| 1. |
- Brynjolfsson, Siggeir, et al.
(författare)
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Long-lived plasma cells in mice and men
- 2018
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Even though more than 30 years have passed since the eradication of smallpox, high titers of smallpox-specific antibodies are still detected in the blood of subjects vaccinated in childhood. In fact, smallpox-specific antibody levels are maintained in serum for more than 70 years. The generation of life-long immunity against infectious diseases such as smallpox and measles has been thoroughly documented. Although the mechanisms behind high persisting antibody titers in the absence of the causative agent are still unclear, long lived plasma cells (LLPCs) play an important role. Most of the current knowledge on LLPCs is based on experiments performed in mouse models, although the amount of data derived from human studies is increasing. As the results from mouse models are often directly extrapolated to humans, it is important to keep in mind that there are differences. These are not only the obvious such as the life span but there are also anatomical differences, for instance the adiposity of the bone marrow (BM) where LLPCs reside. Whether these differences have an effect on the function of the immune system, and in particular on LLPCs, are still unknown. In this review, we will briefly discuss current knowledge of LLPCs, comparing mice and humans. © 2007 - 2018 Frontiers Media S.A.
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| 2. |
- Nilsson, Jonas, 1970, et al.
(författare)
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N-glycoproteomic analyses of human intestinal enteroids, varying in histo-blood group geno- and phenotypes, reveal a wide repertoire of fucosylated glycoproteins
- 2024
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Ingår i: GLYCOBIOLOGY. - 0959-6658 .- 1460-2423. ; 34:6
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Tidskriftsartikel (refereegranskat)abstract
- Human noroviruses, globally the main cause of viral gastroenteritis, show strain specific affinity for histo-blood group antigens (HBGA) and can successfully be propagated ex vivo in human intestinal enteroids (HIEs). HIEs established from jejunal stem cells of individuals with different ABO, Lewis and secretor geno- and phenotypes, show varying susceptibility to such infections. Using bottom-up glycoproteomic approaches we have defined and compared the N-linked glycans of glycoproteins of seven jejunal HIEs. Membrane proteins were extracted, trypsin digested, and glycopeptides enriched by hydrophilic interaction liquid chromatography and analyzed by nanoLC-MS/MS. The Byonic software was used for glycopeptide identification followed by hands-on verifications and interpretations. Glycan structures and attachment sites were identified from MS2 spectra obtained by higher-energy collision dissociation through analysis of diagnostic saccharide oxonium ions (B-ions), stepwise glycosidic fragmentation of the glycans (Y-ions), and peptide sequence ions (b- and y-ions). Altogether 694 unique glycopeptides from 93 glycoproteins were identified. The N-glycans encompassed pauci- and oligomannose, hybrid- and complex-type structures. Notably, polyfucosylated HBGA-containing glycopeptides of the four glycoproteins tetraspanin-8, carcinoembryonic antigen-related cell adhesion molecule 5, sucrose-isomaltase and aminopeptidase N were especially prominent and were characterized in detail and related to donor ABO, Lewis and secretor types of each HIE. Virtually no sialylated N-glycans were identified for these glycoproteins suggesting that terminal sialylation was infrequent compared to fucosylation and HBGA biosynthesis. This approach gives unique site-specific information on the structural complexity of N-linked glycans of glycoproteins of human HIEs and provides a platform for future studies on the role of host glycoproteins in gastrointestinal infectious diseases.
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| 3. |
- Parveen, Nagma, 1988, et al.
(författare)
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Membrane Deformation Induces Clustering of Norovirus Bound to Glycosphingolipids in a Supported Cell-Membrane Mimic
- 2018
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Ingår i: Journal of Physical Chemistry Letters. - : American Chemical Society (ACS). - 1948-7185. ; 9:9, s. 2278-2284
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Tidskriftsartikel (refereegranskat)abstract
- Quartz crystal microbalance with dissipation monitoring and total internal reflection fluorescence microscopy have been used to investigate binding of norovirus-like particles (noroVLPs) to a supported (phospho)lipid bilayer (SLB) containing a few percent of H or B type 1 glycosphingolipid (GSL) receptors. Although neither of these GSLs spontaneously form domains, noroVLPs were observed to form micron-sized clusters containing typically up to about 30 VLP copies, especially for B type 1, which is a higher-affinity receptor. This novel finding is explained by proposing a model implying that VLP-induced membrane deformation promotes VLP clustering, a hypothesis that was further supported by observing that functionalized gold nanoparticles were able to locally induce SLB deformation. Because similar effects are likely possible also at cellular membranes, our findings are interesting beyond a pure biophysicochemical perspective as they shed new light on what may happen during receptor-mediated uptake of viruses as well as nanocarriers in drug delivery. © Copyright 2018 American Chemical Society.
