Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Streptococcus infects humans by thwarting blood clotting

27.08.2004


Streptococcal bacteria may infect humans by using a bacterial enzyme to "hijack" the blood-clotting system, according to new research by Howard Hughes Medical Institute scientists.



In studies published in the August 27, 2004, issue of the journal Science, the researchers establish that the enzyme streptokinase is responsible for the pathogen’s ability to infect humans while exhibiting little activity against other mammals.

The scientists genetically altered strains of mice to make the animals susceptible to infection by streptococcus. They say their strategy outlines a new path for developing animal models for human-specific microbes. The research is also likely to open the way to new understanding of the factors that enable bacteria to evolve host specificity, the researchers said.


Howard Hughes Medical Institute investigator David Ginsburg led the research team, which included lead author Hongmin Sun and colleagues at the University of Michigan and Lund University in Sweden. "Understanding why bacteria in general are so species-specific has been a major problem for a long time," said Ginsburg. "And this species-specificity had greatly hindered our ability to develop an animal model for human-specific bacteria such as Group A streptococci, which are an important human pathogen."

Ginsburg said that Hongmin Sun’s achievement of constructing a transgenic mouse susceptible to streptococcus infection represents a major step not only in understanding infection by that bacterium, but in opening the way to similar studies of other bacteria.

In infecting its human host, the group A streptococcus secretes its own streptokinase, which activates the human form of the enzyme, plasminogen. Plasminogen, in turn, dissolves blood clots by degrading the protein, fibrin. A major question was what role streptokinase played in the bacterium’s overall pathogenicity, said Ginsburg.

To develop the "humanized" mouse that would be vulnerable to bacterial streptokinase, Sun attached the gene for human plasminogen to a regulatory DNA sequence that normally activates the gene for a mouse blood protein, albumin. This protein is produced in large amounts in the animal. The result was a transgenic mouse that made significant amounts of human plasminogen.

To show that the human plasminogen was functional in the mice, Sun crossed the transgenic mice with another strain in which their own plasminogen genes had been deleted. This cross essentially restored plasminogen function in the resulting mice. In test-tube experiments, Sun also demonstrated that streptokinase acted on the human plasminogen from the transgenic mice to dissolve blood clots just as if it were acting on a human clot.

"The critical experiment, though, was when Hongmin infected the skin of these transgenic mice with the group A streptococcus bacteria," said Ginsburg. "She found that the bacteria were much, much more toxic to these mice than the normal mice. This fit with the idea that streptokinase was an important component of the pathogenicity of strep. "I didn’t really think that this would work, because it seemed unlikely that, since pathogenicity seemed to be such a complex process, one factor could have such a dramatic effect by itself," he said.

In further experiments, the researchers found that when they removed the streptokinase gene from group A streptococci bacteria, there was little difference in their infectivity between normal and the transgenic mice.

Such studies have led Ginsburg and his colleagues to theorize that streptokinase "hijacks" the human clot-forming system for the bacteria’s own infective ends. "The theory is that the bacteria cause a local infection and begin to grow. Many of the bacterial products, as well as our immune cells, trigger the human clotting system, which evolved in part as a defense against such infection," said Ginsburg. "This system produces clots in the blood vessels around the infection, closing the highways that the bacteria would use to spread. However, the bacterial streptokinase bypasses this system causing the blood clot to dissolve so the bacteria can spread."

Sure enough, when the researchers bypassed the clotting defense by injecting the streptococcus directly into the bloodstream of both normal and transgenic mice, they both showed similar susceptibility to infection. In another experiment to demonstrate the defensive importance of the clotting system, the researchers administered a substance derived from snake venom that degrades another clotting protein, fibrinogen, discovering that the treatment greatly increased the mice’s mortality from this streptococcus infection.

