Pentraxin 3 protects from MCMV infection and reactivation through TLR sensing pathways leading to IRF3 activation

Abstract

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 IntroductionHuman cytomegalovirus (HCMV), a member of the Herpesviridae family, is a ubiquitous opportunistic pathogen that has an intimate lifelong relationship with its human host and establishes latency after clearance of primary infection. 1-3 Reactivation of latent virus following allogeneic transplantation immune responses results in progressive tissue damage manifesting as overt HCMV disease or complications of this infection, including acute and chronic graft rejection, graft-versus-host disease, and superinfection by other viruses, bacteria, and fungi, particularly Aspergillus species (spp). 3 Efforts have focused on the development of adoptive immunotherapeutic strategies to hasten host immune reconstruction, and cellular immunotherapy appears to be an attractive approach. 4,5 The immune control of murine CMV (MCMV) infection requires elements from both innate and adaptive immune systems. [6][7][8] Through the participation of members of the Toll-like receptors (TLRs) 9-11 and interferon (IFN) regulatory factor 3 (IRF) families, IRF3 in particular, 12,13 MCMV induces early dendritic cell (DC)-dependent type I IFN and interleukin-12 (IL-12) responses essential for mouse resistance to MCMV. 10,11,[14][15][16] The TLR9/ MyD88 signaling pathway mediates antiviral cytokine responses by plasmacytoid DCs (pDCs) that, through their unique capacity to secrete IFN-␣, and to a lesser extent IL-12 and other innate cytokines, are a cornerstone in the initiation of both innate and adaptive immune responses to MCMV. [15][16][17][18][19] However, conventional CD11b ϩ DCs also produce IFN-␣ independently of TLR9 and MyD88. 10,20 In addition to directly interfering with viral replication through ubiquitous cellular mechanisms, IFN-␣ controls natural killer (NK) cell cytotoxic activity 15 and regulates T-cell functions by activating classical DCs to more efficiently present antigens (Ags). 15 IL-12 and IL-18 secretion are instead required to prime a strong NK cell-dependent IFN-␥ response, 17,21,22 a process that is essential to counteract MCMV infection in the liver, in contrast to a perforin-dependent mechanism in the spleen. 23 Pentraxin 3 (PTX3) is a member of a superfamily of conserved proteins characterized by a cyclic mul...

Cutting Edge: Overlapping Functions of TLR7 and TLR9 for Innate Defense against a Herpesvirus Infection

“…In pDCs infected with vesicular stomatitis virus, it has been recently demonstrated that viral cytosolic RNAs could access TLR7 in the endosomes due to the constitutive autophagic activity that occurs in this cell type (23). This mechanism can be excluded in our model, because pDCs are not infected with MCMV (6,24) and in vitro activation of pDCs by the virus is strictly dependent on TLR9 for both IL-12p70 and IFN-␣/␤ production (8). We thus hypothesize that pDCs have the capacity to recognize and engulf apoptotic debris specifically from infected cells that contain viral or cellular mRNAs, which would then be delivered to endosomes for TLR7 triggering and subsequent induction of IFN-␣/␤ and TNF-␣.…”

HDL in Infectious Diseases and Sepsis

“…Similarly to short pentraxins, PTX3 recognizes the highly conserved pathogen-associated molecular patterns (PAMPs) expressed by microorganisms (Iwasaki and Medzhitov 2010) and binds a number of bacteria, fungi, and viruses. A specific binding has been observed to conidia of Aspergillus fumigatus (Garlanda et al 2002), Paracoccidioides brasiliensis, and zymosan (Diniz et al 2004), to selected Gram-positive and Gram-negative bacteria (Bozza et al 2006;Garlanda et al 2002;Jeannin et al 2005), and finally to some viral strains, including human and murine cytomegalovirus and influenza virus type A (IVA) (Bozza et al 2006;Reading et al 2008). Both short pentraxin and PTX3 bind apoptotic cells and facilitate their clearance (Doni et al 2012;Jaillon et al 2009).…”

Antiviral Activity of the Long Chain Pentraxin PTX3 against Influenza Viruses

“…Despite a well documented role in innate host defense against certain bacteria and fungi (17)(18)(19)(20), few studies have addressed the antiviral activities of PTX3. To this end, a recent study described the ability of human PTX3 to bind and inhibit the infectivity of human and murine cytomegaloviruses (21). Furthermore, the short pentraxin SAP has been shown to act as a ␤ inhibitor against influenza viruses, binding in a Ca 2ϩ -dependent manner to mannose-rich glycans on the viral HA to inhibit both hemagglutination and viral infectivity (22,23).…”