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

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.

From Stable to Lab—Investigating Key Factors for Sudden Deaths Caused by Streptococcus suis

“…However, NET induction is only one pathomechanism causing the cytokine storm responsible for the development of DIC [46]. Suilysin in S. suis serotype 2 strains involved in STSS was found to trigger excessive release of IL-1β followed by detrimental inflammation processes [59]. As the pathogenic Zoo strain described in this study was negative for suilysin, other bacterial factors in combination with a lack of an adequate host immune response might have led to DIC.…”

Analysis of Porcine Pro- and Anti-Inflammatory Cytokine Induction by S. suis In Vivo and In Vitro

“…However, in a pig model of S. pneumoniae sepsis, it was directly demonstrated that neutralization of TNF-α has no protective anti-inflammatory effect [51]. In a recent study, the inhibition of an inflammasome-triggered cytokine storm in an S. suis mouse model did not influence the bacterial load, but reduced mortality and clinical score [52]. For a more detailed understanding of the role of cytokines during an invasive infection in pigs, histopathological scoring could be of advantage to investigate the local detrimental effects induced by pro-inflammatory cytokines.…”

Recognition of Lipoproteins by Toll-like Receptor 2 and DNA by the AIM2 Inflammasome Is Responsible for Production of Interleukin-1β by Virulent Suilysin-Negative Streptococcus suis Serotype 2

“…Due the importance of IL-1 in the balance of systemic inflammation [13,34], host survival following SLY-negative S. suis strain 89-1591 infection was evaluated in wild-type and IL-1R -/mice. Survival of IL-1R -/mice was significantly reduced in comparison to wild-type counterparts (p < 0.01) (Figure 7), suggesting a beneficial role of IL-1 signaling during SLY-negative strain 89-1591 infection.…”

“…Moreover, IL-1 signaling was recently demonstrated to play a beneficial role during the systemic infection caused by a highly virulent S. suis serotype 2 ST1 strain via initiation of the inflammatory cascade and promotion of bacterial clearance [13]. However, this effect was not observed following infection with the epidemic ST7 strain responsible for the 2005 human outbreak due to the exacerbated inflammation being too elevated for counterbalancing by IL-1 [13,34]. The mechanism presently described for S. suis-induced IL-1β production involves SLY (both ST1 and ST7 strains are SLY-positive), which promotes its processing [13,34].…”

“…However, this effect was not observed following infection with the epidemic ST7 strain responsible for the 2005 human outbreak due to the exacerbated inflammation being too elevated for counterbalancing by IL-1 [13,34]. The mechanism presently described for S. suis-induced IL-1β production involves SLY (both ST1 and ST7 strains are SLY-positive), which promotes its processing [13,34]. However, a large proportion of virulent S. suis serotype 2 strains recovered from diseased animals do not produce SLY, including the virulent ST25 strains present in Canada and Thailand [10,35], and their capacity to produce IL-1β, including the mechanisms involved, have been little studied.…”