Noroviruses (formerly Norwalk-like viruses) are a major cause of acute gastroenteritis worldwide and are associated with a significant number of nosocomial and food-borne outbreaks. In this study we show that the human secretor FUT2 gene, which codes for an ␣(1,2)-fucosyltransferase synthesizing the H-type 1 antigen in saliva and mucosa, is associated with susceptibility to norovirus infections. Allelic polymorphism characterization at nucleotide 428 for symptomatic (n ؍ 53) and asymptomatic (n ؍ 62) individuals associated with nosocomial and sporadic norovirus outbreaks revealed that homozygous nonsense mutation (428G3A) in FUT2 segregated with complete resistance for the disease. Of all symptomatic individuals, 49% were homozygous (SeSe) and 51% heterozygous (Sese 428 ) secretors, and none were secretor negative (se 428 se 428 ), in contrast to 20% nonsecretors (se 428 se 428 ) among Swedish blood donors (n ؍ 104) (P < 0.0002) and 29% for asymptomatic individuals associated with nosocomial outbreaks (P < 0.00001). Furthermore, saliva from secretorpositive and symptomatic patients but not from secretor-negative and asymptomatic individuals bound the norovirus strain responsible for that particular outbreak. This is the first report showing that the FUT2 nonsecretor (se 428 se 428 ) genotype is associated with resistance to nosocomial and sporadic outbreaks with norovirus.Noroviruses are the major cause of acute gastroenteritis worldwide among adults and are associated with the illness "winter vomiting disease," characterized by a short incubation period (24 to 48 h) and significant vomiting and diarrhea. While the viruses are highly contagious, with attack rates up to 70% (12), volunteer challenge studies have shown that a subset of individuals remain uninfected even after repeated challenges (2,20,26). At present, it is not clear why a fraction of individuals remain uninfected in norovirus outbreaks and why some volunteers are repeatedly resistant to experimental Norwalk virus inoculations. Recently, it was suggested that histo-blood group antigens and the secretor status might be associated with experimental Norwalk virus infections (4,10,11,16,17).The FUT2 gene, which is responsible for the secretor phenotype, encodes an ␣(1,2)-fucosyltransferase that regulates the expression of the ABH antigens in saliva and mucosal tissues and secretions. The FUT2 gene has a significant polymorphism with typical ethnic specificity (13). The nonsense mutation 428G3A (Trp1433stop) is characteristic for the dominating nonsecretor allele (se 428 ) in Europeans and appears in about 20% of the Caucasian population (13).The facts that about 20% of Europeans are nonsecretors and norovirus attack rates seldom exceeds 80% in a given outbreak led us to investigate, throughout a series of prospective studies, if the FUT2 secretor gene was associated with resistance to nosocomial and sporadic outbreaks caused by genogroup II (GGII) noroviruses, which dominate in all parts of the world (14). MATERIALS AND METHODSSubjects and sampl...
DNA transfer by bacterial conjugation requires a mating pair formation (Mpf) system that specifies functions for establishing the physical contact between the donor and the recipient cell and for DNA transport across membranes. Plasmid RP4 (IncP␣) contains two transfer regions designated Tra1 and Tra2, both of which contribute to Mpf. Twelve components are essential for Mpf, TraF of Tra1 and 11 Tra2 proteins, TrbB, -C, -D, -E, -F, -G, -H, -I, -J, -K, and -L. The phenotype of defined mutants in each of the Tra2 genes was determined. Each of the genes, except trbK, was found to be essential for RP4-specific plasmid transfer and for mobilization of the IncQ plasmid RSF1010. The latter process did not absolutely require trbF, but a severe reduction of the mobilization frequency occurred in its absence. Transfer proficiency of the mutants was restored by complementation with defined Tra2 segments containing single trb genes. Donor-specific phage propagation showed that traF and each of the genes encoded by Tra2 are involved. Phage PRD1, however, still adsorbed to the trbK mutant strain but not to any of the other mutant strains, suggesting the existence of a plasmid-encoded receptor complex. Strains containing the Tra2 plasmid in concert with traF were found to overexpress trb products as well as extracellular filaments visualized by electron microscopy. Each trb gene and traF are needed for the formation of the pilus-like structures. The trbK gene, which is required for PRD1 propagation and for pilus production but not for DNA transfer on solid media, encodes the RP4 entry-exclusion function. The components of the RP4 Mpf system are discussed in the context of related macromolecule export systems.
Mutations in genes required for the glycosylation of α-dystroglycan lead to muscle and brain diseases known as dystroglycanopathies. However, the precise structure and biogenesis of the assembled glycan are not completely understood. Here we report that three enzymes mutated in dystroglycanopathies can collaborate to attach ribitol phosphate onto α-dystroglycan. Specifically, we demonstrate that isoprenoid synthase domain-containing protein (ISPD) synthesizes CDP-ribitol, present in muscle, and that both recombinant fukutin (FKTN) and fukutin-related protein (FKRP) can transfer a ribitol phosphate group from CDP-ribitol to α-dystroglycan. We also show that ISPD and FKTN are essential for the incorporation of ribitol into α-dystroglycan in HEK293 cells. Glycosylation of α-dystroglycan in fibroblasts from patients with hypomorphic ISPD mutations is reduced. We observe that in some cases glycosylation can be partially restored by addition of ribitol to the culture medium, suggesting that dietary supplementation with ribitol should be evaluated as a therapy for patients with ISPD mutations.
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