ZmpB, a Novel Virulence Factor ofStreptococcus pneumoniaeThat Induces Tumor Necrosis Factor Alpha Production in the Respiratory Tract

Abstract
Inflammation is a prominent feature ofStreptococcus pneumoniaeinfection in both humans and animal models. Indeed, an intense host immune response to infection is thought to contribute significantly to the pathology of pneumococcal pneumonia and meningitis. Previously, induction of the inflammatory response following infection withS. pneumoniaehas been attributed to certain cell wall constituents and the toxin pneumolysin. Here we present data implicating a putative zinc metalloprotease, ZmpB, as having a role in inflammation. Null mutations were created in thezmpBgene of the virulent serotype 2 strain D39 and analyzed in a murine model of infection. Isogenic mutants were attenuated in pneumonia and septicemia models of infection, as determined by levels of bacteremia and murine survival. Mutants were not attenuated in colonization of murine airways or lung tissue. Examination of cytokine profiles within the lung tissue revealed significantly lower levels of the proinflammatory cytokine tumor necrosis factor alpha following challenge with theΔzmpBmutant (Δ739). These data identify ZmpB as a novel virulence factor capable of inducing inflammation in the lower respiratory tract. The possibility that ZmpB was involved in inhibition of complement activity was examined, but the data indicated that ZmpB does not have a significant effect on this important host defense. The regulation of ZmpB by a two-component system (TCS09) located immediately upstream of thezmpBgene was examined. TCS09 was not required for the expression ofzmpBduring exponential growth in vitro.