# TNFRSF Genetics Related to NK Cell Control of MCMV

> **NIH NIH R21** · UNIVERSITY OF VIRGINIA · 2020 · $199,591

## Abstract

Project Summary.
Infectious diseases are a major global threat to human life. Certain individuals, however, carry naturally selected
genetic factors which provide essential protection against life-threatening infections. Genetic approaches thus
are essential to unravel the basis of host resistance to viral infection and resulting disease. We have shown that
host resistance to murine cytomegalovirus (MCMV) infection differs greatly in MA/My and C57L mice. Thus we
combined classical genetics with immune cell phenotyping to screen large numbers of MA/My x C57L cross
offspring for genetic modifiers of viral immunity. Our whole genome approach detected a quantitative trait locus
(QTL) on distal chromosome 4 (dc4) which controls MCMV levels in spleen within days after infection. Two
additional QTLs that control host body weight, or NK cells frequency in spleen during infection were separately
mapped to the same locus (86.5 cM) on dc4, which hints that it harbors a critical gene or genes essential to NK
cells and host resistance to viral infection. Intriguingly, dc4 overlaps a nest of Tumor Necrosis Factor Receptor
Superfamily (TNFRSF) member genes which are known to regulate immune cell activities. TNF signaling via
TNFRSF members is crucial in lymphoid organogenesis, lymphocyte survival and proliferation, autoimmune dis-
ease, cancer and viral infection.!Indeed, several dc4 TNFR-family members and their conserved human coun-
terparts have been shown to regulate natural killer (NK) cells in different virus infections. We predict variation in
dc4 TNFR-family member gene expression or polymorphism might underlie antiviral immunity or host response
differences observed in C57L and MA/My mice during MCMV infection. A broad, long-term objective of this
project is to discover the genetic basis of dc4 control of MCMV resistance, weight loss and NK cells during
MCMV infection. We will thus combine classical and exploratory genetics approaches to identify and characterize
high priority dc4 candidates. In Aim 1, precision genetics will be applied to pinpoint a dc4 QTL in congenic and
recombinant congenic mice. Assessment of immune cell responsiveness and MCMV control in key recombinant
congenic mice will underpin gene expression screening and selection of high priority dc4 candidates based on
positional mapping, allelic differences and expression variation in vital immune cells. Aim 2 examines antiviral
NK cell responses, including NK activation, proliferation, survival and trafficking during MCMV infection in dc4-
disparate mice. This effect will be further investigated by comparing mixed dc4 donor NK cells responding to
MCMV in the same adoptive transfer hosts, followed by analysis of dc4-regulated NK cell-specific gene expres-
sion. High priority candidates will be vetted in CRISPR-modified primary T cells developed to assess the effect
of dc4/Tnfrsf expression variation or polymorphism in lymphocyte activities following antigen-specific stimulation
with plat...

## Key facts

- **NIH application ID:** 9936358
- **Project number:** 5R21AI141943-02
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Michael G. Brown
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $199,591
- **Award type:** 5
- **Project period:** 2019-06-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9936358

## Citation

> US National Institutes of Health, RePORTER application 9936358, TNFRSF Genetics Related to NK Cell Control of MCMV (5R21AI141943-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9936358. Licensed CC0.

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