Brains and Brawn: Toxoplasma Infections of the Central Nervous System and Skeletal Muscle

Abstract

Toxoplasma gondii is a widespread parasitic pathogen that infects over a third of the world's population. Following an acute infection, the parasite can persist within its mammalian host as intraneuronal or intramuscular cysts. Cysts will occasionally reactivate, and - depending on the host's immune status and site of reactivation - encephalitis or myositis can develop. Because these diseases have high levels of morbidity and can be lethal, it is important to understand how Toxoplasma traffics to these tissues, how the immune response controls parasite burden and contributes to tissue damage, and what mechanisms underlie neurological and muscular pathologies that toxoplasmosis patients present with. This review aims to summarize recent important developments addressing these critical topics.

Keywords: Plasmodium; blood–brain barrier; chronic infections; myositis; parasite; seizures.

Figure 1. Toxoplasma Interactions in the Brain and Skeletal Muscle

In the brain, Toxoplasma gains entry by traversing across endothelial cells. Once inside the brain, the parasite forms tissue cysts within neurons. Immune pressure from a variety of central nervous system resident and peripheral cells prevents cyst reactivation and infection of non-neuronal cells. The presence of Toxoplasma and infection-induced inflammation can lead to a combination of increased excitatory and decreased inhibitory neurotransmission causing increased susceptibility to seizures. In skeletal muscle, Toxoplasma forms tissue cysts and can induce tissue damage due to the development of pathogenic regulatory T cells (Treg). T cell production of interferon-gamma (IFN-γ) remains important, however, in contrast to the brain little is known about Toxoplasma-induced changes to the peripheral nervous system. M1, pro-inflammatory macrophages; M2, pro-regenerative macrophages.

Figure 2. Toxoplasma Down Regulates GLT-1 to Increase Excitatory Glutamatergic Synaptic Transmission

GLT-1 is an astrocytic glutamate transporter that removes extracellular glutamate from the synaptic cleft (left panel). Upon Toxoplasma infection, GLT-1 expression is downregulated leading to increased levels of extracellular glutamate and excitatory glutamatergic signaling and neuronal damage (right panel).

Figure 3. Toxoplasma Alters GAD67 Localization to Decrease Inhibitory GABAergic Synaptic Transmission

GAD67 is clustered in presynaptic termini on the surface synaptic vesicles, which facilitates efficient GABA synthesis and packaging within the vesicles (left panel). Toxoplasma infection leads to a loss of clustering and subsequent decrease in GABAergic synaptic activity (right panel). This decrease in activity will increase the probability that an action potential will be triggered in the postsynaptic neuron.

Figure 4. Toxoplasma Induces Pathogenic Tregs That Hinder Skeletal Muscle Regeneration

Regeneration of skeletal muscle from injury is a stepwise process that requires monocytes and pro-inflammatory macrophages (IM/M1) for the clearance of damaged myofibers and a transition in situ to pro-regenerative macrophages (M2) and activation of satellite cells for the regeneration of myofibers. Suppressive regulatory T cells (Tregs) are required for the IM/M1 to M2 transition (top panel). Toxoplasma infection in skeletal muscle significantly alters the function of Tregs such that they acquire pathogenic action and promote IM/M1 accumulation and persistence, which results in an impaired skeletal muscle repair response (bottom panel).