Pentraxin 3 protects from MCMV infection and reactivation through TLR sensing pathways leading to IRF3 activation.
Reactivation of latent human cytomegalovirus (HCMV) following allogeneic transplantation is a major cause of morbidity and mortality and predisposes to severe complications, including superinfection by Aspergillus species (spp). Antimicrobial polypeptides, including defensins and mannan-binding lectin, are known to block viral fusion by cross-linking sugars on cell surface. Pentraxin 3 (PTX3), a member of the long pentraxin family, successfully restored antifungal immunity in experimental hematopoietic transplantation. We assessed here whether PTX3 binds HCMV and murine virus (MCMV) and the impact on viral infectivity and superinfection in vivo. We found that PTX3 bound both viruses, reduced viral entry and infectivity in vitro, and protected from MCMV primary infection and reactivation as well as Aspergillus superinfection. This occurred through the activation of interferon (IFN) regulatory factor 3 (IRF3) in dendritic cells via the TLR9/MyD88-independent viral recognition sensing and the promotion of the interleukin-12 (IL-12)/IFN-gamma-dependent effector pathway.
Bozza
Silvia
S
Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, 06122 Perugia, Italy.
Bistoni
Francesco
F
Gaziano
Roberta
R
Pitzurra
Lucia
L
Zelante
Teresa
T
Bonifazi
Pierluigi
P
Perruccio
Katia
K
Bellocchio
Silvia
S
Neri
Mariella
M
Iorio
Anna Maria
AM
Salvatori
Giovanni
G
De Santis
Rita
R
Calvitti
Mario
M
Doni
Andrea
A
Garlanda
Cecilia
C
Mantovani
Alberto
A
Romani
Luigina
L
D000818:Animals; D002097:C-Reactive Protein / Q000276:immunology / Q000502:physiology*; D003587:Cytomegalovirus / Q000378:metabolism / Q000472:pathogenicity; D003713:Dendritic Cells; D006566:Herpesviridae Infections; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D007371:Interferon-gamma; D018664:Interleukin-12; D051379:Mice; D018345:Mice, Knockout; D018146:Muromegalovirus / Q000378:metabolism / Q000472:pathogenicity*; D053594:Myeloid Differentiation Factor 88; D009419:Nerve Tissue Proteins / Q000276:immunology / Q000502:physiology*; D000683:Serum Amyloid P-Component / Q000276:immunology / Q000502:physiology; D015398:Signal Transduction; D051217:Toll-Like Receptor 9 / Q000378:metabolism*; D014775:Virus Activation; D000099153:Pentraxins
D002097:C-Reactive Protein; D050838:Interferon Regulatory Factor-3; D007371:Interferon-gamma; D018664:Interleukin-12; D053594:Myeloid Differentiation Factor 88; D009419:Nerve Tissue Proteins; D000683:Serum Amyloid P-Component; D051217:Toll-Like Receptor 9; D000099153:Pentraxins; C494233:Irf3 protein, mouse; C507780:Myd88 protein, mouse