Abstract
Innate immunity is critical in the early containment of influenza A virus (IAV) infection and surfactant protein D (SP-D) plays a crucial role in innate defense against IAV in the lungs. Multivalent lectin-mediated interactions of SP-D with IAVs result in viral aggregation, reduced epithelial infection, and enhanced IAV clearance by phagocytic cells. Previous studies showed that porcine SP-D (pSP-D) exhibits distinct antiviral activity against IAV as compared to human SP-D (hSP-D), mainly due to key residues in the lectin domain of pSP-D that contribute to its profound neutralizing activity. These observations provided the basis for the design of a full-length recombinant mutant form of hSP-D, designated as “improved SP-D” (iSP-D). Inspired by pSP-D, the lectin domain of iSP-D has 5 amino acids replaced (Asp324Asn, Asp330Asn, Val251Glu, Lys287Gln, Glu289Lys) and 3 amino acids inserted (326Gly-Ser-Ser). Characterization of iSP-D revealed no major differences in protein assembly and saccharide binding selectivity as compared to hSP-D. However, hemagglutination inhibition measurements showed that iSP-D expressed strongly enhanced activity compared to hSP-D against 31 different IAV strains tested, including (pandemic) IAVs that were resistant for neutralization by hSP-D. Furthermore, iSP-D showed increased viral aggregation and enhanced protection of MDCK cells against infection by IAV. Importantly, prophylactic or therapeutic application of iSP-D decreased weight loss and reduced viral lung titers in a murine model of IAV infection using a clinical isolate of H1N1pdm09 virus. These studies demonstrate the potential of iSP-D as a novel human-based antiviral inhalation drug that may provide immediate protection against or recovery from respiratory (pandemic) IAV infections in humans.
Highlights
Influenza is an infectious respiratory disease, caused by influenza A viruses (IAVs), that affects a wide range of natural hosts including humans, pigs and birds
The inhibitory activity of porcine SP-D (pSP-D) and human surfactant protein D (SP-D) (hSP-D) was compared to that of improved SP-D” (iSP-D) by assessing the minimal concentration of SP-D required to prevent hemagglutination induced by IAV for 31 different strains (Table 2)
The innate immune response is considered crucial for containment of viral spread at early stages of infection and many previous studies, in vitro and in vivo, have shown that SP-D is known to play an important role in protection against IAV infection [4]
Summary
Influenza is an infectious respiratory disease, caused by influenza A viruses (IAVs), that affects a wide range of natural hosts including humans, pigs and birds. In particular, are susceptible to co-infection by both avian and human IAVs and as a consequence, novel reassorted IAVs can be introduced to the human population as illustrated by the swine-origin pandemic flu of 2009 [3]. During the early stages of IAV respiratory infection, the innate immune response plays a key role in limiting IAV replication and thereby spread of infection, modulating the inflammatory and adaptive responses. Distinct responses cause the differences in pathogenicity that result from infection by pandemic vs seasonal IAVs [4]. Given the important role of pigs in being susceptible for co-infection by a broad range of IAVs and since persistence of infection readily occurs in this animal species [5], studies were initiated to investigate porcine pulmonary innate responses against IAV in more detail
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