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| 4. |
- Rimkute, Inga
(författare)
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Gastrointestinal norovirus infections and the development of the next generation of mucosal vaccines
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Human norovirus (HuNoV) is the causative agent of the winter vomiting disease and the leading cause of outbreaks of gastrointestinal infections across all settings and age groups in the world. The virus is highly contagious making outbreaks difficult or often impossible to control and having a high impact on societal costs and resources. Therefore, there is a high urge for the design and development of a HuNoV vaccine. Since research on HuNoV biology and pathogenesis has been hampered by the inability to infect and efficiently propagate the virus in cell cultures, HuNoV receptor studies that address antibody-mediated protection against HuNoV have not been possible. However, such a model has recently been developed. This thesis has focused on two crucial steps towards the development of a novel mucosal subcomponent HuNoV vaccine. The first was to identify membrane components carrying histo-blood group antigens (HBGAs) that are required for HuNoV infection in the epithelial cells of the human intestine, represented as cultures of human intestinal enteroids (HIEs). The second step was to identify highly immunogenic peptides from the HuNoV capsid for generating a subcomponent vaccine that stimulates strong and long-lasting HuNoV-specific immune responses. The key findings have advanced our basic knowledge on the lipid, glycolipid and glycoprotein composition of HIEs, established from jejunal biopsies of individuals with different ABO, secretor and Lewis status. These components may all be of importance for understanding the pathogenesis of HuNoV gastrointestinal infection, as well as contribute in designing a mucosal subcomponent vaccine against HuNoV effectively preventing future HuNoV disease and outbreaks.
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| 5. |
- Rimkute, Inga, et al.
(författare)
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Histo-blood group antigens of glycosphingolipids predict susceptibility of human intestinal enteroids to norovirus infection
- 2020
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Ingår i: Journal of Biological Chemistry. - : Elsevier. - 0021-9258 .- 1083-351X. ; 295:47, s. 15974-15987
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Tidskriftsartikel (refereegranskat)abstract
- The molecular mechanisms behind infection and propagation of human restricted pathogens such as human norovirus (HuNoV) have defied interrogation because they were previously unculturable. However, human intestinal enteroids (HIEs) have emerged to offer unique ex vivo models for targeted studies of intestinal biology, including inflammatory and infectious diseases. Carbohydrate-dependent histo-blood group antigens (HBGAs) are known to be critical for clinical infection. To explore whether HBGAs of glycosphingolipids contribute to HuNoV infection, we obtained HIE cultures established from stem cells isolated from jejunal biopsies of six individuals with different ABO, Lewis, and secretor genotypes. We analyzed their glycerolipid and sphingolipid compositions and quantified interaction kinetics and the affinity of HuNoV virus-like particles (VLPs) to lipid vesicles produced from the individual HIE-lipid extracts. All HIEs had a similar lipid and glycerolipid composition. Sphingolipids included HBGA-related type 1 chain glycosphingolipids (GSLs), with HBGA epitopes corresponding to the geno- and phenotypes of the different HIEs. As revealed by single-particle interaction studies of Sydney GII.4 VLPs with glycosphingolipid-containing HIE membranes, both binding kinetics and affinities explain the patterns of susceptibility toward GII.4 infection for individual HIEs. This is the first time norovirus VLPs have been shown to interact specifically with secretor gene-dependent GSLs embedded in lipid membranes of HIEs that propagate GII.4 HuNoV ex vivo, highlighting the potential of HIEs for advanced future studies of intestinal glycobiology and host-pathogen interactions.
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