TY - JOUR
T1 - TNFRSF13B polymorphisms counter microbial adaptation to enteric IgA
AU - Platt, Jeffrey L.
AU - de Mattos Barbosa, Mayara Garcia
AU - Huynh, Daniel
AU - Lefferts, Adam R.
AU - Katta, Juhi
AU - Kharas, Cyra
AU - Freddolino, Peter
AU - Bassis, Christine M.
AU - Wobus, Christiane
AU - Geha, Raif
AU - Bram, Richard
AU - Nunez, Gabriel
AU - Kamada, Nobuhiko
AU - Cascalho, Marilia
N1 - Publisher Copyright:
Copyright: © 2021, Platt et al.
PY - 2021/7/22
Y1 - 2021/7/22
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.148208
DO - 10.1172/jci.insight.148208
M3 - Article
C2 - 34111031
AN - SCOPUS:85111028227
SN - 2379-3708
VL - 6
JO - JCI Insight
JF - JCI Insight
IS - 14
M1 - e148208
ER -