title: Fucosyltransferase IV and VII-directed selectin ligand function determines long-term survival in experimental tuberculosis.
abstract: In order to determine the relative importance of fucosyltransferase (Fuc-T)-directed functionalization of selectin ligands for chronic inflammatory and antibacterially protective responses in vivo, mice selectively deficient for Fuc-TIV, Fuc-TVII or both were infected by aerosol with Mycobacterium tuberculosis H37Rv. Fuc-TIV/Fuc-TVII-deficient, and to a lesser extent, Fuc-TVII-deficient mice succumbed significantly faster to infection than Fuc-TIV-deficient and wildtype (WT) mice, although no differentially increased bacterial load or qualitatively different histopathology was apparent in moribund mice. To determine if the cause of accelerated death was associated with defective induction of immune responses in the lung due to the diminished T cell content in the mediastinal lymph nodes of Fuc-T-deficient mice, intravenous infection in WT or double-deficient mice was performed. Again, Fuc-TIV/Fuc-TVII mice succumbed significantly faster than WT mice. To determine whether the early demise of Fuc-TIV/Fuc-TVII-deficient mice was due to accelerated tissue pathology, a mouse model of mycobacteria-induced granuloma necrosis was used. There was no difference in the kinetics and quality of caseation induced by Mycobacterium avium TMC724 in all mouse strains investigated. Together, our data show that a deficiency in Fuc-TVII, and in a more pronounced fashion, a combined deficiency in both Fuc-TIV and Fuc-TVII, leads to accelerated death following M. tuberculosis infection that is neither caused by increased bacterial proliferation nor by discernibly gross differences in tissue pathology. These results suggest that targeting selectin ligand function during treatment of chronic inflammatory disorders may run the risk of accelerating TB disease progression.
authors.affiliation: Molecular Inflammation Medicine, Christian-Albrechts-Universität, Kiel, Germany; Microbial Inflammation Research, Research Center Borstel, Parkallee 1, 23845 Borstel, Borstel, Germany. sehlers@fz-borstel.de
authors.forename: Stefan
authors.initials: S
authors.lastname: Ehlers
authors.forename: Tanja
authors.initials: T
authors.lastname: Schreiber
authors.forename: Annette
authors.initials: A
authors.lastname: Dunzendorfer
authors.forename: John B
authors.initials: JB
authors.lastname: Lowe
authors.forename: Christoph
authors.initials: C
authors.lastname: Hölscher
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D018450:Disease Progression; D005647:Fucosyltransferases / Q000235:genetics / Q000276:immunology*; D007108:Immune Tolerance; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D009162:Mycobacterium avium / Q000276:immunology* / Q000472:pathogenicity; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000472:pathogenicity; D019087:Selectins / Q000276:immunology / Q000378:metabolism*; D014397:Tuberculosis, Pulmonary / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D014774:Virulence
chemical_list: D019087:Selectins; D005647:Fucosyltransferases; C541914:Fut4 protein, mouse; C514210:fucosyltransferase VII, mouse