An NLRP3 inflammasome-triggered cytokine storm contributes to Streptococcal toxic shock-like syndrome (STSLS)

• Published in: PLoS pathogens 2019-06, Vol.15 (6), p.e1007795
• Main Authors: Lin, Lan, Xu, Lei, Lv, Weihua, Han, Li, Xiang, Yaozu, Fu, Lei, Jin, Meilin, Zhou, Rui, Chen, Huanchun, Zhang, Anding
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - immunology; Agriculture; Animal models; Animals; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - immunology; Biocompatibility; Biology and Life Sciences; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - immunology; Caspase; Caspase-1; Cytokine storm; Cytokines; Cytokines - genetics; Cytokines - immunology; Development and progression; DNA-Binding Proteins - genetics; DNA-Binding Proteins - immunology; Efflux; Epidemics; Fatalities; Genes; Immune system; Infection; Infections; Inflammasomes; Inflammasomes - genetics; Inflammasomes - immunology; Inflammation; Inflammatory response; Laboratories; Medicine and Health Sciences; Meningitis; Mice; Mice, Inbred BALB C; Mortality; Mutation; Neutrophils; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; NLR Family, Pyrin Domain-Containing 3 Protein - immunology; Organs; Pathogens; Perforation; Research and Analysis Methods; Risk factors; Septic shock; Shock; Shock, Septic - genetics; Shock, Septic - immunology; Shock, Septic - pathology; Streptococcal Infections - genetics; Streptococcal Infections - immunology; Streptococcal Infections - pathology; Streptococcus; Streptococcus infections; Streptococcus suis - immunology; Suilysin; Toxic shock syndrome; Transcription activation; Tumor necrosis factor-TNF; Veterinarians; Veterinary colleges; Veterinary medicine; Virulence; Virulence (Microbiology)
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1007795

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.