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.