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Infection and Immunity, August 2007, p. 4148-4157, Vol. 75, No. 8
0019-9567/07/$08.00+0     doi:10.1128/IAI.00181-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Transcriptome Analysis of Murine Macrophages in Response to Infection with Streptococcus pyogenes Reveals an Unusual Activation Program{triangledown}

Oliver Goldmann,1 Maren von Köckritz-Blickwede,1 Claudia Höltje,1 Gursharan S. Chhatwal,2 Robert Geffers,3 and Eva Medina1*

Infection Immunology Research Group, Department of Microbial Pathogenesis, Helmholtz Center for Infection Research, Inhoffenstraße 7, 38124 Braunschweig, Germany,1 Department of Microbial Pathogenesis, Helmholtz Center for Infection Research, Inhoffenstraße 7, 38124 Braunschweig, Germany,2 Mucosal Immunity, Helmholtz Center for Infection Research, Inhoffenstraße 7, 38124 Braunschweig, Germany3

Received 2 February 2007/ Returned for modification 13 April 2007/ Accepted 15 May 2007

The complex response of murine macrophages to infection with Streptococcus pyogenes was investigated at the level of gene expression with a high-density oligomer microarray. More than 400 genes were identified as being differentially regulated. Many of the up-regulated genes encode molecules involved in the immune response and in inflammation, transcription, signaling, apoptosis, the cell cycle, electron transport, and cell adhesion. Of particular interest was the up-regulation of proinflammatory cytokines, typical of the classically activated macrophages (M1 phenotype), such as tumor necrosis factor alpha, interleukin 1 (IL-1), and IL-6, and as well as the up-regulation of anti-inflammatory mediators, such as IL-1 decoy receptor and IL-10, associated with alternative macrophage activation (M2 phenotype). Furthermore, the gene encoding inducible nitric oxide synthase (iNOS), an enzyme typically implicated in classical activation, was not induced in infected macrophages. Instead, the gene encoding arginase, a competitor for the iNOS substrate arginine involved in the alternative activation pathway, was up-regulated in S. pyogenes-infected cells. Thus, the microarray-based gene expression analysis demonstrated that S. pyogenes induces an atypical activation program in macrophages, with some but not all features of the classical or alternative activation phenotypes. The microarray data also suggested that the bactericidal activity of macrophages against S. pyogenes is mediated by phagocyte oxidase, as p47phox was up-regulated in infected cells. Indeed, the in vivo and in vitro killing of S. pyogenes was markedly diminished in the absence of functional phagocyte (p47phox–/–) but not in the absence of iNOS (iNOS–/–). An understanding of how macrophages respond to S. pyogenes at the molecular level may facilitate the development of new therapeutic paradigms.

* Corresponding author. Mailing address: Infection Immunology Research Group, Helmholtz Center for Infection Research, Inhoffenstraße 7, 38124 Braunschweig, Germany. Phone: 49 531 6181 4500. Fax: 49 531 6181 4499. E-mail: eva.medina{at}helmholtz-hzi.de

{triangledown} Published ahead of print on 25 May 2007.

Editor: D. L. Burns

Infection and Immunity, August 2007, p. 4148-4157, Vol. 75, No. 8
0019-9567/07/$08.00+0     doi:10.1128/IAI.00181-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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