Myeloid cells are tunable by a polyanionic polysaccharide derivative and co-determine host rescue from lethal virus infection.
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.
Li
Sandra
S
Rega Institute for Medical Research, Department of Microbiology and Immunology, University of Leuven, Minderbroedersstraat 10, Leuven, Belgium.
Starckx
Sofie
S
Martens
Erik
E
Dillen
Chris
C
Lamerant-Fayel
Nathalie
N
Berghmans
Nele
N
Gouwy
Mieke
M
van Pel
Melissa
M
Heremans
Hubertine
H
Kieda
Claudine
C
Fibbe
Willem E
WE
Billiau
Alfons
A
Van Damme
Jo
J
Opdenakker
Ghislain
G
D000688:Amylose / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use; D018188:Cardiovirus Infections / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology; D016207:Cytokines / Q000235:genetics; D006801:Humans; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology; D008574:Mengovirus; D051379:Mice; D022423:Myeloid Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D011134:Polysaccharides / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D014765:Viral Vaccines; D014777:Virus Diseases / Q000276:immunology* / Q000401:mortality
D000998:Antiviral Agents; D016207:Cytokines; D011134:Polysaccharides; D012333:RNA, Messenger; D014765:Viral Vaccines; C002668:oxyamylose; D000688:Amylose