TNFRSF13B polymorphisms counter microbial adaptation to enteric IgA
Jeffrey L. Platt, Mayara Garcia de Mattos Barbosa, Daniel Huynh, Adam R. Lefferts, Juhi Katta, Cyra Kharas, Peter Freddolino, Christine M. Bassis, Christiane Wobus, Raif Geha, Richard Bram, Gabriel Nunez, Nobuhiko Kamada, Marilia Cascalho
Jeffrey L. Platt, Mayara Garcia de Mattos Barbosa, Daniel Huynh, Adam R. Lefferts, Juhi Katta, Cyra Kharas, Peter Freddolino, Christine M. Bassis, Christiane Wobus, Raif Geha, Richard Bram, Gabriel Nunez, Nobuhiko Kamada, Marilia Cascalho
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Research Article Immunology Microbiology

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.

Authors

Jeffrey L. Platt, Mayara Garcia de Mattos Barbosa, Daniel Huynh, Adam R. Lefferts, Juhi Katta, Cyra Kharas, Peter Freddolino, Christine M. Bassis, Christiane Wobus, Raif Geha, Richard Bram, Gabriel Nunez, Nobuhiko Kamada, Marilia Cascalho

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Figure 1

Tnfrsf13b mutant mice resist infection with C. rodentium.

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Tnfrsf13b mutant mice resist infection with C. rodentium. To evaluate b...
To evaluate baseline resistance to enteric infection with C. rodentium, WT C57BL/6 mice, and mice with mono- or biallelic mutations in Tnfrsf13b (A144E) and mice with targeted disruption of Tnfrsf13b (Tnfrsf13b-KO) were infected with 108 C. rodentium by oral gavage, and the numbers of viable organisms in stool were measured by counting CFU/g of feces after 18 hours of incubation on MacConkey plates at the peak of infection. (A) Graph depicts the maximum CFU/g feces in the course of infection for each of the infected mouse strains. Values were analyzed by 1-way ANOVA, the Kruskal-Wallis test (P < 0.0001), with multiple comparisons comparing values in Tnfrsf13b mutant mice to WT showing P = 0.0492 for A144E/WT, P < 0.0001 for A144E/A144E, and for Tnfrsf13b-KO mice. (B) Mean number of viable C. rodentium in stool (expressed in log10 CFU/g feces) at various times after infection. Comparisons to C57BL/6 at day 14 yielded P < 0.0001 (1-way ANOVA and the Kruskal-Wallis test), and multiple comparisons test to WT yielded P = 0.0048 for A144E/WT, P < 0.0001 for A144E/A144E, and for Tnfrsf13b-KO mice. (C) Quantification of C. rodentium–binding IgA in feces of mice prior to infection. IgA in feces was measured by flow cytometry analysis of IgA+ GFP+ C. rodentium and detected with anti-IgA PE-labeled. y axis, Average of 3 independent measurements of IgA mean fluorescence intensity (MFI); x axis, feces supernatant dilutions. Analysis of results by 1-way ANOVA yielded P < 0.0001. Comparisons of undiluted mutant mice antibodies with those obtained from C57BL/6 mice by Dunnett’s multiple comparisons test yielded P = 0.0004 for A144E/WT, P = 0.0002 for A144E/A144E, and P < 0.0001 for Tnfrsf13b-KO mice. *P < 0.05; ***P < 0.001; ****P < 0.0001.