# TNRSF13B polymorphisms and the control of innate B cell responses – a double edged sword

> **NIH NIH R21** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $195,000

## Abstract

Abstract
Enteric bacterial pathogens profoundly impact the health and development of children, especially in developing
countries. We unexpectedly discovered that polymorphisms of tnfrsf13b in mouse determine resistance to an
enteric pathogen that belongs to a family of organisms that cause much of chronic enteric infection in developing
countries, and to a lesser extent in developed regions. TNFRSF13B encodes the Transmembrane Activator and
CAML interactor (TACI), the receptor for BAFF and APRIL, that governs differentiation of B lymphocytes into
plasma cells and production of large amounts of antigen-specific immunoglobulin (Ig).
We recently discovered that a highly polymorphic gene, TNFRSF13B controls susceptibility to a murine
enteropathogen, C. rodentium, that models EHEC and EPEC. How tnfrsf13b alleles govern susceptibility versus
resistance is incompletely understood but our preliminary work connects these properties to the control of natural
IgA sequences and production. Thus, natural IgA from wild type mice induces expression of C. rodentium
virulence genes whereas IgA in tnfrsf13b-mutant and -KO mice does not. What connects the common mutations,
properties of IgA and IgA independent factors to susceptibility or resistance to C. rodentium is a central goal the
research we propose to conduct.
The research proposed will determine how tnfrsf13b missense mutations controlling distinct properties of IgA
and other features of mutant mice promote resistance to C. rodentium infection, pathogenesis and transmission.
We will also investigate how “natural” IgA produced by WT animals triggers the transcription of C. rodentium
virulence genes by exploring a Tn5-mutagenized library with a negatively selectable marker driven by the ler
promoter. Conducting the work proposed in this application will not only advance conceptual understanding
about the co-evolution of the mammalian immune system and an important class of enteric pathogens, it may
also provide specific molecular targets for development of agents to prevent or reverse the devastating impact
of enteropathogenic bacteria on vulnerable individuals.

## Key facts

- **NIH application ID:** 10330588
- **Project number:** 5R21AI159219-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** MARILIA Isabel CASCALHO
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $195,000
- **Award type:** 5
- **Project period:** 2021-01-19 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10330588

## Citation

> US National Institutes of Health, RePORTER application 10330588, TNRSF13B polymorphisms and the control of innate B cell responses – a double edged sword (5R21AI159219-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10330588. Licensed CC0.

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