Streptococcal bacteria disrupts blood clotting to infect humans

University of Michigan researchers have captured a glimpse of the endless arms race between infectious agents and the human immune system in a bacterium that uses a mimic of a human blood-clotting enzyme to advance its infection.

Streptococcal bacteria use an enzyme called streptokinase to block the blood clotting response and allow themselves to move more freely around the human host's circulatory system. The molecule is so specific, it only works on humans, not on other animals.

"The theory is that, as bacteria cause a local infection and begin to grow, the clotting system produces clots in the blood vessels around the infection, closing the highways that the bacteria would use to spread," said David Ginsburg, a research professor at the U-M Life Sciences Institute and a Howard Hughes Medical Institute investigator.

"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," Ginsburg said.

"The bacterial streptokinase enzyme bypasses this blood-clotting system by causing the blood clot to dissolve so the bacteria can spread," Ginsburg said. Streptokinase secreted by group A streptococcus works by activating the human form of the enzyme plasminogen, which routinely dissolves blood clots in the body.

Human plasminogen is specific to our species, so U-M postdoctoral fellow Hongmin Sun had to develop a genetically engineering humanized mouse that made significant amounts of human plasminogen to test the researchers' ideas about group A streptococci.

Ginsburg adds that making this mouse susceptible to human-type streptococcus infection may represent a significant step not only in understanding infection by this bacterium, but also opening the way to similar studies of other bacteria that afflict humans.

"Understanding why bacteria in general are so species-specific has been a major problem for a long time," Ginsburg said. "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."

To further demonstrate the defensive importance of the clotting system, the researchers administered a substance derived from snake venom that degrades another clotting protein, fibrinogen, and found that it too greatly increased the mice's mortality from this streptococcus infection.

To Ginsburg, who has spent much of his career studying the genetics of blood clotting and clotting disorders such as hemophilia, the findings highlight an 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," Ginsburg said. "But then the bacteria could mutate their streptokinase to keep up."

The findings also suggest that subtle variations in plasminogen genes among humans may explain why some people are more susceptible to strep infections than others.

Ginburg's laboratory is now 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," Ginsburg said.

The research, being published in the Aug. 26 issue of the journal Science, also included colleagues at Lund University in Sweden.