The known interaction of the mannose receptor with influenza virus in mice allows as fusion proteins

However, since off-target interference effects have been reported with lower similarities, this observation does not completely exclude the possibility of cross reaction with the product of another MRC1L gene. In a second experiment, figure S7, we observed that that the KUL01 antibody only identified MRC1-B when expression plasmids coding for potential extracellular regions of all five MRCIL genes, were transfected into COS-7 cells. This provides compelling evidence that the KUL01 anybody binds the product of the MRC1L-B gene and not the remaining paralogues. Whilst the qRT-PCR analysis of MRC1L-B transcripts is consistent with the observed staining patterns reported with KUL01 across a number of immunerelated tissues it is not possible from the present data to infer the cellular distribution of the expression of the remaining MRC1L molecules, although, except for MRC1L-A in the liver, the similarity of the transcript profiles would be consistent with their predominant expression in the same cells as MRC1L-B. In mammals, MRC1 is a multi-functional molecule. Being a pathogen-associated pattern recognition receptor, its involvements in uptake of antigen for presentation are important functions in innate and adaptive immune responses, but it also has roles in the clearance of hormones and the regulation of circulating cytokine levels. Cellular expression of the molecule is not restricted to macrophage alone but is also present on immature dendritic cells, reflecting its role in antigen capture. The information presented here does not tell us whether a shared ancestor of birds and mammals had multiple MRC1L genes, with subsequent gene loss in the mammalian lineage, or whether it had a single gene that was subsequently duplicated only in the avian lineage. The former possibility would allow the hypothesis that the modern functions of mammalian MRC1 might have been distributed between the original paralogous genes. The latter model would have allowed the evolution of novel functional roles for the newly duplicated genes. The similarities between the cytoplasmic domains of MRC1L-A and MRC1L-B, especially with regard to trafficking signals, suggest biological functions similar to the mammalian MRC1, with the possibility of functional redundancy between these molecules. The very different cytoplasmic sequences of the other genes might reflect substantial functional divergence of these from the mammalian MRC1 genes. The immune functions of MRC1 in the macrophage have given it an important role in determining the effectiveness of the response to influenza virus infection, at least in the lungs of mice. This presents a single interaction that is likely to be an effective target for evolution of viral virulence. If the additional genes in birds have similar functions in avian macrophages, then there is scope for redundant interactions with the virus that might be harder to evade. Expression of all these genes in macrophages is suggestive of conservation of these interactions. It will therefore be important to investigate whether these molecules have suitable carbohydrate binding activities, whether they are LDK378 involved in endocytosis and phagocytosis, and whether modulation of their expression affects the susceptibility and response to influenza infection of avian macrophages. We have observed abortive replication of influenza in an avian macrophage cell line, which would allow a similar protective role for the MRC1L genes to that of MRC1 in the mouse, in generating effective responses. The involvement of multiple molecules, increasing redundancy in virus receptors, could increase the robustness of this immune mechanism in birds.

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