Infection’s Sweet Tooth: How Glycans Mediate Infection and Disease Susceptibility

Taylor, Steven; McGuckin, Michael A.; Wesselingh, Steve; Rogers, Geraint B.

doi:10.1016/j.tim.2017.09.011

Cited by 46 publications

(53 citation statements)

References 92 publications

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“…HIEs provide an excellent tool for future studies on intestinal enzymes involved in glycosylation and how glycosylation alters glycoprotein localization. An association of enteric commensals and pathogens with host secretor status has led to increased recognition of secretor glycans being susceptibility factors important in infection and disease outcomes (30,31). The exact role played by the glycans in these infections is not fully understood.…”

Section: Discussionmentioning

confidence: 99%

Genetic Manipulation of Human Intestinal Enteroids Demonstrates the Necessity of a Functional Fucosyltransferase 2 Gene for Secretor-Dependent Human Norovirus Infection

Haga

Ettayebi

Tenge

et al. 2020

mBio

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Human noroviruses (HuNoVs) are the leading cause of nonbacterial gastroenteritis worldwide. Histo-blood group antigen (HBGA) expression is an important susceptibility factor for HuNoV infection based on controlled human infection models and epidemiologic studies that show an association of secretor status with infection caused by several genotypes. The fucosyltransferase 2 gene (FUT2) affects HBGA expression in intestinal epithelial cells; secretors express a functional FUT2 enzyme, while nonsecretors lack this enzyme and are highly resistant to infection and gastroenteritis caused by many HuNoV strains. These epidemiologic associations are confirmed by infections in stem cell-derived human intestinal enteroid (HIE) cultures. GII.4 HuNoV does not replicate in HIE cultures derived from nonsecretor individuals, while HIEs from secretors are permissive to infection. However, whether FUT2 expression alone is critical for infection remains unproven, since routinely used secretor-positive transformed cell lines are resistant to HuNoV replication. To evaluate the role of FUT2 in HuNoV replication, we used CRISPR or overexpression to genetically manipulate FUT2 gene function to produce isogenic HIE lines with or without FUT2 expression. We show that FUT2 expression alone affects both HuNoV binding to the HIE cell surface and susceptibility to HuNoV infection. These findings indicate that initial binding to a molecule(s) glycosylated by FUT2 is critical for HuNoV infection and that the HuNoV receptor is present in nonsecretor HIEs. In addition to HuNoV studies, these isogenic HIE lines will be useful tools to study other enteric microbes where infection and/or disease outcome is associated with secretor status.IMPORTANCE Several studies have demonstrated that secretor status is associated with susceptibility to human norovirus (HuNoV) infection; however, previous reports found that FUT2 expression is not sufficient to allow infection with HuNoV in a variety of continuous laboratory cell lines. Which cellular factor(s) regulates susceptibility to HuNoV infection remains unknown. We used genetic manipulation of HIE cultures to show that secretor status determined by FUT2 gene expression is necessary and sufficient to support HuNoV replication based on analyses of isogenic lines that lack or express FUT2. Fucosylation of HBGAs is critical for initial binding and for modification of another putative receptor(s) in HIEs needed for virus uptake or uncoating and necessary for successful infection by GI.1 and several GII HuNoV strains.

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Section: Discussionmentioning

confidence: 99%

Genetic Manipulation of Human Intestinal Enteroids Demonstrates the Necessity of a Functional Fucosyltransferase 2 Gene for Secretor-Dependent Human Norovirus Infection

Haga

Ettayebi

Tenge

et al. 2020

mBio

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Section: Dietary Fucosylated Hmos and Hmgs Have Anti-adhesive Propertiesmentioning

confidence: 99%

“…The lack of the α1,2-fucosylated HMOs and soluble α1,2-fucosylated HMGs in non-secretor mothers' milk is responsible for absence of inhibition of the adhesion of α1,2-fucose dependent pathogens to the epithelial host cells (Figure 4a). In the presence of α1,2-fucosylated HMOs and soluble α1,2-fucosylated HMGs in secretor mothers milk the adhesion of α1,2-fucose dependent pathogens to the epithelial host cells is blocked (Figure 4b) [117]. It has been shown that 2ʹ-FL and additionally 3ʹ-SL can reduce the incidence of viral infections caused by respiratory syncytial virus (RSV) in vitro by significantly reducing RSV viral load and the level of cytokines in the airway epithelium [119].…”

Section: Dietary Fucosylated Hmos and Hmgs Have Anti-adhesive Propertiesmentioning

confidence: 99%

“…As was reported by Barboza and coworkers [67] based on the in vitro invasion assay, N-glycans derived from human milk lactoferrin blocked the invasion of Caco2 intestinal epithelial cells by Salmonella. [117,118].…”

Section: Dietary Fucosylated Hmos and Hmgs Have Anti-adhesive Propertiesmentioning

confidence: 99%

“…The impact of non-secretor (a) and secretor (b) status of mother on inhibition of α1,2-fucose dependent pathogen adhesion to epithelial cells of the newborn's/infant's gastrointestinal tract[117,118].…”

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The Impact of Dietary Fucosylated Oligosaccharides and Glycoproteins of Human Milk on Infant Well-Being

Orczyk-Pawiłowicz

Lis-Kuberka

2020

Nutrients

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Apart from optimal nutritional value, human milk is the feeding strategy to support the immature immunological system of developing newborns and infants. The most beneficial dietary carbohydrate components of breast milk are human milk oligosaccharides (HMOs) and glycoproteins (HMGs), involved in both specific and nonspecific immunity. Fucosylated oligosaccharides represent the largest fraction of human milk oligosaccharides, with the simplest and the most abundant being 2′-fucosyllactose (2′-FL). Fucosylated oligosaccharides, as well as glycans of glycoproteins, as beneficial dietary sugars, elicit anti-adhesive properties against fucose-dependent pathogens, and on the other hand are crucial for growth and metabolism of beneficial bacteria, and in this aspect participate in shaping a healthy microbiome. Well-documented secretor status related differences in the fucosylation profile of HMOs and HMGs may play a key but underestimated role in assessment of susceptibility to fucose-dependent pathogen infections, with a potential impact on applied clinical procedures. Nevertheless, due to genetic factors, about 20% of mothers do not provide their infants with beneficial dietary carbohydrates such as 2′-FL and other α1,2-fucosylated oligosaccharides and glycans of glycoproteins, despite breastfeeding them. The lack of such structures may have important implications for a wide range of aspects of infant well-being and healthcare. In light of the above, some artificial mixtures used in infant nutrition are supplemented with 2′-FL to more closely approximate the unique composition of maternal milk, including dietary-derived fucosylated oligosaccharides and glycoproteins.

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Antiadhesive Carbohydrates and Glycomimetics

Cramer1,2,

Pang3,

Ernst1

2023

Carbohydrate‐Based Therapeutics

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Infection’s Sweet Tooth: How Glycans Mediate Infection and Disease Susceptibility

Cited by 46 publications

References 92 publications

Genetic Manipulation of Human Intestinal Enteroids Demonstrates the Necessity of a Functional Fucosyltransferase 2 Gene for Secretor-Dependent Human Norovirus Infection

Genetic Manipulation of Human Intestinal Enteroids Demonstrates the Necessity of a Functional Fucosyltransferase 2 Gene for Secretor-Dependent Human Norovirus Infection

The Impact of Dietary Fucosylated Oligosaccharides and Glycoproteins of Human Milk on Infant Well-Being

Antiadhesive Carbohydrates and Glycomimetics

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