Myeloid cells are tunable by a polyanionic polysaccharide derivative and co-determine host rescue from lethal virus infection

Abstract

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.

Intradermal air pouch leukocytosis as an in vivo test for nanoparticles

“…As alternative to the air pouch test, we also used intraperitoneal injection. 43 Because the peritoneal cavity is a larger space, dilution of samples occurs and, in addition, sample retrieval is more variable and demands better skills. The air pouch test can be executed by any well-trained scientist and, in principle, does not need sophisticated equipment.…”

Interference with Glycosaminoglycan-Chemokine Interactions with a Probe to Alter Leukocyte Recruitment and Inflammation In Vivo

“…Because many heparan sulphate preparations are heterogeneous and may vary from batch to batch, we used a heparan sulphate preparation with similar molecular characteristics as COAM, as detailed previously [18]. In addition, previously we also compared COAM with other glycosaminoglycans, including chondroitin sulphate and heparan sulphate preparations for binding to GCP-2/CXCL6 and demonstrated higher affinities for COAM than for both glycosaminoglycans [16]. Recombinant mouse chemokines were obtained from Peprotech (Londen, UK).…”

“…Recently, we have described a polyanionic polysaccharide derivative, designated COAM (for chlorite-oxidized oxyamylose), as an immunomodulator with antiviral activity [15], [16]. When injected intraperitoneally (i.p.…”

“…When injected intraperitoneally (i.p. ), COAM induces the recruitment of neutrophils and macrophages that are in part essential to control viral burden and mortality upon acute infection with a neurotropic virus [16]. This effect of COAM, mediated by binding of GCP-2/CXCL6, illustrates that neutrophils contribute to antiviral resistance by the host, and can be further exploited to combat acute neuroinflammation [17], and cancer [18].…”

“…In fact, COAM possesses higher affinities to mouse GCP-2/CXCL6 than heparan sulphate and chondroitin sulphate [16]. This fact incites systematic investigations about local and general effects of COAM on leukocytes.…”