Genetic immune modulation of Ran GTPase against different microbial pathogens.

Septic shock characterized by pro-inflammatory cytokine storm can be induced by a variety of microbial infections. Typical pro-inflammatory cytokines include TNFalpha, IL1 and IL6. Although one or more of them is often expressed in any given microbial infection, usually it is the elevation of one cytokine that becomes predominant at a particular time in a given infection. Here we showed that administration of adenoviral antigens alone led to a predominant elevation of serum IL6 but not TNFalpha Administration of endotoxin together with adenoviral antigens led to elevation of both serum IL6 and TNFalpha. In vivo expression of RanC/d, but not RanT/n or LacZ into peritoneal macrophages rapidly down-modulated the levels of these cytokines in both experimental situations. It also correlated with reduced liver inflammatory damage and increased resistance to septic shock. We conclude that RanC/d can be applied to down-modulating production of cytokines induced by microbial products other than endotoxin and to render resistance to mice against septic shock induced by one or more microbial pathogens. The ability of using RanC/d to down-modulate and RanT/n to up regulate host innate immune response induced by multiple microbial pathogens is illustrated in this study. Incorporation of either or both RanC/d and RanT/n alleles into appropriate vectors will produce genetics vaccines valuable for biodefense and medically important illness in which host immune system against invading agents is severely burdened.