Streptococcal cysteine protease augments lung injury induced by products of group A streptococci

Streptococcus pyogenes infections in humans may be associated with severe clinical manifestations, including adult respiratory distress syndrome and a toxic shock-like syndrome. These observations have led to the investigation of products of group A streptococci that may contribute to increased virulence. Streptococcal pyrogenic exotoxin B is a highly conserved precursor of an extracellular cysteine protease that is secreted by S. pyogenes. We investigated the ability of this streptococcal cysteine protease (SCP) to act synergistically with either streptococcal cell wall antigen (SCW) or streptolysin-O (SLO) to augment lung injury in rats. Intratracheal administration of either SCW or SLO alone caused lung injury, as measured by pulmonary vascular leak. Bronchoalveolar lavage (BAL) fluid analysis showed that SCW induced neutrophil accumulation and appearance of interleukin-1β and tumor necrosis factor alpha. In contrast, SLO induced neither neutrophil influx nor significant cytokine elevations in BAL fluids. Intratracheal administration of SCP with either SCW or SLO resulted in synergistic augmentation of lung vascular permeability and accumulation of BAL neutrophils. The synergy was reduced when SCP was either heat inactivated or coinstilled with a peptide inhibitor of the protease. SCP in the presence of SCW resulted in a significant increase in BAL fluid tumor necrosis factor alpha content but not in immunoreactive interleukin-1β. Moreover, the copresence of SCP with SCW resulted in increased BAL fluid nitrite-nitrate levels, indicative of nitric oxide production. These data demonstrate that SCP acts synergistically with other S. pyogenes products (SCW or SLO) to increase tissue injury and provide additional evidence that SCP may function as an important virulence factor in group A streptococcal infections.