Innate Defense against Influenza A Virus: Activity of Human Neutrophil Defensins and Interactions of Defensins with Surfactant Protein D

Abstract

Surfactant protein D (SP-D) plays important roles in innate host defense against influenza A virus (IAV) infection, in part by modifying interactions with neutrophils. Human neutrophil defensins (HNPs) inhibit infectivity of enveloped viruses, including IAV. Our goal in this study was to characterize antiviral interactions between SP-D and HNPs. Recombinant and/or natural forms of SP-D and related collectins and HNPs were tested for antiviral activity against two different strains of IAV. HNPs 1 and 2 did not inhibit viral hemagglutination activity, but they interfered with the hemagglutination-inhibiting activity of SP-D. HNPs had significant viral neutralizing activity against divergent IAV strains. However, the HNPs generally had competitive effects when combined with SP-D in assays using an SP-D-sensitive IAV strain. In contrast, cooperative antiviral effects were noted in some instances when relatively SP-D-resistant strains were treated with SP-D and HNPs. HNPs were found to bind to the neck and/or carbohydrate recognition domain of SP-D. This binding was specific because no, or minimal, binding to other collectins was found. HNPs precipitated SP-D from bronchoalveolar lavage fluid and reduced the antiviral activity of bronchoalveolar lavage fluid. HNP-1 and -2 differed somewhat in their independent antiviral activity and their binding to SP-D. These results are relevant to the early phase of host defense against IAV, and suggest a complex interplay between SP-D and HNPs at sites of active inflammation.

Human Neutrophil Defensins Increase Neutrophil Uptake of Influenza A Virus and Bacteria and Modify Virus-Induced Respiratory Burst Responses

“…SP-D also protects neutrophils against IAV-induced neutrophil dysfunction (20,21). We have recently shown that HNPs bind to SP-D and significantly modify its interactions with IAV (27). In this study, we show that HNPs promote IAV and bacterial uptake by neutrophils and modify neutrophil respiratory burst responses to IAV.…”

“…Of interest, it has been reported that HNPs suppress the oxidative metabolism of neutrophils and reduce their ability to kill S. aureus (34). We have found that HNPs bind to SP-D, which could account in part for the ability of HNPs to counteract the SP-D-induced increase in respiratory burst responses to IAV (27). We have found that several other components of respiratory fluids including surfactant protein A, mucins, and scavenger receptor-rich gp340 counteract the ability of SP-D to increase IAV-induced H 2 O 2 responses and have shown that BALF per se does not increase H 2 O 2 responses to IAV (26).…”

Neutrophils Ameliorate Lung Injury and the Development of Severe Disease during Influenza Infection

“…Neutrophils themselves have been reported as both nonpermissive (6) and susceptible to influenza virus infection (71,72) and to respond to virus exposure via TLR7-and/or TLR8-mediated production of proinflammatory cytokines (71). Neutrophil granules, including azurophil/primary, secondary, and secretory granules, contain an array of molecules with potential for antiviral activity, including ␣ and ␤ defensins and pentraxins, which have been shown to exert antiviral activities against a range of viruses, including influenza (73)(74)(75).…”

Interactions of α-, β-, and θ-Defensins with Influenza A Virus and Surfactant Protein D

“…HNPs can inhibit influenza viral replication with treatment before and after infection (7,8). Human ␤-defensins (HBDs) are of considerable interest with respect to respiratory viral infection.…”