, Ehrlich explains, by continuously realigning the genomes of white blood cells so they can recognize and destroy foreign pathogens.

Ehrlich notes that in addition to the general challenges that scientists face, his team also faced hurdles that were bioinformatic in nature.

"There weren't adequate software programs out there for coding whole genome alignments and bacterial-size genomes and identifying regions of recombination," he explains. "We were actually working with the software developers to come up with the software to do the analyses we needed to do."

Going forward, Ehrlich says the next step for the AGH team is to do a broader study of gene transfer involving more species of bacteria.

"We suspect that this is not the only species of bacteria that does this," Ehrlich says. "Once we have verified that horizontal gene transfer is indeed a common occurrence in chronic bacterial infections, and we expect that to be the case, it opens the door to a realm of promising new directions in the study and treatment of these diseases."

One of the next organisms to work with, according to Ehrlich, is influenza. The team at AGH will work with groups at the University at Buffalo and the University of Michigan on the next phase of the research.

In addition to Ehrlich and Post, other key members of the Center for Genomic Sciences staff who contributed to the PLoS Pathogens paper included Fen Z. Hu, Luisa Hiller, and Azad Ahmed.

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