IL-18 Signaling Is Essential for Causing Streptococcal Toxic Shock-like Syndrome (STSLS).

Streptococcus suis (S. suis) is an emerging zoonotic pathogen that can cause multiple diseases, including streptococcal toxic shock-like syndrome (STSLS). The S. suis SC-19 strain could cause NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome hyperactivation, then induce a cytokine storm and STSLS. Although IL-18 is the downstream effector of NLRP3 signaling, the role of IL-18 signaling on STSLS remains to be elucidated. Thus, il18r1 gene knockout mice were constructed and challenged with the SC-19 strain. Alleviated clinical signs and tissue damages, as well as improved survival were observed in il18r-/- mice compared with the WT mice post-SC-19 challenge. Meanwhile, an obvious decrease in the inflammatory cytokine levels in blood was observed in the il18r-/- mice infected with SC-19. Therefore, IL-18, the downstream effector of NLRP3 inflammasome activation, was responsible for the cytokine storm and STSLS development caused by S. suis, suggesting that IL-18/IL-18Rα signaling could serve as a new target for STSLS.

Interleukin-17A Contributed to the Damage of Blood-CNS Barriers During Streptococcus suis Meningitis.

Streptococcus suis (S. suis) is an emerging zoonotic agent that can cause meningitis in humans with high mortality and morbidity. Meningitic S. suis can induce higher level of IL-17 than non-meningitic S. suis. Besides, IL-17A plays various roles on bacterial clearance or disruption of blood-CNS barriers through the downregulation and reorganization of tight junction (TJ) molecules. However, it remains to be elucidated for the role of IL-17A on the infection with meningitic S. suis. Here, we found that meningitic S. suis infection could not only cause acute death due to the damage of multiple organs, but also cause meningitis and clinical nervous signs since 60 h of post-infection due to the penetration of blood-CNS barriers after lasting bacteremia. In contrast, the mice with deficiency of il17a gene could not significantly change the acute inflammatory response and acute death, but it could not show obvious meningitis and clinical nervous signs caused by the meningitic S. suis infection. In addition, we also found that IL-17A could inhibit the transcription and expression of TJ proteins that facilitated the leakage of blood-CNS barriers since 60 h of post-infection during meningitic S. suis infection. Thus, our findings demonstrated that IL-17A could downregulate TJ proteins, which undoubtedly facilitated the leakage of blood-CNS barriers for bacterial invasion and then caused S. suis meningitis, providing potential targets for future prevention and treatment of this disease.

Interleukin-17A Contributes to Bacterial Clearance in a Mouse Model of Streptococcal Toxic Shock-Like Syndrome.

Streptococcus suis (S. suis), an emerging zoonotic pathogen, can cause streptococcal toxic shock-like syndrome (STSLS) in humans with high mortality. STSLS is characterized by high bacterial burden, an inflammatory cytokine storm, multi-organ dysfunction, and ultimately acute host death. Although it has been found that a significantly high level of IL-17A was induced in an NLRP3-dependent manner during STSLS development, the role of IL-17A on S. suis STSLS remains to be elucidated. In this study, we found that the epidemic strain SC 19 caused a significantly higher level of IL-17A than the non-epidemic strain P1/7. In addition, higher bacterial burden was observed from SC 19-infected il17a-/- mice than il17a+/+ mice, although acute death, tissue injury and inflammatory cytokines storm were observed in both types of mice. Furthermore, compared with il17a+/+ mice, the level of neutrophils recruitment was lower in il17a-/- mice, and the levels of induced antimicrobial proteins, such as CRAMP, S100A8 and lipocalin-2, were also decreased in il17a-/- mice. In conclusion, this study demonstrated that IL-17A does not contribute to the severe inflammation, although it may play a minor role for bacterial clearance by inducing antimicrobial proteins and promoting neutrophil recruitment during STSLS.