Pharmacologic augmentation of hypoxia-inducible factor-1alpha with mimosine boosts the bactericidal capacity of phagocytes.

Hypoxia-inducible factor (HIF)-1alpha is activated on exposure to bacterial pathogens and regulates the innate immune functions of phagocytes. We show here that the HIF-1alpha agonist mimosine can boost the capacity of human phagocytes and whole blood to kill the leading pathogen Staphylococcus aureus in a dose-dependent fashion and reduce the lesion size in a murine model of S. aureus skin infection. This provides the first proof of principle for a novel approach to the treatment of bacterial infection by pharmacologically augmenting the host phagocytic function.

[1]  S. Normark,et al.  Capsule and d‐alanylated lipoteichoic acids protect Streptococcus pneumoniae against neutrophil extracellular traps , 2007, Cellular microbiology.

[2]  Ramy K. Aziz,et al.  DNase Expression Allows the Pathogen Group A Streptococcus to Escape Killing in Neutrophil Extracellular Traps , 2006, Current Biology.

[3]  Erwin G. Van Meir,et al.  Hypoxia inducible factor-1: a novel target for cancer therapy , 2005, Anti-cancer drugs.

[4]  K. Garber.  New drugs target hypoxia response in tumors. , 2005, Journal of the National Cancer Institute.

[5]  V. Nizet,et al.  Staphylococcus aureus golden pigment impairs neutrophil killing and promotes virulence through its antioxidant activity , 2005, The Journal of experimental medicine.

[6]  V. Nizet,et al.  HIF-1alpha expression regulates the bactericidal capacity of phagocytes. , 2005, The Journal of clinical investigation.

[7]  H. Malech,et al.  HIF-1α: a master regulator of innate host defenses? , 2005 .

[8]  C. Print,et al.  Hypoxia-induced neutrophil survival is mediated by HIF-1α–dependent NF-κB activity , 2005, The Journal of experimental medicine.

[9]  A. Zychlinsky,et al.  Neutrophil Extracellular Traps Kill Bacteria , 2004, Science.

[10]  R. Strieter.  Mastering innate immunity , 2003, Nature Medicine.

[11]  R. Jaenisch,et al.  HIF-1α Is Essential for Myeloid Cell-Mediated Inflammation , 2003, Cell.

[12]  J. Musser,et al.  Murine model of cutaneous infection with gram-positive cocci , 1992, Infection and immunity.

[13]  J. Brock,et al.  The effect of synthetic iron chelators on bacterial growth in human serum. , 1988, FEMS microbiology immunology.