Researchers discover a trigger that turns streptococcal infections into a carnivorous disease



PICTURE

PICTURE: This is a scanning electron microscope image of the bacterium Staphylococcus pyogenes (pink).
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Credit: NIH's National Institute of Allergy and Infectious Diseases (NIAID)

HOUSTON- (February 18, 2019) – Methodist researchers in infectious diseases in Houston discovered a previously unknown trigger that turned a relatively trivial infection into a devouring, all-consuming, flesh-eating disease.

Group A streptococcus is an organism that causes more than 700 million cases of human infection each year worldwide. Although most of these cases are caused by strep throat, it is also a common cause of serious invasive disease.

One of these diseases is childhood fever, which strikes mothers and their newborns after childbirth. Few people know this uglier and meaner cousin of strep throat, but it can worsen in a very unpleasant way, leaving its victims without limbs, nor worse.

"Puerperal sepsis, more commonly known as Infantile Fever, causes many deaths worldwide in women during childbirth or shortly after birth," said James M. Musser, MD, Ph.D. the corresponding author on an article published on February 18 in the newspaper Nature Genetics. "It is estimated that about 10% of all women who contract an infant fever will eventually die, which is devastating and can sometimes result in the death of the child."

VIDEO: Dr. Musser explains the research: https: //vimeo.com /309151434 [ Password: HM_V!DEO ] (click here to download)

Musser, chairman of the Houston Methodist's Department of Pathology and Genomic Medicine, and his research team have done something unprecedented in the study of this carnivorous pathogen. They studied the relationship between three distinct entities of group A streptococcus. A first in the field of bacterial research to be conducted at this scale, they examined the interaction between genome, transcriptome and virulence. This generated a huge amount of data that allowed to then use artificial intelligence to analyze it.

"By understanding the relationship and interaction between genome, transcriptome, and virulence, we are much more likely to be able to successfully create new vaccines and treatments for infected patients, as well as to find new ones." other ways to prevent or at least minimize the damage they cause to humans, "said Musser.

Having a relationship with the three at the same time has allowed them to better understand how the body works and how it actually works to become a pathogen and cause illness.

"We and others have been studying this problem for over 100 years and we still have no effective group A streptococcal vaccine. I believe the future of many researches on bacterial pathogenesis is to generate and analyze much larger data sets and use to help us better understand the disease, "said Musser. "The breadth of data we generated for this bacterial pathogenesis paper is unprecedented. It allowed us to use new and more sophisticated tools like artificial intelligence to examine it." With these new types of analyzes, we are making an important step toward ultimately having an effective vaccine to eradicate Group A streptococcus from the earth's surface. "

The ability to apply artificial intelligence to the data has led to an unexpected discovery, to better understand how group A angina causes infection in humans.

"One of the very unexpected and exciting things we have discovered is a strategy used by streptococcus A to cause serious illness in humans," said Musser. "This new mechanism that we have discovered controls virulence and determines whether the organism is just a pathogen or a very angry flesh-eating pathogen." This discovery would not have been possible without the provision of this unusually large dataset for artificial intelligence analysis. "

To do this, they examined the group M streptococcal strain M28, which is causing a large number of invasive cases and a high incidence of childhood fever. , in particular. In many countries, it is one of the five most common strains of group A streptococci, causing serious invasive disease in humans.

"Numerically, the M28 are very important causes of human infections, so we wanted to know more about it because if you start to understand the processes of molecular pathogenesis, then you have the opportunity to potentially develop new treatments and diagnoses, "he said. . "We are now able, through these very large data sets, to analyze them much more thoroughly and with different sets of eyes than we could before."

The overall strategy used by Musser and his colleagues is a strategy commonly used in cancer research.

"History teaches us that the more we understand the functioning of cancer cells, the more we are able to generate new ways to prevent them from causing human disease." Until 20 years ago, we did not We do not understand most of the genetic changes that lead to them Now we understand them in much more detail because of the in-depth research and analysis of cancer genes, "said Musser. "With regard to cancer, you will understand that it will be very important not only to analyze an aspect, such as the genome of a cancer cell, but also to determine which proteins are made by the cancer cell and how cancer invades other areas of the body ".

Musser's team took a similar approach by simultaneously analyzing the three entities in group A strep. He points out that the ability to generate these large datasets at a reasonable cost, as they had done in this study, was not possible even five years ago.

"We have been able to clearly point out new ways of how the Group A streptococcal strain M28 causes infection, and this gives us a roadmap for understanding how this organism causes maternal sepsis," he said. -he declares. "This vast knowledge that we have now gives us an idea of ​​how we could begin to tackle important downstream research, such as the development of a vaccine or a vaccine. new treatment to combat this organism and potentially eradicate it in the future. "

The data they generated will be cataloged so that others can use them in genomic databases, easily available around the world. They hope that by making it freely available to other investigators, others will be able to watch it with a fresh eye and see what his group has not noticed.

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Priyanka Kachroo, Jesus M. Eraso, Stephen B. Beres, Randall J. Olsen, Luchang Zhu, Waleed Nasser, Paul E. Bernard, Concepcion C. Cantu, Matthew Ojeda Saavedra and María José Arredondo also collaborated on this study . Benjamin Strope, Hackwon Do, Muthiah Kumaraswami, Samantha Kubiak, Hoang AT Nguyen, and S. Wesley Long of the Houston Methodist Research Institute; Jaana Vuopio and Kirsi Gröndahl-Yli-Hannuksela of the University of Turku in Finland; Karl G. Kristinsson and Magnus Gottfredsson of the University of Iceland; Maiju Pesonen, Johan Pensar and Jukka Corander from the University of Oslo, Norway; Emily R. Davenport and Andrew G. Clark Cornell University in Ithaca; Dominique A. Caugant with the Norwegian Institute of Public Health; Shahin Gaini and Marita Debess Magnussen with laboratories in the Faroe Islands; and Adeline R. Porter and Frank R. DeLeo, of NIH Rocky Mountain Laboratories, of the National Institute of Allergic and Infectious Diseases in Montana.

This work was funded by grants from the Fondren Foundation, the Houston Methodist Hospital, the Houston Methodist Research Institute, the Academy of Finland (255636), the European Research Council (742158), the National Institutes of Medicine, Health (1R01AI109096-01A1) and the NIH Internal Research Program. of the National Institute of Allergy and Infectious Diseases.

The sequences reported in this document have been filed in the archive archive of the National Biotechnology Information Center (NCBI) archive under the accession number SRP132980 and in the following. NCBI Gene Expression Highway (GEO) under accession number GSE113058.

For more information: The integrated analysis of population genomics, transcriptomics and virulence provides new information on the pathogenesis of Streptococcus pyogenes. Nature Genetics. (online 18 February 2019) P. Kachroo, JM Eraso, SB Beres, RJ Olsen, L. Zhu, W. Nasser, PE Bernard, CC Cantu, MO Saavedra, MJ Arredondo, B. Strope, H. Do., M. Kumaraswami, J. Vuopio, K. Gröndahl-Yli Hannuksela, KG Kristinsson, M. Gottfredsson, M. Pesonen, J. Pensar, ER Davenport, Clark AG, J. Corander, DA Caugant, S. Gaini, MD Magnussen, SL Kubiak, HAT Nguyen, S. W. Long, A. R. Porter, F. R. DeLeo and J. M. Musser. DOI: https: //do I.org /ten.1038 /s41588-018-0343-1


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