Kallistatin Modulates Immune Cells and Confers Anti-Inflammatory Response To Protect Mice from Group A Streptococcal Infection

Abstract

i Group A streptococcus (GAS) infection may cause severe life-threatening diseases, including necrotizing fasciitis and streptococcal toxic shock syndrome. Despite the availability of effective antimicrobial agents, there has been a worldwide increase in the incidence of invasive GAS infection. Kallistatin (KS), originally found to be a tissue kallikrein-binding protein, has recently been shown to possess anti-inflammatory properties. However, its efficacy in microbial infection has not been explored. In this study, we transiently expressed the human KS gene by hydrodynamic injection and investigated its anti-inflammatory and protective effects in mice via air pouch inoculation of GAS. The results showed that KS significantly increased the survival rate of GAS-infected mice. KS treatment reduced local skin damage and bacterial counts compared with those in mice infected with GAS and treated with a control plasmid or saline. While there was a decrease in immune cell infiltration of the local infection site, cell viability and antimicrobial factors such as reactive oxygen species actually increased after KS treatment. The efficiency of intracellular bacterial killing in neutrophils was directly enhanced by KS administration. Several inflammatory cytokines, including tumor necrosis factor alpha, interleukin 1␤, and interleukin 6, in local infection sites were reduced by KS. In addition, KS treatment reduced vessel leakage, bacteremia, and liver damage after local infection. Therefore, our study demonstrates that KS provides protection in GAS-infected mice by enhancing bacterial clearance, as well as reducing inflammatory responses and organ damage.

Kallistatin in Sepsis: Protective Actions and Potential Therapeutic Applications

“…Human kallistatin treatment signiicantly enhances bacterial clearance and antimicrobial activity in group A streptococcus-infected mice by increasing superoxide production in immune cells [65]. Likewise, kallistatin administration leads to more than 10-fold decrease of bacterial counts in the peritoneal luid of mice with polymirobial sepsis [29].…”

“…Kallistatin via its heparin-binding domain blocks TNF-α-and HMGB1-induced NF-κB activation, inlammatory gene expression, and ROS formation [20,29]. However, kallistatin's active site is involved in superoxide formation in immune cells, leading to a bacterial killing efect [65]. The signaling pathways mediated by kallistatin in the protection against sepsis are shown in Figure 2. …”

“…The bactericidal activity of kallistatin is most likely atributed to elevated ROS formation in peritoneal neutrophils [61]. Kallistatin also enhances immune cell viability and reduces their apoptosis [65]. Kallistatin through its active site increases SOCS3 expression in macrophages and SIRT1 synthesis in endothelial cells, but the efects are blocked by genistein [28].…”

“…Transgenic mice expressing kallistatin are highly resistant to mortality induced by LPS [66]. Moreover, kallistatin gene transfer reduces mortality, bacterial counts, and inlammatory cell numbers, as well as skin and liver damage, in a mouse model of streptococcal infection [65]. Kallistatin treatment in septic mice with polymicrobial infection atenuates lethality, peritoneal bacterial counts, renal injury and inlammation, and splenic apoptosis [29].…”

“…A human kallistatin gene polymorphism is correlated with a decreased risk of developing acute kidney injury in patients with septic shock [64]. Kallistatin treatment exerts beneicial efects in Gram-negative and Gram-positive bacteremia, as well as "mixed" polymicrobial infection [29,35,48,65]. Transgenic mice expressing kallistatin are highly resistant to mortality induced by LPS [66].…”