Researchers at the University of Wollongong, University of California San Diego (UCSD), University of Tennessee and the Helmholtz Centre for Infection Research (Germany) have discovered an explanation for how a deadly strain of “flesh-eating” bacteria have evolved to produce serious human infections worldwide.

The research, reported in an advance online publication of the prestigious journal, Nature Medicine, focuses on the major human pathogen group A Streptococcus (“strep”). The lead author is Professor Mark Walker from the University of Wollongong’s School of Biological Sciences. Among the most important of all human infectious disease agents, strep is responsible for a wide range of diseases, ranging from simple throat and skin infections to life-threatening invasive conditions such as necrotizing fasciitis (“flesh-eating disease”) and toxic shock syndrome.

Strep is estimated to cause more than 700 million infections each year, with over 650,000 of these dangerous invasive forms. The incidence of serious strep infections has risen dramatically in the last three decades, and this increase is largely attributed to the spread around the globe of a single strain of strep known as the invasive M1T1 clone.

The research group has sought to identify what special characteristics make the invasive M1T1 strep clone so virulent for humans. Recently, they observed that during the early stages of a simple skin infection, a small subpopulation of the strep bacteria hijack a protein from the human bloodstream called plasminogen, attach it to their own surfaces, then activate it into the enzyme, protease, which is capable of destroying cells and tissues, thus allowing the bacteria to break out and spread through the body. The researchers have discovered that a specific genetic mutation in the M1T1 strep clone controls the shift to this invasive form.

In the present study, the researchers identify how the human immune system applies the pressure of natural selection that normally would clear a localised infection, but in the case of the M1T1 strep clone, favours the emergence of the invasive mutants. This property of the M1T1 strep clone can be traced to an event that occurred about 30 years ago, when a virus known as a bacteriophage infected the strep bacteria and introduced a new gene that allowed the bacteria to resist clearance by the human immune system.

“Just like a computer virus might come in and reprogram your hard drive, this bacteriophage reprogrammed the genetic machinery of the M1T1 strep into a more virulent form,” according to Professor Walker.

 “The consequences of this event on human health are still being felt three decades later,” he said.

Present on the bacteriophage acquired by the M1T1 strep is a gene which encodes an enzyme that allows the bacteria to escape entrapment and killing by neutrophils, white blood cells that play a front line role in human’s immune defence by pathogenic microbes. The same genetic mutation that allows the strep bacteria to acquire and activate plasminogen to spread through the body also increases production of the bacteriophage-encoded enzyme that blocks neutrophil killing. When neutrophils of the immune system are summoned to clear a simple strep infection, they apply a natural selective pressure favouring the genetic mutation that allows the bacteria to not only survive neutrophil killing, but unfortunately also to spread and destroy tissues as seen in necrotising fasciitis and other severe forms of strep infection.

In key experiments, the research team used genetically engineered mice expressing human plasminogen and infected them with M1T1 strep clone, discovering that the bacteria routinely mutated to the invasive form, then spread throughout the body to produce a fatal infection. When the researchers eliminated the single bacteriophage gene encoding the neutrophil resistance factor, the M1T1 strep strain lost the ability to undergo the dangerous mutation and could no longer spread to produce severe infection. Ancestral strains of the M1T1 strep, isolated before the acquisition of the bacteriophage, also failed to undergo the mutation to produce serious disease.

“Our study provides a model whereby natural selection exerted by the human immune system can generate hypervirulent bacterial variants with increased risk of producing invasive infections,” said Victor Nizet, UCSD Professor of Pediatrics and Pharmacy.

 “In this case, a bacteriophage provided the bacterium a genetic advantage that turned a relatively benign pathogen into a potential deadly disease agent”, Professor Nizet said.