Synergistic effects of streptolysin S and streptococcal pyrogenic exotoxin B on the mouse model of group A streptococcal infection

Abstract

Streptococcus pyogenes is a group A streptococcus (GAS) and an important human pathogen that causes a variety of diseases. Streptococcal pyrogenic exotoxin B (SPE B) and streptolysin S (SLS) are important virulence factors involved in GAS infection, but it is not clear which one is more virulent. Using an air pouch infection model, the wild-type strain NZ131, its isogenic mutants, and complementary mutants were used to examine the effects of SPE B and SLS on GAS infection. The results of the skin lesion and mouse mortality assays showed that although SPE B and SLS had a synergistic effect on GAS infection, SPE B played a more important role in local tissue damage while SLS had a more prominent effect on mouse mortality. Surveys of the exudates from the air pouch revealed that the expression of inflammatory cytokines was significantly inhibited in the sagB/speB-double-mutant JM4-infected mice. Furthermore, in vivo and in vitro studies showed that the isogenic mutant strains were more susceptible to the immune cell killing than the wild-type strain and that the sagB/speB-double-mutant JM4 was the most sensitive among these strains. Moreover, infection with the sagB/speB-double-mutant JM4 strain caused the least amount of macrophage apoptosis compared to infection with the wild-type NZ131 and the other complementary strains, which express only SPE B or SLS or both. Taken together, these results indicate that both SPE B and SLS contributed to GAS evasion from immune cell killing, local tissue damage, and mouse mortality.

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

“…Another virulence factor, SPE B, a cysteine proteinase, was shown to facilitate bacterial dissemination, colonization, and invasion and inhibit wound healing (7,27,28). Because the KS gene sequence is highly conserved with ␣-antitrypsin (33), and ␣-antitrypsin inhibits not only serine proteinase but also cysteine proteinase, we speculated that, even though SPE B is a cysteine proteinase, KS might have an inhibitory effect on SPE B.…”

The Transcriptional Regulator CpsY Is Important for Innate Immune Evasion in Streptococcus pyogenes

“…Most relevant to immune cell resistance was the induced set of known virulence factors of GAS (i.e., speB, spd, nga [spn], prtS [SpyCEP], and sse). Expression of the SpeB cysteine protease promotes colonization and aids in immune cell evasion (44)(45)(46), whereas downregulation of SpeB expression is linked to neutrophil-dependent selection of invasive GAS strains (47)(48)(49). Streptococcal nucleases like the one encoded by spd enhance GAS evasion of the innate immune response (50) by degrading neutrophil extracellular traps (NETs) (51).…”

The Wide World of Ribosomally Encoded Bacterial Peptides

“…Interestingly, several microbial peptide toxins have also been shown to have synergistic activity with other bacterial virulence factors, suggesting that, in fact, these bacterial peptides may serve the dual role of causing direct damage to the host while also increasing the overall virulence output. For example, Hung et al utilized a murine infection model to demonstrate that the peptide toxin SLS synergizes with the unrelated streptococcal pyrogenic exotoxin B (SpeB) during infection to enhance several features of pathogenesis, including inhibition of phagocytic clearance and the induction of macrophage apoptosis [16]. In commensal bacteria such as Lactobacillus plantarum , it has been shown that production of antimicrobial bacteriocins can modulate the immune response of dendritic and peripheral blood mononuclear cells as well as alter host cytokine profiles versus nonbacteriocin producing mutants [17].…”