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Pentraxin PTX3 Against Influenza Viruses Antiviral Activity of the Long Chain

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Pentraxin PTX3 Against Influenza Viruses Antiviral Activity of the Long Chain Antiviral Activity of the Long Chain Pentraxin PTX3 against Influenza Viruses Patrick C. Reading, Silvia Bozza, Brad Gilbertson, Michelle Tate, Silvia Moretti, Emma R. Job, Erika C. Crouch, Andrew This information is current as G. Brooks, Lorena E. Brown, Barbara Bottazzi, Luigina of September 26, 2021. Romani and Alberto Mantovani J Immunol 2008; 180:3391-3398; ; doi: 10.4049/jimmunol.180.5.3391 http://www.jimmunol.org/content/180/5/3391 Downloaded from References This article cites 45 articles, 16 of which you can access for free at: http://www.jimmunol.org/content/180/5/3391.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 26, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Antiviral Activity of the Long Chain Pentraxin PTX3 against Influenza Viruses1 Patrick C. Reading,2* Silvia Bozza,† Brad Gilbertson,* Michelle Tate,* Silvia Moretti,† Emma R. Job,* Erika C. Crouch,¶ Andrew G. Brooks,* Lorena E. Brown,* Barbara Bottazzi,‡ Luigina Romani,3† and Alberto Mantovani3‡§ Proteins of the innate immune system can act as natural inhibitors of influenza virus, limiting growth and spread of the virus in the early stages of infection before the induction of adaptive immune responses. In this study, we identify the long pentraxin PTX3 as a potent innate inhibitor of influenza viruses both in vitro and in vivo. Human and murine PTX3 bound to influenza virus and mediated a range of antiviral activities, including inhibition of hemagglutination, neutralization of virus infectivity and inhibition of viral neuraminidase. Antiviral activity was associated with binding of the viral hemagglutinin glycoprotein to sialylated ligands present on PTX3. Using a mouse model we found PTX3 to be rapidly induced following influenza infection and that PTX3؊/؊ mice Downloaded from were more susceptible than wild-type mice to infection by PTX3-sensitive virus strains. Therapeutic treatment of mice with human PTX3 promoted survival and reduced viral load in the lungs following infection with PTX3-sensitive, but not PTX3-resistant, influenza viruses. Together, these studies describe a novel antiviral role for PTX3 in early host defense against influenza infections both in vitro and in vivo and describe the therapeutic potential of PTX3 in ameliorating disease during influenza infection. The Journal of Immunology, 2008, 180: 3391–3398. http://www.jimmunol.org/ nfluenza is an important annual respiratory infection that re- The antiviral activities of collectins have been well described mains a leading cause of illness and death throughout the with strong evidence to suggest that surfactant protein-D (SP-D)4 I world. In the early stages of infection, innate immune mech- is of particular importance during influenza infections. Both sur- anisms represent the main line of host defense, acting to limit virus factant protein-A (SP-A) and SP-D mediate a range of activities spread in host tissues before the induction of the adaptive response. against influenza virus, including inhibition of hemagglutination, Innate mechanisms that may contribute to defense against influ- virus neutralization, virus aggregation, and opsonizaton of the vi- enza infection include the intrinsic resistance of macrophages, the rus for interaction with neutrophils (2–8), with SP-D acting as a induction of IFN and proinflammatory cytokines and activation of more potent inhibitor than SP-A in vitro (4). Levels of SP-D re- by guest on September 26, 2021 NK cells, macrophages, and neutrophils in the airways. In addi- covered from the airways by lavage increase significantly follow- ing infection of mice with influenza virus (3, 9–11), and SP-DϪ/Ϫ tion, serum and airway fluids contain a number of innate proteins mice exhibit enhanced viral replication and illness (9, 11). capable of recognizing and inhibiting influenza viruses, including SP-AϪ/Ϫ mice also display enhanced susceptibility to influenza in- members of the collectin and pentraxin families, mucins and sal- fections in some studies (9, 10), but not others (12); however, the ivary scavenger receptor-rich glycoprotein 340 (1). Ϫ Ϫ effect is less pronounced than that observed in SP-D / mice. Of interest, the mechanisms by which SP-A and SP-D act against influenza virus are different. SP-D functions as a classic ␤ inhibitor, binding in a Ca2ϩ-dependent manner through its lectin *Department of Microbiology and Immunology, University of Melbourne, Parkville, domains to oligosaccharides on the viral hemagglutinin (HA) and † Victoria, Australia; Microbiology Section, Department of Experimental Medicine neuraminidase (NA) glycoproteins (6). As such, the degree or pat- and Biochemical Sciences, University of Perugia, Perugia and Fondazione “Istituto di Ricovero e Cura per le Biotecnologie Trapiantologiche,” Perugia; ‡Instituto Clinico tern of glycosylation is a major factor in determining the sensitiv- Humanitas, Istituto Di Ricovero e Cura a Carattere Scientifico; §State University of ity of a particular virus strain to inhibition by SP-D (3). In contrast, ¶ Milan, Milan, Italy; and Department of Pathology and Immunology, Washington 2ϩ University School of Medicine, St. Louis, MO 63110 SP-A inhibits influenza viruses via Ca -independent binding of the viral HA to terminal sialic acid expressed on the SP-A mole- Received for publication August 7, 2007. Accepted for publication December 26, 2007. cule, thereby blocking the receptor binding site on the viral HA The costs of publication of this article were defrayed in part by the payment of page such that it can no longer access cellular receptors. SP-A is there- charges. This article must therefore be hereby marked advertisement in accordance fore classified as a ␥ inhibitor, acting in a similar manner to the with 18 U.S.C. Section 1734 solely to indicate this fact. serum inhibitor ␣2-macroglobulin (13, 14). 1 This work was supported by Project Grant 400226 and a Programme Grant from The The long chain pentraxin (PTX3) is a 45-kDa protein that as- National Health and Medical Research Council of Australia, and by Research Grant RIGP/05/CR90 from Tecnogen Societa`Per Azioni Italy (to L.R.). E.C.C. was sup- sembles to form high m.w. multimers linked by interchain disul- ported by Grants HL44015 and HL29594 from the National Institutes of Health. A.M. fide bonds (15). The C-terminal domain (203 aa) of PTX3 shares was supported by Cariplo Foundation (Project Next Generation Optical Network for Broadband European Leadership), Telethon, Project Fluinnate, and Mugen from the European Commission. P.C.R. is a National Health and Medical Research Council R. D. Wright Research Fellow. 4 Abbreviations used in this paper: SP-D, surfactant protein D; SP-A, surfactant pro- 2 tein A; HA, hemagglutinin; NA, neuraminidase; CHO, Chinese hamster ovary; HAU, Address correspondence and reprint requests to Dr. Patrick C. Reading, Department hemagglutinating unit; MDCK, Madin-Darby canine kidney; BAL, bronchoalveolar of Microbiology and Immunology, University of Melbourne, Parkville 3010, Victoria, lavage; HI, hemagglutination inhibition; SA, sialic acid. Australia. E-mail address: [email protected] 3 L.R. and A.M. contributed equally to this study. Copyright © 2008 by The American Association of Immunologists, Inc. 0022-1767/08/$2.00 www.jimmunol.org 3392 ANTIVIRAL ACTIVITY OF PTX3 AGAINST INFLUENZA homology with the classic short pentraxins C-reactive protein and (both IgG1), were obtained by immunization of PTX3Ϫ/Ϫ mice (18) with SAP, whereas the N-terminal domain (178 aa) does not show any purified murine PTX3. C1q from human serum was purchased from Cal- significant homology with other known proteins. PTX3 plays a biochem. Recombinant human SP-D was expressed by CHO-K1 cells and purified by sequential maltosyl-agarose and gel filtration chromatography; complex nonredundant role in vivo, recognizing a diverse range of dodecamers were used in all experiments as verified by ultrastructural anal- pathogens, modulating complement activity by binding C1q and ysis. The rabbit anti-human SP-D Ab was prepared using purified, C-ter- facilitating pathogen recognition by macrophages and dendritic minal domains of natural SP-D as Ag (1). cells (reviewed in Ref. 16). Despite a well documented role in Detection of PTX3 or SP-D binding to influenza virus by ELISA innate host defense against certain bacteria and fungi (17–20), few studies have addressed the antiviral activities of PTX3. To this To compare the binding of PTX3 or SP-D to different influenza viruses, wells of a microtiter tray were coated with increasing concentrations of end, a recent study described the ability of human PTX3 to bind purified influenza virus in 50 ␮l of TBS (0.05 M Tris-HCl, 0.15 M NaCl and inhibit the infectivity of human and murine cytomegaloviruses (pH 7.2)), blocked for Ͼ1 h with 10 mg of BSA per ml, and washed with (21). Furthermore, the short pentraxin SAP has been shown to act TBS containing 0.05% Tween 20 (TBST). Wells were incubated for 2 h as a ␤ inhibitor against influenza viruses, binding in a Ca2ϩ-de- with 50 ␮l of biotin-labeled human PTX3 (bPTX3; 0.1 ␮g/ml) or rhSP-D (1.0 ␮g/ml) in TBS-T containing 5 mg of BSA per ml and either 20 mM pendent manner to mannose-rich glycans on the viral HA to inhibit 2ϩ CaCl2 (BSA5-TBST-Ca ) or 5 mM EDTA (BSA5-TBST-EDTA) and then both hemagglutination and viral infectivity (22, 23).
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