Trigger for group A streptococcal M1T1 invasive disease.
The globally disseminated Streptococcus pyogenes M1T1 clone causes a number of highly invasive human diseases. The transition from local to systemic infection occurs by an unknown mechanism; however invasive M1T1 clinical isolates are known to express significantly less cysteine protease SpeB than M1T1 isolates from local infections. Here, we show that in comparison to the M1T1 strain 5448, the isogenic mutant delta speB accumulated 75-fold more human plasmin activity on the bacterial surface following incubation in human plasma. Human plasminogen was an absolute requirement for M1T1 strain 5448 virulence following subcutaneous (s.c.) infection of humanized plasminogen transgenic mice. S. pyogenes M1T1 isolates from the blood of infected humanized plasminogen transgenic mice expressed reduced levels of SpeB in comparison with the parental 5448 used as inoculum. We propose that the human plasminogen system plays a critical role in group A streptococcal M1T1 systemic disease initiation. SpeB is required for S. pyogenes M1T1 survival at the site of local infection, however, SpeB also disrupts the interaction of S. pyogenes M1T1 with the human plasminogen activation system. Loss of SpeB activity in a subpopulation of S. pyogenes M1T1 at the site of infection results in accumulation of surface plasmin activity thus triggering systemic spread.
Cole
Jason N
JN
School of Biological Sciences, University of Wollongong, Wollongong, New South Wales, 2522, Australia.
McArthur
Jason D
JD
McKay
Fiona C
FC
Sanderson-Smith
Martina L
ML
Cork
Amanda J
AJ
Ranson
Marie
M
Rohde
Manfred
M
Itzek
Andreas
A
Sun
Hongmin
H
Ginsburg
David
D
Kotb
Malak
M
Nizet
Victor
V
Chhatwal
G S
GS
Walker
Mark J
MJ
D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics; D005098:Exotoxins / Q000235:genetics; D005341:Fibrinolysin / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010958:Plasminogen / Q000502:physiology*; D013290:Streptococcal Infections / Q000209:etiology / Q000382:microbiology*; D013297:Streptococcus pyogenes / Q000737:chemistry / Q000472:pathogenicity*; D014774:Virulence
D001426:Bacterial Proteins; D005098:Exotoxins; C027951:erythrogenic toxin; D010958:Plasminogen; D005341:Fibrinolysin