Modulation of hypoxia-inducible factor-1 expression by leading gram-positive bacterial pathogens

Group A Streptococcus (GAS) and Staphylococcus aureus are two leading human bacterial pathogens responsible for a wide spectrum of mucosal and skin infections. The host innate immune system, which includes phagocytes and epithelial cells, is a critical first line of host defense against such invading microorganisms. The transcription factor hypoxia-inducible factor-1 (HIF-1) is a master regulator of many bactericidal and inflammatory activities in phagocytes and skin epithelial cells (keratinocytes), as demonstrated by infection studies using different bacterial species. However, the specific bacterial factors recognized by host cells for the modulation of HIF-1 activation are poorly understood. Such factors may contribute to the pathogenicity of GAS and S. aureus by interfering with normal HIF-1 expression. To identify these bacterial components, we have developed a luciferase-based reporter assay in keratinocytes and monocytes with which to screen a panel of GAS and S. aureus mutants against the wild-type parental strains for differences in HIF-1 activation. We have identified several putative bacterial gene products that influence HIF-1 levels. We are currently using infection models on different in vitro and in vivo HIF-1 knockout systems to probe the functional consequences of the modulations in HIF-1 expression on the host innate immune response and infection outcome. Given that GAS and S. aureus can produce severe infections, even in previously healthy individuals, these findings may contribute to our understanding of the mechanisms through which the coordinated actions of multiple bacterial virulence determinants are able to resist the multifaceted constituents of the host’s innate immunity.