Dataset Information

TNFRSF13B polymorphisms counter microbial adaptation to enteric IgA.

ABSTRACT: TNFRSF13B encodes the transmembrane activator and CAML interactor (TACI) receptor, which drives plasma cell differentiation. Although TNFRSF13B supports host defense, dominant-negative TNFRSF13B alleles are common in humans and other species and only rarely associate with disease. We reasoned that the high frequency of disruptive TNFRSF13B alleles reflects balancing selection, the loss of function conferring advantage in some settings. Testing that concept, we investigated how a common human dominant-negative variant, TNFRSF13B A181E, imparts resistance to enteric pathogens. Mice engineered to express mono- or biallelic A144E variants of tnrsf13B, corresponding to A181E, exhibited a striking resistance to pathogenicity and transmission of Citrobacter rodentium, a murine pathogen that models enterohemorrhagic Escherichia coli, and resistance was principally owed to natural IgA deficiency in the intestine. In WT mice with gut IgA and in mutant mice reconstituted with enteric IgA obtained from WT mice, IgA induces LEE expression of encoded virulence genes, which confer pathogenicity and transmission. Taken together, our results show that C. rodentium and most likely other enteric organisms appropriated binding of otherwise protective antibodies to signal induction of the virulence program. Additionally, the high prevalence of TNFRSF13B dominant-negative variants reflects balancing selection.

SUBMITTER: Platt JL

PROVIDER: S-EPMC8410086 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

TNFRSF13B polymorphisms counter microbial adaptation to enteric IgA.

Platt Jeffrey L JL de Mattos Barbosa Mayara Garcia MG Huynh Daniel D Lefferts Adam R AR Katta Juhi J Kharas Cyra C Freddolino Peter P Bassis Christine M CM Wobus Christiane C Geha Raif R Bram Richard R Nunez Gabriel G Kamada Nobuhiko N Cascalho Marilia M

JCI insight 20210722 14

TNFRSF13B encodes the transmembrane activator and CAML interactor (TACI) receptor, which drives plasma cell differentiation. Although TNFRSF13B supports host defense, dominant-negative TNFRSF13B alleles are common in humans and other species and only rarely associate with disease. We reasoned that the high frequency of disruptive TNFRSF13B alleles reflects balancing selection, the loss of function conferring advantage in some settings. Testing that concept, we investigated how a common human dom ...[more]

PMID: 34111031

Similar Datasets

Project description:Environmental enteric dysfunction (EED) (also referred to as environmental enteropathy) is a subclinical chronic intestinal disorder that is an emerging contributor to early childhood malnutrition. EED is common in resource-limited settings, and is postulated to consist of small intestinal injury, dysfunctional nutrient absorption, and chronic inflammation that results in impaired early child growth attainment. Although there is emerging interest in the hypothetical potential for chemical toxins in the environmental exposome to contribute to EED, the propensity of published data, and hence the focus of this review, implicates a critical role of environmental microbes. Early childhood malnutrition and EED are most prevalent in resource-limited settings where food is limited, and inadequate access to clean water and sanitation results in frequent gastrointestinal pathogen exposures. Even as overt diarrhea rates in these settings decline, silent enteric infections and faltering growth persist. Furthermore, beyond restricted physical growth, EED and/or enteric pathogens also associate with impaired oral vaccine responses, impaired cognitive development, and may even accelerate metabolic syndrome and its cardiovascular consequences. As these potentially costly long-term consequences of early childhood enteric infections increasingly are appreciated, novel therapeutic strategies that reverse damage resulting from nutritional deficiencies and microbial insults in the developing small intestine are needed. Given the inherent limitations in investigating how specific intestinal pathogens directly injure the small intestine in children, animal models provide an affordable and controlled opportunity to elucidate causal sequelae of specific enteric infections, to differentiate consequences of defined nutrient deprivation alone from co-incident enteropathogen insults, and to correlate the resulting gut pathologies with their functional impact during vulnerable early life windows.

Dataset Information

TNFRSF13B polymorphisms counter microbial adaptation to enteric IgA.

Publications

TNFRSF13B polymorphisms counter microbial adaptation to enteric IgA.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets