Skeletal muscle repair is a critical process for the maintenance of tissue integrity and regulatory T cells are requisite to this process. Regeneration occurs in response to acute traumatic injury, exercise induced damage, chronic degenerative diseases and infection. Myopathies, including muscular dystrophy, polymyositis, dermatomyositis, and aged skeletal muscle show Tregs deficiencies in either numbers or function in patients, supporting the role of Tregs in regeneration. Surprisingly, little is known about the skeletal muscle immune response and regulation to Toxoplasma gondii infection, even though this is a primary site of encystment. We showed infection with T. gondii elaborates extensive muscle damage and prolonged disruption of macrophage homeostasis Infection of the skeletal muscle with T. gondii i) causes skeletal muscle damage and myositis, ii) disrupts resident skeletal muscle macrophage populations that are necessary for tissue repair, iii) ablation of Tregs rescues skeletal muscle regeneration and the pro-regenerative M2 population and iv) infection impairs Treg de novo generation and suppressive function. These data are the basis of our proposal. The overarching hypothesis for this proposal is that the chronic inflammatory environment induces a pathogenic program in skeletal muscle Tregs that promotes immunopathology. Using this model, we will dissect the factors and cell targets of Tregs that impair the regenerative process from proceeding. The goal of the current proposal is to define the mechanisms by which Tregs modulate the immune response to T. gondii in the skeletal muscle.
We aim to (1) define the mechanisms that lead to the impairment of Treg function in infected skeletal muscle and (2) determine if Tregs directly promote the polarization, migration or survival of M1 macrophages in infected skeletal muscle during T. gondii infection.
The goal of this project is to determine how Regulatory T cells (Tregs) can deviate from their normally immune suppressive function, become tissue-injurious and contribute to skeletal muscle damage. We will determine the events leading to the development of these pathogenic cells and Treg interactions with macrophages in the skeletal muscle. This is important because therapies are being developed that rely on giving patients a bolus of Tregs to help reduce inflammation however a better understanding of how well those Tregs will function is needed in order for these therapies to be as beneficial as possible.
| Jin, Richard M; Warunek, Jordan; Wohlfert, Elizabeth A (2018) Therapeutic administration of IL-10 and amphiregulin alleviates chronic skeletal muscle inflammation and damage induced by infection. Immunohorizons 2:142-154 |
| Jin, Richard M; Warunek, Jordan; Wohlfert, Elizabeth A (2018) Chronic infection stunts macrophage heterogeneity and disrupts immune-mediated myogenesis. JCI Insight 3: |
| Wohlfert, Elizabeth A; Blader, Ira J; Wilson, Emma H (2017) Brains and Brawn: Toxoplasma Infections of the Central Nervous System and Skeletal Muscle. Trends Parasitol 33:519-531 |
