Innate immune activation as a broad-spectrum biodefense strategy: prospects and research challenges

Abstract

Biodefense strategies require protection against a broad and largely unforeseen spectrum of pathogens--the forte of innate immune system defenses--that have evolved over millennia to function within moments of encountering either ancient or newly emerging pathogens. Although constitutive, the innate immune system is activated by the presence of microbes or their products, providing a rationale for a potential biodefense strategy. Both prophylactic and postexposure strategies involving innate immune stimulation have been shown to be plausible to prevent or ameliorate infections in animal models. Innate immune-activating compounds based on conserved microbial components recognized by toll-like molecules and other receptors could be synthesized and delivered like drugs by using an entirely different strategy from conventional vaccination. However, important theoretic and practical questions emerge about developing and deploying innate immune protective strategies for biodefense. This rostrum discusses prospects and problems in the overall approach itself. Important topics include microbe-specific issues about innate immune system effectiveness against highly virulent pathogens and general questions, such as whether innate immune responses will be safe and effective if used in a diverse human population of different age groups and with different genetic makeups.

FIG 1

Comparison of proposed innate immune stimulation strategies with conventional vaccination. Vaccination uses whole pathogens or their subunits to expand antigen-specific B and T cells, leading to the development of specific and highly effective long-term protection over several weeks. Innate immune stimulants will likely be chemically synthesized compounds, possibly delivered by means of aerosol, that activate dendritic cells, macrophages, and other cells in a nonclonal manner aimed to provide rapid, broad, but impermanent protection against many potential pathogens.