Insight into molecular and cellular mechanisms of innate immunity is critical to understand viral pathogenesis and immunopathology and might be exploited for
therapy. Whereas the molecular mechanisms of the IFN defense are well established, cellular mechanisms of
antiviral immunity are only emerging, and their pharmacological triggering remains unknown.
COAM is a
polysaccharide derivative with
antiviral activity but without comprehension about its mechanism of action. The
COAM mixture was fractionated, and prophylactic treatment of mice with
COAM polymers of high MW resulted in a conversion from 100% lethal mengovirus
infection to an overall survival rate of 93% without obvious clinical sequelae. Differential and quantitative analysis of peritoneal leukocytes demonstrated that
COAM induced a profound influx of neutrophils. Selective cell depletion experiments pointed toward neutrophils and macrophages as key effector cells in the rescue of mice from lethal mengovirus.
COAM was able to induce
mRNA and
protein expression of the mouse neutrophil
chemokine GCP-2. Binding of GCP-2 to
COAM was demonstrated in
solution and confirmed by SPR technology. Although
COAM was not chemotactic for neutrophils,
COAM-anchored muGCP-2 retained chemotactic activity for human and mouse neutrophils. In conclusion, this study established that
COAM rescued mice from acute and lethal mengovirus
infection by recruiting
antiviral leukocytes to the site of
infection, as proposed through the induction, binding, and concentration of endogenous
chemokines. These findings reinforce the role of neutrophils and macrophages as critical cells that can be manipulated toward
antiviral defense.