The Role and Molecular Mechanism of Action of Surfactant Protein D in Innate Host Defense Against Influenza A Virus

Abstract

Influenza A viruses (IAVs) continue to pose major risks of morbidity and mortality during yearly epidemics and periodic pandemics. The genomic instability of IAV allows it to evade adaptive immune responses developed during prior infection. Of particular concern are pandemics which result from wholesale incorporation of viral genome sections from animal sources. These pandemic strains are radically different from circulating human strains and pose great risk for the human population. For these reasons, innate immunity plays a strong role in the initial containment of IAV infection. Soluble inhibitors present in respiratory lining fluids and blood provide a level of early protection against IAV. In general, these inhibitors act by binding to the viral hemagglutinin (HA). Surfactant protein D (SP-D) and mannose-binding lectin (MBL) attach to mannosylated glycans on the HA in a calcium dependent manner. In contrast, surfactant protein A, ficolins, and other inhibitors present sialic acid rich ligands to which the HA can bind. Among these inhibitors, SP-D seems to be the most potent due to its specific mode of binding to viral carbohydrates and its ability to strongly aggregate viral particles. We have studied specific properties of the N-terminal and collagen domain of SP-D that enable formation of highly multimerized molecules and cooperative binding among the multiple trimeric lectin domains in the protein. In addition, we have studied in depth the lectin activity of SP-D through expression of isolated lectin domains and targeted mutations of the SP-D lectin binding site. Through modifying specific residues around the saccharide binding pocket, antiviral activity of isolated lectin domains of SP-D can be markedly increased for seasonal strains of IAV. Wild-type SP-D causes little inhibition of pandemic IAV, but mutated versions of SP-D were able to inhibit pandemic IAV through enhanced binding to the reduced number of mannosylated glycans present on the HA of these strains. Through collaborative studies involving crystallography of isolated lectin domains of SP-D, glycomics analysis of the HA, and molecular modeling, the mechanism of binding of wild type and mutant forms of SP-D have been determined. These studies could guide investigation of the interactions of SP-D with other pathogens.

Measuring site-specific glycosylation similarity between influenza A virus variants with statistical certainty

“…We observed that 144-NSSF and 246-NSTG had high glycosylation similarity, which suggests that these sites may be contributing to the architectural stability of the receptor-binding site, while 165-NVTM, which showed low glycosylation similarity between our two strains, may be exposed to antibody pressure. 165-NVTM has also been shown to bind to surfactant protein D, a collectin molecule that is part of the innate immune system (24,44). Exposure to innate immune pressure may also be driving glycosylation variation at this site.…”

Staphylococcus aureus Lung Infection Results in Down-Regulation of Surfactant Protein-A Mainly Caused by Pro-Inflammatory Macrophages

“…The direct effect of extracellular S. aureus proteases impairs the bacterial clearance and results in enhanced adherence and invasion of S. aureus to epithelial cells [21]. Additionally, surfactant proteins affect IAV infection [12]. However, an interfering effect of IAV infection on SP-A has not been described.…”

“…During the IAV invasion into the lung, the viral hemagglutinin binds to sialic acid residues on the surface of epithelial cells to initiate viral internalization [11]. Surfactant protein-A (SP-A) also presents sialic acid residues to bind IAV [12]. The agglutination of SP-A reduces the infectivity and dissemination of the virus and supports its clearance by immune cells [9].…”

The Importance of Vaccinating Children and Pregnant Women against Influenza Virus Infection

“…Binding and/or internalization of the virus to cells of the epithelium leads to intracellular signaling that alters ion transport, contributing to symptoms of infection [49]. Antiviral responses are initiated, including the release of antimicrobial peptides such as surfactants, mucins, LL-37 and β-defensins, which decrease viral binding to epithelial cells and promote recruitment of innate immune cells such as neutrophils [47,50,51]. Surfactant proteins are capable of binding to virus, which helps to limit infectivity and disease severity [52][53][54][55].…”