Coordinating the sort of full-spectrum analysis more commonly deployed in cancer research, scientists based at Houston Methodist examined flesh-eating strains of Streptococcus pyogenes both genomically and transcriptomally. Once the scientists had amassed an unusually large data set, they sifted through it with artificial intelligence tools and discovered a novel virulence mechanism. In addition to explaining how a run-of-the-mill strep infection can turn into a devastating flesh-eating disease, the mechanism may guide efforts to develop vaccines and therapies.

“By understanding the relationship and interplay between the genome, transcriptome, and virulence, we have a much greater chance of being able to successfully create new vaccines and therapies for infected patients, as well as find other ways to prevent or at least minimize how much damage they cause to humans,” said James M. Musser, MD, PhD, chairman of the department of pathology and genomic medicine at Houston Methodist.

Taking on the relationships of all three at one time gave Musser’s team a richer understanding of how S. pyogenes ticks and how it really functions to become a pathogen and cause disease.

Details of the team’s work appeared February 18 in the journal Nature Genetics, in an article titled, “Integrated analysis of population genomics, transcriptomics and virulence provides novel insights into Streptococcus pyogenes pathogenesis.”

“We sequenced the genomes of 2,101 emm28 S. pyogenes invasive strains, from which we selected 492 phylogenetically diverse strains for transcriptome analysis and 50 strains for virulence assessment,” wrote the article’s authors. “Genome-wide association study, expression quantitative trait loci analysis, machine learning, and isogenic mutant strains identified and confirmed a one-nucleotide indel in an intergenic region that significantly alters global transcript profiles and ultimately virulence.”

Group A streptococcus is an organism that causes more than 700 million cases of human infection every year globally. While most of those cases are strep throat, which most people have had, it’s also a common cause of severe invasive diseases.

One such disease is childbed fever, which strikes moms and their newborns following childbirth. Not many people are familiar with this uglier, meaner cousin of strep throat, but it can turn serious in a very nasty way, leaving its victims without limbs or worse.

Many invasive cases of strep and a high incidence of childbed fever, in particular, are caused by the M28 strain of group A streptococcus. This strain is also among the top five most common group A strep strains causing serious invasive disease in humans. Consequently, this strain was chosen as the focus of the Houston Methodist study.

“Numerically, the M28s are very important causes of human infections, so we wanted to get new insight on it, because if you begin to understand the molecular pathogenesis processes, then you have the ability to begin potentially developing new therapeutics and diagnostics,” said Musser. “We’re now able, using these very large data sets, to analyze them far more extensively and with different sets of eyes than we were able to in the past.

“History teaches us that the more we understand how cancer cells work, the better we’re able to generate new ways to inhibit them from causing human disease. Until 20 years ago, we didn’t understand most of the genetic changes that result in cancers. We now understand those in far more detail because of extensive research and analysis of cancer genes,” Musser explained. “In cancer, you can appreciate that it’s going to be very important to not just analyze one aspect, such as the genome of a cancer cell, but also to analyze what proteins are being made by the cancer cell and then exactly how cancer is invading other areas of the body.”

Musser and colleagues took a similar approach in their analysis of group A strep’s virulence. That is, they applied an integrative strategy, one that may be generally applicable to any microbe and, ultimately, lead to new therapeutics for many human pathogens

“We were able to clearly show new routes about how the M28 strain of group A strep causes infection, and it gives us a roadmap for understanding how this organism causes maternal sepsis,” Musser noted. “This extensive knowledge gives us insight into how one might begin to attack important downstream research like developing a vaccine or new treatment to fight this organism and potentially eradicate it in the future.”

The data Musser and colleagues generated will be cataloged for others to use in genomics databases, readily available worldwide. Musser hopes that by making his team’s data freely available to other investigators, others may look at it with fresh eyes and see things his team didn’t notice.

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