Thinking Globally, Acting Locally: Harnessing the Immune System to Deal with Recalcitrant Pathogens

ABSTRACT Traditional approaches to harnessing the immune system to confront infectious diseases depend on vaccines, which have generally proven highly effective, but for many infections these either are not available or are of limited effectiveness. Al-though antibiotic therapy has been extremely successful in reducing the burden of bacterial disease, the emergence of resistance among several important pathogens threatens to undermine this accomplishment, and despite some successes chemotherapeutic treatments for viral, fungal, and parasitic infections are more limited. Understanding the mechanisms whereby pathogens ma-nipulate the immune system to favor their survival, or exploit weaknesses in host immunity, can lead to novel approaches for the treatment of infections by redirecting host immune responses against the pathogen. Such treatments may be most effectively applied at the mucosal locations which are frequently the sites of initial infection andmay also suggest new approaches for vac-cine development. For the past ~70 years, bacterial infections have been treatedlargely bymeans of antibiotics, generally with spectacular suc-cess, and as a result, at least in affluent countries, the threat of infectious disease has been dramatically diminished. However, as theWorld Health Organization, the U.S Centers for Disease Con-trol and Prevention (CDC), and the U.S. National Institutes of Health are now warning, the emergence of multiple-antibiotic