||Keywords: inflammation; selectin ligands; fucosyltransferase; tuberculosis; animal model |
The recruitment of inflammatory cells to sites of infection is regulated in part by the interaction of selectins with their counter-receptors, the selectin ligands. P- and E- selectin ligands on granulocytes and lymphocytes are involved in directing the migration of these cells into inflammatory tissues as part of antimicrobial defense strategies, while L-selectin ligands on high endothelial venules (HEV) of lymph nodes control, to a large extent, the homing of lymphocytes during primary antigen recognition. Selectin ligands are characterized by their Lewisx moieties which, in HEV and leukocytes, become functional only after sialylation, sulfation and a-(1,3)-fucosylation via the fucosyltransferases (FucT) IV and VII. The activity of FucTVII is pivotal during the acute, largely granulocytic inflammatory reaction and for functional delayed hypersensitivity to some toxic compounds, whereas the contribution of FucTIV activity for the function of L-selectin ligands is less certain. Thus far, there have been no studies on the role of fucosylated selectin ligands in models of chronic inflammation or bacterial infections.
Our study will analyze the development of specific immune responses against a chronic infection and the migration of antigen-specific lymphocytes into the lung in mice selectively deficient for FucTIV, FucTVII or both FucTs. Aerosol infection with Mycobacterium tuberculosis, the etiologic agent of tuberculosis, will be used to delineate the relative contribution of fucosyltransferases for granuloma formation and antimycobacterial protection.
Important parameters such as bacterial growth and granuloma development, phenotype and function of immune cells in both lymph nodes and pulmonary infiltrations will be determined to define the relevance of fucosyltransferase activity during the induction and effector phases of the specific immune response. Special emphasis will be laid on the analysis of putative compensatory mechanisms apparent in infected mice deficient in only one of the two fucosyltransferases. In this context, the binding affinity of selectin ligands and the regulation of FucT mRNA expression will be compared in wildtype and knock-out mice. The results of this study may enhance our appreciation of innovative anti-inflammatory strategies which seek to specifically inhibit fucosyltransferase activities, both in terms of their therapeutic efficiency as well as their risks (exacerbation of latent infections).