The influenza HA binds to sialic acids of glycoproteins and glycolipids. However the macromolecule carrying the receptor sialoglycan is not known. In the course of this thesis several approaches were undertaken to find a cellular interaction partner. Sep-aration of membrane proteins by 2D PAGE, Western blotting and overlay assays (as in section 3.3.8) as well as precipitation using Sepharose beads led to unsatisfying re-sults and bands that could not be isolated or further investigated. The approach shown in this thesis with simple cell lysates and overlay assays is a first attempt, that gave re-producible results in form of a band at 130 kDa - at least for H9Fc. This band was only detected when Calu-3 cell lysates were overlayed with H9Fc (fig.4.28). Unfortunately it is not possible to relate this band to one in a gel as the amount of proteins in cell lysates is quite high. Blotting onto PVDF membrane might circumvent this problem.
When overlayed and stained with alkaline phosphatase conjugated antibodies a grey band appears that can be cut out and directly be used for mass spectrometry which is not possible with nitrocellulose membranes. However protocols for blotting on PVDF and colorimetric detection have to be optimized for overlay assays. The potential inter-action partner found by this method does not have to be a cell surface protein as whole cell lysates were used.
In Western blot overlay, proteins are obviously the target. But on the cell surface also sialic acid carrying glycolipids, gangliosides, are present. In a collaboration with the Institute of Hygiene at the University of Münster, the working group of Prof. Dr. Jo-hannes Müthing, our solHAs are used to investigate the interaction of the influenza HA with gangliosides from different host species like human, cattle and others.
Another application for solHAs is to test whether binding of the HA to the cell is suf-ficient to activate the Raf/Mek/ERK cascade that is important for efsuf-ficient replication (Pleschka et al. [2001]).
SolHAs are a simple but valuable tool to investigate the influence of point mutations in the HA or the consequences of removing N-glycosylation sites. In detail, amino acid changes found by Herfst et al. [2012] and Imai et al. [2012] in the H5 that conferred transmissibility in the ferret model may be inserted into a solHA and change in binding to different tissues may be analysed, without having to work with infectious virus. The role of Neu5Gc for the binding of H1_WFc will also be subject of further research in collaboration with Prof.Johannes Müthing from Münster. The H5 and H1 solHAs will also be tested in glycan array analysis to see what glycan structures are recognized by either HA and how the closely related H1 subtypes differ in this respect. Glycan array studies with membrane bound HA, soluble HAs produced e.g. in insect cells or of full virus can be found in increasing number in the literature (Bateman et al. [2010], Stevens et al. [2006], Liao et al. [2010], Song et al. [2011] to name a few) and also with strains used in this work. It will be interesting to see how different solHA and virus binding is in this test. Therefore, the H9N2 strain and the H7N7 strain used for the virus binding test will be analysed by the same glycan array.
The affinity of H7Fc and H9Fc toα2,8- andα2,9-linked sialic acids observed in the gly-can array is also quite interesting and will be subject to further investigations. Binding of influenza HAs to α2,8-linked sialic acids has already been reported for H1 subtypes (Wu & Air [2004], Stevens et al. [2006]) but even in this publications these findings have not been subject to further investigations.
As mentioned before, including avian lung sections and human sections in the bind-ing studies will also help to understand receptor specificity and HA bindbind-ing in different hosts. Last but not least, many questions concerning the H17 remain. As it was not possible so far to propagate the complete virus, using only the HA is a possible way to find out which receptor is used by this particular HA.
The matter of receptor recognition, expression of this receptor on different cell types and what changes in the HA favor host switching is a complex issue and was simplified
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