Mechanism Governing Association Between Viral Respiratory Infection Relapse Generation and Disease Progression in Persons with MS
Abstract
Multiple sclerosis (MS) is a disease of the brain and spinal cord in which the patient s own immune system damages tissue, causing disability. It has been estimated that 85% of persons with multiple sclerosis are initially diagnosed with a relapsing-remitting form of disease. This type of MS is characterized by periods of increased disease activity (relapses) followed by periods of partial recovery (remission). Since 1965, data have repeatedly shown that disease symptoms worsen in an estimated 27%-41% of relapsing-remitting MS patients within 5 weeks of contracting a respiratory viral infection. More recent research has indicated that many different types of viruses including those that cause the common cold, influenza virus, and SARS-CoV-2 (the virus that causes COVID-19) are linked to this phenomenon. However, how these common viruses act to increase disease activity in the brains of persons with MS is not yet known. Since 85% of persons with MS are initially diagnosed with having the relapsing-remitting subtype of disease, a very large proportion of patients remain at risk for increased disease activity once they get a respiratory infection. Until we understand exactly how viral infections worsen disease, this patient population will continue to be at risk for disease exacerbation when exposed to prevalent viruses such as SARS-CoV-2. We previously performed experiments in mice to address the role of influenza virus infection on the disease course of an animal model of MS. As occurs in the human disease, our data show that mice developed relapses shortly after exposure to virus and developed worse disease than control mice. Notably, a subset of immune cells, termed T cells, were found to be affected by infection in a manner that made them able to worsen disease. The ability for T cells to cause disease in the animal model is dependent on signals from a separate type of cell, termed dendritic cells, which also act to detect viral infections. Therefore, we developed the hypothesis that viral infections affect T cell function indirectly by targeting dendritic cells. To test this hypothesis we will determine if proteins from different types of viruses (i.e., influenza and SARS-CoV-2) are capable of affecting the interactions between dendritic cells and T cells in a manner that causes T cells to stimulate disease activity. We will also determine how T cells from virus-infected mice affect the cells that make up the brain (neurons, microglia, astrocytes, endothelial cells, and oligodendrocytes). By understanding these interactions we hope to determine targets for future drugs that can inhibit cell death that occurs within the brains of persons with MS. Finally, we have identified a specific pathway, activated by infection, that we hypothesize promotes the generation of disease-causing T cells. We will test whether inhibiting this pathway can decrease the likelihood of infection-induced relapse. Since the immune system is needed to protect against viral infections we will also test whether the drug is safe to use during an active viral infection. While this research relies heavily on animal models of disease, we expect to identify a novel, but unifying, mechanism whereby viruses influence relapse generation and disease progression that is applicable to human MS. The results from our proposed experiments should reveal molecular targets that may prove to be clinically beneficial in the prevention of infection-induced disease exacerbations and may slow disease progression in general. Finally, identifying specific interactions between T cells and cells within the brain should shed light on mechanisms that control cell death. Our hope is that these data could be capitalized upon to reduce disease or promote repair.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310692
Entities
People
- Andrew Steelman
Organizations
- United States Army
- University of Illinois Urbana–Champaign