# Mechanisms of Viral-Induced Beta Cell Damage

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2021 · $468,000

## Abstract

Project Description.
 Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease characterized by selective destruction
of the insulin secreting b-cells found in pancreatic islets of Langerhans. While T-lymphocytes are the primary
mediators of b-cell destruction during disease development, the pathways that initiate this autoimmune attack
are unknown. There is a genetic predisposition for diabetes development, but the low concordance rate among
identical twins (less than 40%) suggest that environmental factors participate in the induction of autoimmune
diabetes. While virus infection is one environmental factor that has been proposed to initiate b-cell damage
during the development of diabetes, the effects of infection on b-cell function and viability as well as the activation
of b-cell defense responses to infection are poorly understood. The broad goals of this research program are to
define the biochemical mechanisms by which environmental factors, specifically virus infection, contribute to
disease development. Much of the focus of this competitive renewal application is on the mechanisms by which
b-cells participate in disease tolerance to virus infection. Disease tolerance is an evolutionary conserved defense
strategy that limits the impact of a pathogen on host fitness without directly modifying the pathogen. Using a
mouse tropic enterovirus that is known to infect and replicate in b-cells and that induces diabetes in susceptible
strains of mice (Encephalomyocarditis virus, EMCV), we have identified a novel pathway by which b-cell resist
EMCV infection. This protective pathway is mediated by nitric oxide, the same free radical produced by b-cell
following cytokine stimulated inducible nitric oxide synthase (NOS) expression. We show that nitric oxide, in b-
cell selective manner, enhances b-cell fitness by limiting virus replication and we hypothesize that it is when this
disease tolerance is broken that diabetes ensues.

## Key facts

- **NIH application ID:** 10119892
- **Project number:** 2R01AI044458-20A1
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** JOHN A CORBETT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $468,000
- **Award type:** 2
- **Project period:** 1998-09-30 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10119892

## Citation

> US National Institutes of Health, RePORTER application 10119892, Mechanisms of Viral-Induced Beta Cell Damage (2R01AI044458-20A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10119892. Licensed CC0.

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