Abstract
Group A Streptococcus (GAS) causes invasive human diseases with the cytokine storm. Interleukin-33 (IL-33)/suppression of tumorigenicity 2 (ST2) axis is known to drive TH2 response, while its effect on GAS infection is unclear. We used an air pouch model to examine the effect of the IL-33/ST2 axis on GAS-induced necrotizing fasciitis. GAS infection induced IL-33 expression in wild-type (WT) C57BL/6 mice, whereas the IL-33- and ST2-knockout mice had higher mortality rates, more severe skin lesions and higher bacterial loads in the air pouches than those of WT mice after infection. Surveys of infiltrating cells in the air pouch of GAS-infected mice at the early stage found that the number and cell viability of infiltrating cells in both gene knockout mice were lower than those of WT mice. The predominant effector cells in GAS-infected air pouches were neutrophils. Absence of the IL-33/ST2 axis enhanced the expression of inflammatory cytokines, but not TH1 or TH2 cytokines, in the air pouch after infection. Using in vitro assays, we found that the IL-33/ST2 axis not only enhanced neutrophil migration but also strengthened the bactericidal activity of both sera and neutrophils. These results suggest that the IL-33/ST2 axis provided the protective effect on GAS infection through enhancing the innate immunity.
Highlights
Group A Streptococcus (GAS; Streptococcus pyogenes) infection causes a wide range of human diseases, extending from noninvasive pharyngitis, impetigo, and scarlet fever to invasive cellulitis, necrotizing fasciitis, and streptococcal toxic shock syndrome
Based on the results mentioned above, we suggest that the absence of the IL‐33/suppression of tumorigenicity 2 (ST2) axis worsens the GAS infection through decreasing infiltrating cells, as well as their cell viability, at the early stage, and further enhancing bacterial burdens in 5 of 16 the air pouches after GAS infection
Our results indicate that the IL-33/ST2 axis provided a protective effect on the GAS-induced air pouch infection model, and its mechanism was through enhancing the innate immunity, including increasing the bactericidal activity of sera as well as neutrophils (Figures 5 and 6b), and enhancing neutrophil migration into the infected sites (Figure 3b)
Summary
Group A Streptococcus (GAS; Streptococcus pyogenes) infection causes a wide range of human diseases, extending from noninvasive pharyngitis, impetigo, and scarlet fever to invasive cellulitis, necrotizing fasciitis, and streptococcal toxic shock syndrome. Clinical observations have indicated that patients who suffered with GAS invasive infections, such as necrotizing fasciitis, as well as streptococcal toxic shock syndrome, produce higher inflammatory cytokines than those patients with non-invasive infections, such as scarlet fever; the high expression of inflammatory cytokines is associated with a high mortality rate [2,3,4]. Using the in vitro assays, we found that IL-33/ST2 affected neutrophil migration and the bactericidal activity of both the serum and neutrophils These results suggest that IL-33/ST2 plays a protective role in the GAS-induced air pouch infective model through enhancing the innate immunity, but not by the induction of a type 2 response. Intra‐air pouch infection of GAS caused invasive necrotizing fasciitis in mice [19,20] Surveys of both exudates of air pouches and sera from GA found that the expression of IL‐33 significantly increased after GA3 oSf 16infectio tary Figure S1).
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