Streptokinase’s importance to group A streptococci may generalize to many other human-specific bacteria that have evolved their own distinctive plasminogen-activating enzymes, said Ginsburg. Also, he said, the findings highlight the evolutionary arms race between bacteria and humans. "Clearly, if we could mutate our plasminogen so it still worked, yet was resistant to a bacterial streptokinase, it would give us an advantage," said Ginsburg. "But then the bacteria could mutate their streptokinase to keep up. So, you can see how one bacterial species and one host get locked in this evolutionary dance and would evolve apart from other host-bacterial pairs -- ending up with a multitude of variants of streptococci, one for each host. "This evolutionary mechanism probably functions for many other pathogenicity factors, not just streptokinase, and probably underlies the species-specificity of all kinds of infectious organisms," said Ginsburg.

Such findings also hint that subtle variations in plasminogen genes among humans could partially explain differences in susceptibility to certain infection in different people. Thus, he said, his laboratory is exploring the genetic variations in the blood-clotting system that might affect risk factors for infection. "Although this is speculation at this point, it might ultimately be possible to tailor treatment of infections to the pattern of genetic variability in clotting genes or other pathogenicity factors," said Ginsburg.

Jim Keeley | EurekAlert!
Further information:
http://www.hhmi.org

More articles from Life Sciences:

nachricht Monitoring biodiversity with sound: how machines can enrich our knowledge
18.06.2019 | Georg-August-Universität Göttingen

nachricht Uncovering hidden protein structures
18.06.2019 | Universität Konstanz

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: The hidden structure of the periodic system

The well-known representation of chemical elements is just one example of how objects can be arranged and classified

The periodic table of elements that most chemistry books depict is only one special case. This tabular overview of the chemical elements, which goes back to...

Im Focus: MPSD team discovers light-induced ferroelectricity in strontium titanate

Light can be used not only to measure materials’ properties, but also to change them. Especially interesting are those cases in which the function of a material can be modified, such as its ability to conduct electricity or to store information in its magnetic state. A team led by Andrea Cavalleri from the Max Planck Institute for the Structure and Dynamics of Matter in Hamburg used terahertz frequency light pulses to transform a non-ferroelectric material into a ferroelectric one.

Ferroelectricity is a state in which the constituent lattice “looks” in one specific direction, forming a macroscopic electrical polarisation. The ability to...

Im Focus: Determining the Earth’s gravity field more accurately than ever before

Researchers at TU Graz calculate the most accurate gravity field determination of the Earth using 1.16 billion satellite measurements. This yields valuable knowledge for climate research.

The Earth’s gravity fluctuates from place to place. Geodesists use this phenomenon to observe geodynamic and climatological processes. Using...

Im Focus: Tube anemone has the largest animal mitochondrial genome ever sequenced

Discovery by Brazilian and US researchers could change the classification of two species, which appear more akin to jellyfish than was thought.

The tube anemone Isarachnanthus nocturnus is only 15 cm long but has the largest mitochondrial genome of any animal sequenced to date, with 80,923 base pairs....

Im Focus: Tiny light box opens new doors into the nanoworld

Researchers at Chalmers University of Technology, Sweden, have discovered a completely new way of capturing, amplifying and linking light to matter at the nanolevel. Using a tiny box, built from stacked atomically thin material, they have succeeded in creating a type of feedback loop in which light and matter become one. The discovery, which was recently published in Nature Nanotechnology, opens up new possibilities in the world of nanophotonics.

Photonics is concerned with various means of using light. Fibre-optic communication is an example of photonics, as is the technology behind photodetectors and...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

SEMANTiCS 2019 brings together industry leaders and data scientists in Karlsruhe

29.04.2019 | Event News

Revered mathematicians and computer scientists converge with 200 young researchers in Heidelberg!

17.04.2019 | Event News

First dust conference in the Central Asian part of the earth’s dust belt

15.04.2019 | Event News

 
Latest News

Uncovering hidden protein structures

18.06.2019 | Life Sciences

Monitoring biodiversity with sound: how machines can enrich our knowledge

18.06.2019 | Life Sciences

Schizophrenia: Adolescence is the game-changer

18.06.2019 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>