The essentiality of α‐2‐macroglobulin in human salivary innate immunity against new H1N1 swine origin influenza A virus

Abstract

A novel strain of influenza A H1N1 emerged in the spring of 2009 and has spread rapidly throughout the world. Although vaccines have recently been developed that are expected to be protective, their availability was delayed until well into the influenza season. Although anti‐influenza drugs such as neuraminidase inhibitors can be effective, resistance to these drugs has already been reported. Although human saliva was known to inhibit viral infection and may thus prevent viral transmission, the components responsible for this activity on influenza virus, in particular, influenza A swine origin influenza A virus (S‐OIV), have not yet been defined. By using a proteomic approach in conjunction with beads that bind α‐2,6‐sialylated glycoprotein, we determined that an α‐2‐macroglobulin (A2M) and an A2M‐like protein are essential components in salivary innate immunity against hemagglutination mediated by a clinical isolate of S‐OIV (San Diego/01/09 S‐OIV). A model of an A2M‐based “double‐edged sword” on competition of α‐2,6‐sialylated glycoprotein receptors and inactivation of host proteases is proposed. We emphasize that endogenous A2M in human innate immunity functions as a natural inhibitor against S‐OIV.

2009 pandemic H1N1 influenza virus elicits similar clinical course but differential host transcriptional response in mouse, macaque, and swine infection models

“…Closer inspection of each species inflammatory response DE gene set showed noteworthy representation of GR Signaling related genes, such as A2M, FGG, HSPA5, IL4, and MAPK13 genes in mice, FKBP4, JAK1, NCOA2 (also known as GRIP-1), and NRAS genes in macaques, and HSPA4 (also known as HSP70) in addition to JAK3, and STAT5A genes in swine. Alpha-2-macroglobulin (A2M) identified by mass spectrometry in human saliva was found to exhibit antiviral activity against pH1N1 virus [24]. …”

Nasal commensal Staphylococcus epidermidis counteracts influenza virus

“…The antiviral activity of the eluted proteins (100 μl) in each fraction was tested with an HI test using A/San Diego/1/09(H1N1 pdm09). The eluted proteins in fraction 12 with the most potent inhibition of virus-induced haemagglutination were digested with trypsin and subjected to Nano-LC-LTQ MS/MS analysis (Thermo Scientific, San Jose, CA)47. The automated Nano-LC-LTQ MS/MS setup consisted of an Eksigent Nano 2D LC system, a switch valve, a C18 trap column (Agilent, Santa Clara, CA), and a capillary reversed-phase column (10 cm in length, 75 mm internal diameter) packed with 5 mm, C18 AQUASIL resin with an integral spray tip (Picofrit, 15 mm tip, New Objective, Woburn, MA).…”

“…*** P  < 0.001 (one-way ANOVA followed by Dunnett’s multiple comparison test). ( c ) RPMI-2650 cells (10 7 cells) were incubated with the NS1-GFP virus (MOI = 1) in the presence of TSB medium or culture supernatant of S. epidermidis 1585, 1585 v or M135 overnight in virus growth medium47. The replication of NS1-GFP-virus (arrows) and fluorescence were viewed with a Leica TCS SP2 confocal microscope.…”

Contribution of murine innate serum inhibitors toward interference within influenza virus immune assays

“…When the H2N2 viruses, and subsequently H3N2 viruses, emerged the dominant serum inhibitors were resistant to 56°C, but sensitive to neuraminidase (RDE) [31]. It is worth noting that influenza viruses isolated during the H1N1 pandemic of 2009–10 do not interact with the influenza virus β class inhibitor, mannose- binding lectin [32], and that human A2-M inhibits hemagglutination by these H1N1 viruses [33]. These historical and recent findings support a re-evaluation of the contribution of innate serum inhibitors from all three classes toward influenza virus immunity in humans.…”