Abstract
Infection with the Streptococcus suis (S. suis) epidemic strain can cause Streptococcal toxic shock-like syndrome (STSLS), which is characterized by a cytokine storm, dysfunction of multiple organs and a high incidence of mortality despite adequate treatment. Despite some progress concerning the contribution of the inflammatory response to STSLS, the precise mechanism underlying STSLS development remains elusive. Here, we use a murine model to demonstrate that caspase-1 activity is critical for STSLS development. Furthermore, we show that inflammasome activation by S. suis is mainly dependent on NLRP3 but not on NLRP1, AIM2 or NLRC4. The important role of NLRP3 activation in STSLS is further confirmed in vivo with the NLRP3 inhibitor MCC950 and nlrp3-knockout mice. By comparison of WT strain with isogenic strains with mutation of various virulence genes for inflammasome activation, Suilysin is essential for inflammasome activation, which is dependent on the membrane perforation activity to cause cytosolic K+ efflux. Moreover, the mutant strain msly (P353L) expressing mutagenic SLY without hemolytic activity was unable to activate the inflammasome and does not cause STSLS. In summary, we demonstrate that the high membrane perforation activity of the epidemic strain induces a high level of NLRP3 inflammasome activation, which is essential for the development of the cytokine storm and multi-organ dysfunction in STSLS and suggests NLRP3 inflammasome as an attractive target for the treatment of STSLS.
Highlights
Streptococcus suis (S. suis) is a major swine pathogen that is responsible for severe economic losses in the porcine industry and represents a significant threat to human health [1,2,3,4]
We identified a novel mechanism of Streptococcal toxic-shock-like syndrome (STSLS) in that increased suilysin expression in S. suis highly virulent strain could induce high level of cytosolic K+ efflux, an essential event for NLRP3 inflammasome activation, and further cause a cytokine storm, dysfunction of multiple organs and a high incidence of mortality, the characters of STSLS
Subsequent studies further confirmed that the induction of an inflammatory cytokine storm was essential for STSLS [9, 10], which was further supported by the finding that inhibition of the excessive inflammatory response with anti-inflammatory drugs improved survival against STSLS [11]
Summary
Streptococcus suis (S. suis) is a major swine pathogen that is responsible for severe economic losses in the porcine industry and represents a significant threat to human health [1,2,3,4]. Two large-scale human S. suis epidemics in China (the first was 25 cases with 14 deaths in Jiangsu in 1998, and the second was 204 cases with 38 deaths in Sichuan in 2005) raised serious concerns for global public health and challenged the conventional perception that S. suis infections are sporadic in humans [2, 6, 7] This infection causes unusual development of Streptococcal toxic-shock-like syndrome (STSLS), including the hallmarks of acute high fever, blood spots, hypotension, shock, and dysfunction of multiple organs, as well as acute death (mortality is more than 80% despite adequate treatment) [7, 8]. These data highlight the great potential that comprehensive understanding of the molecular mechanisms by which S. suis induces a high level of inflammatory responses may contribute to identify new therapeutic targets for S. suiscaused conditions, including STSLS [11, 12]
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