Peroxynitrite contributes to the candidacidal activity of nitric oxide-producing macrophages

Abstract

Nitric oxide (NO) is associated with functions as diverse as peristalsis, blood flow, neuroendosecretion, visual transduction, smooth muscle relaxation, and microbial killing (H. H. W. H. Schmidt and V. Walter, Cell 78:919-925, 1994). Despite the well-established role of NO in macrophage candidacidal activity (E. Cenci, L. Romani, A. Mancacci, R. Spaccapelo, E. Schiaffella, P. Puccetti, and F. Bistoni, Eur. J. Immunol. 23:1034-1038, 1993; J. Jones-Carson, A. Vazquez-Torres, H. Van der Heide, R. D. Wagner, T. Warner, and E. Balish, Nature Med. 1:552-557, 1995; and A. Vazquez-Torres, J. Jones-Carson, T. Warner, and E. Balish, J. Infect. Dis. 172:192-198, 1995), NO is not directly candidacidal for Candida albicans (A. Vazquez-Torres, J. Jones-Carson, and E. Balish, Infect. Immun. 63:1142-1144, 1995). Because macrophages can produce both NO and superoxide anion (02-), we postulated that peroxynitrite (ONOO-), a product of the dilution-limited reaction of NO and O2-, is the candidacidal molecule of activated macrophages. We now report that ONOO-, in addition to being candidacidal in vitro, is responsible for the candidacidal activity of NO-producing macrophages. ONOO- synthesis by NO-producing macrophages was triggered by two independent mechanisms: one was nonopsonic and dependent on fungal cell wall glucan moieties, and the other was dependent on opsonic antibodies. As we have demonstrated for the pathogenic fungus C. albicans, ONOO- may also be the molecule that enables macrophages to kill other microbes that are resistant to both O2- and NO.