A lectin-carbohydrate recognition event without enzymatic function is proposed as molecular basis for an important innate immune response to enveloped viruses. It involves the hemagglutinin-neuraminidase (HN) glycoprotein of Newcastle disease virus (NDV) and sialic acid expressing cellular receptors on human natural interferon (IFN) α producing cells. This conclusion is based on two types of experimental evidence: (a) strong UV irradiation of NDV, which destroyed the cell binding and hemadsorption (HAd) but not the neuraminidase (NA) activity of HN, also destroyed its IFN-α inducing activity; (b) DNA transfectants expressing HN mutant molecules with greatly reduced NA but not HAd activity induced IFN-α while transfectants expressing HN mutant molecules with greatly reduced NA and HAd activity were incapabable of inducing IFN-α in human peripheral blood mononuclear cells. The results clarify molecular mechanisms involved in pattern recognition during innate immune responses.