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Meeting the Challenge of Emerging Diseases
CHORI Scientist Discovers Rampant Recombination in Obligate Intracellular Organism

In a new study now in advance publication in Genome Research, one of the county’s leading genetics journals, CHORI senior scientist Deborah Dean, MD, MPH, demonstrates for the first time the occurrence of rampant recombination in an obligate intracellular organism. While previous studies in Rickettsia have suggested the potential for intracellular organisms to undergo limited recombination, no one, least of all Dr. Dean, could have predicted these watershed results.

“What we found was unbelievable,” says Dr. Dean. “There was so much more recombination than we ever would have dreamed was possible. When we looked at our data, we were so shocked that we ended up going back and re-sequencing every isolate to make sure our results were right.”

Recombination, the mixing of different strains of DNA between organisms, has long been observed in free-living bacteria, but has generally been assumed to be far less common in intracellular bacteria.

“It’s a much more complicated event in intracellular organisms because each one of the infectious particles that infects a cell can form its own intracytoplasmic vacuole,” explains Dr. Dean. “Two different strains have to find the same cell, form their own different vacuoles inside that cell, and then fuse together.”

There were some indications, however, that recombination was occurring in Chlamydia trachomatis, the bacterium responsible for the second-leading cause of preventable blindness world-wide and infecting over 600 million people across the globe.

“Genotyping in C. trachomatis has been based on just one gene,” Dr. Dean says of the pathogen she has been studying over two decades now.

As a result, Dr. Dean and her colleagues wanted to explore different genes in the genome that had not been previously investigated. They also felt it was critically important to use both reference strains that have been laboratory adapted and recent clinical isolates.

"It’s well-known that lab strains adapt to their in vitro environment and become different from clinical strains that are currently circulating in human populations,” Dr. Dean says.

Investigators have continued to use these reference strains for C. trachomatis, however, because using the same reference strains meant that data from different labs could be compared and verified. In addtition, the organism is both difficult to isolate and analyze.

"You can’t just throw it on a Petri dish and get tons of organisms to work with,” says Dr. Dean.

In Dr. Dean’s study, the challenge of analyzing the clinical isolates had a huge pay off, however. The results were stunning – all 10 clinical isolates that her team analyzed demonstrated rampant recombination that was additionally confirmed by statistically-based recombination programs – and have profound implications.

“To begin with,” says Dr. Dean, “You can’t just use one or two different genes to type Chlamydia anymore. You have to use multilocus sequence-based typing of genes dispersed throughout the genome."

"You also can’t really use reference strains anymore in pathogenesis studies except for comparative purposes," she continues. "We really need to start using clinical isolates to understand disease pathogenesis and evolution.”

In addition to the impact the study will have on research practice in the field of Chlamydia, the results also provide significant clues about the nature of intracellular organisms.

“This is how these pathogens undergo divergence and evolution,” says Dr. Dean. “Obligate intracellular organisms have so many more possibilities to become fit in the human host than we ever knew before.”

Thankfully, however, scientists like CHORI’s Dr. Dean continue to push beyond the known boundaries of possibility. It is exactly this kind of research that will continue to meet the challenges inherent in our world of emerging infectious diseases.

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Monday, May 16, 2011 11:33 PM

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