Implications of Chronic Infection on Skeletal Muscle Immunity, Regeneration, and Function

Skeletal muscle function is indispensable for activities critical to an organism’s long-term survival such as voluntary movement, posture, and respiration. Given its importance, several mechanisms exist to ensure the maintenance of proper skeletal muscle function despite exposure to a variety of insults from pathogens to mechanical injury.

Among these mechanisms include the robust regenerative potential of the tissue and skeletal muscle immunity. Notably, tissue regeneration and immunity are intricately intertwined. The cellular events that coordinate skeletal muscle repair to acute sterile injuries have been well-studied. However, how chronic inflammatory settings – a hallmark of persistent infection and progressive myopathies – interfere with tissue immunity and the regenerative process remains an outstanding question in the field.

To address this gap in knowledge, I use the obligate intracellular protozoan parasite, Toxoplasma gondii, to establish a chronic infection in the skeletal muscle. In these studies, I:

1. investigate how chronic T.gondii infection remodels the immunologic landscape of skeletal muscle,
   
2. determine whether changes to skeletal muscle immunity and function due to chronic infection could be therapeutically alleviated and,
   
3. test how chronic infection-induced inflammation affects the regenerative capacity of skeletal muscle.
   

In the first part of these studies, I show that T. gondii infection leads to loss of muscle function accompanied by ongoing muscle damage and persistent Th1 inflammation. Surprisingly, we demonstrate that Tregs – in contrast to their well-established tissue protective role in other inflammatory settings – become pathogenic during chronic infection and facilitate the injurious accumulation of inflammatory macrophages.

In the second part of this study, I show that therapeutic administration of IL-10 and amphiregulin during chronic infection can augment the proportion restorative macrophages in the skeletal muscle and improve overall skeletal muscle fitness.

Finally, in the third part of these studies, I show the regenerative capacity of skeletal muscle is disrupted during chronic T. gondii infection.

Compared to the current paradigm of skeletal muscle repair, my results reveal macrophages responding to injury exhibit vast heterogeneity defined by unique transcriptional states, not confined to traditional “inflammatory” and “restorative” nomenclature. Furthermore, dysfunctions in skeletal muscle repair during chronic infection are associated with the inability of macrophages to progress toward reparative transcriptional states.

Collectively, I demonstrate long-term remodeling of skeletal muscle immunity during chronic T.gondii infection leads to reductions in the function and reparative capacity of skeletal muscle. Tissue-immunity must balance the ability to fight infections, heal injuries, and ultimately maintain tissue homeostasis.

My findings highlight how chronic inflammation due to infection can continually tip this balance and destabilize the preservation of tissue homeostasis. A greater understanding of the mechanisms underlying how chronic inflammatory conditions, such as persistent infection or progressive myopathies, alter tissue immunity will embolden the development of targeted therapeutics for these diseases.

Elizabeth Wohlfert, PhD