Oral Presentation Lorne Infection and Immunity 2013

Probing the Host-Pathogen Interface for New Therapeutic Targets (#1)

Victor Nizet 1
  1. UCSD School of Medicine, , United States

Certain human bacterial pathogens such as Staphylococcus aureus (SA) and group A Streptococcus (GAS) are capable of producing a wide range of mucosal and invasive infections even in previously healthy individuals. The production of serious disease by each agent reflects their multifaceted abilities to resist clearance by the phagocytic cells of the human innate immune system, which themselves deploy a diverse arsenal of intracellular and extracellular bacterial killing mechanisms.  Specific examples include SA pigment-based resistance to phagocyte oxidative burst or GAS escape from DNA-based phagocyte extracellular traps and release of pore-forming hemolytic toxins.  Understanding the molecular basis of such phagocyte resistance reveals novel therapeutic targets for treatment or prevention of invasive bacterial infection.  Here, instead of directly killing the pathogen, these approaches block disease progression by neutralizing specific virulence factors to allow host innate immune clearance.  A second novel therapeutic concept derives from recent advances in our understanding of the transcriptional regulation of phagocyte function.  Genetic studies indicate that the transcriptional regulator hypoxia-inducible factor (HIF) is a critical regulator of phagocyte bactericidal activities at the site of infection.  HIF stabilization can be achieved pharmacologically to enhance innate immunity against difficult bacterial infections, such as those complicated by resistance to traditional antibiotics.