Editors' ChoiceInnate Immunity

Creating a Barrier to Infection

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Science's STKE  04 Oct 2005:
Vol. 2005, Issue 304, pp. tw348
DOI: 10.1126/stke.3042005tw348

Defensins, antimicrobial peptides expressed by leukocytes and epithelial cells, function as part of the innate immune system; the θ-defensins are found in Old World monkeys but not in humans. Retrocyclin 2 (RC2), a synthetic θ-defensin based on a human pseudogene, inhibits human immunodeficiency virus (HIV) infection (see Phillips). Many viruses, including HIV and human influenza virus, infect cells by binding through viral envelope glycoproteins to cell membrane receptors and then fusing the viral membrane envelope with the cell membrane. Leikina et al. found that RC2 inhibited influenza virus infection when added to virus-bound Madin-Darby canine kidney (MDCK) cells during or before viral internalization. Experiments with fluorescently labeled virus, or involving red cell binding to cells expressing the influenza virus coat protein hemagglutinin (HA), and experiments visualizing clathrin-mediated endocytosis, indicated that RC2 inhibited neither influenza virus binding nor endocytosis. Rather, RC2 inhibited membrane fusion. RC2 also inhibited influenza virus fusion with and infection of a human pulmonary mucoepidermoid carcinoma cell line and primary bronchial epithelial cells, as well as fusion mediated by baculovirus gp64 and Sindbis virus E1. RC2 inhibited fusion when applied only to the target membrane, and its inhibition of fusion was abolished by cell surface deglycosylation. Fluorescence recovery after photobleaching (FRAP) analysis indicated that RC2, a lectin capable of binding up to five carbohydrate moieties, crosslinked and immobilized membrane glycoproteins. Mannin-binding lectin and human β-defensin 3 also immobilized membrane proteins and inhibited fusion. Thus, the authors proposed that RC2 and other lectin-like defense molecules immobilize cell surface glycoproteins, preventing protein displacement and thereby creating a barrier to membrane fusion.

E. Leikina, H. Delanoe-Ayari, K. Melikov, M.-S. Cho, A. Chen, A. J. Waring, W. Wang, Y. Xie, J. A. Loo, R. I. Lehrer, L. V. Chernomordik, Carbohydrate-binding molecules inhibit viral fusion and entry by crosslinking membrane glycoproteins. Nat. Immunol. 6, 995-1001 (2005). [PubMed]

R. Phillips, Back to the past: New drugs from ancient molecules? Nat. Immunol. 6, 963-964 (2005). [PubMed]

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