Toxoplasma gondii is an obligate intracellular protozoan that causes chronic infection in approximately 1/3 of the world population. T. gondii is a leading cause of infectious retinitis and an important cause of encephalitis in humans. T. gondii survives within host cells by avoiding targeting by autophagosomes. We uncovered that cell mediated immunity activates autophagic killing of the parasite via CD40 and that both autophagy and CD40 are critical for protection against ocular and cerebral toxoplasmosis. We identified the signaling pathways by which CD40 stimulates autophagic targeting of T. gondii (Figure 1).
Figure 1
Subauste, C. S. (2021). Recent advances in the roles of autophagy and autophagy proteins in host cells during Toxoplasma gondii infection and potential therapeutic implications. Frontiers in Cell and Developmental Biology, 9. https://doi.org/10.3389/fcell.2021.673813
Autophagy is a constitutive process of lysosomal degredation. We identified molecular events activated by the parasite that result in Epidermal Growth Factor Receptor (EGFR) activation in host cells and blockade of autophagosomes from targeting T. gondii (Figure 2). T. gondii micronemal proteins with EGF-like domains act as the initial trigger for early EGFR → Akt signaling in host cells resulting in avoidance of autophagic targeting of the parasite. Next, during the process of invasion of host cells, T. gondii activates FAK → Src → EGFR transactivation → STAT3 signaling. This pathway prevents autophagic killing of the parasite by impairing activation of the pro-autophagy protein PKR. Finally, during its intracellular state, T. gondii causes prolonged PKC⍺/PKCβ-dependent Src signaling that maintains activation of EGFR and Akt in host cells. Pharmacologic inhibition of EGFR in previously infected cells causes autophagic killing of the parasite. These studies have led to the successful use of low doses of EGFR tyrosine kinase inhibitor for the treatment of ocular and cerebral toxoplasmosis in mice.
Figure 2
Subauste, C. S. (2021). Recent advances in the roles of autophagy and autophagy proteins in host cells during Toxoplasma gondii infection and potential therapeutic implications. Frontiers in Cell and Developmental Biology, 9. https://doi.org/10.3389/fcell.2021.673813
T. gondii causes activation of Src, a ubiquitous signaling molecule that is highly expressed in the retina and brain. Src activation occurs even in cells that lack EGFR. Src induces activation of Class I PI3K and Akt (Figure 3). Activated Akt accumulates in the membrane of the parasitophorous vacuole. Activated Src associates with PTEN causing PTEN deactivation. Deactivated PTEN is unable to inhibit Akt activation. Knockdown of Src or treatment with the Src family kinase inhibitor Saracatinib inhibits Src and the association of Src to PTEN. Activated PTEN is recruited to the membrane of the parasitophorous vacuole. This results in autophagic killing of T. gondii and protection against ocular and cerebral toxoplasmosis.
Figure 3
Hubal A, Vendhoti A, Shaffer CN, Vos S, Lopez Corcino Y, Subauste CS. 2025. Inhibition of Src signaling induces autophagic killing of Toxoplasma gondii via PTEN-mediated deactivation of Akt. PLoS Pathogens Jan 27, 2025 https://doi.org/10.1371/journal.ppat.1012907
Relavent Publications
Hubal A, Vendhoti A, Shaffer CN, Vos S, Lopez Corcino Y, Subauste CS. 2025. Inhibition of Src signaling induces autophagic killing of Toxoplasma gondii via PTEN-mediated deactivation of Akt. PLoS Pathogens Jan 27, 2025 https://doi.org/10.1371/journal.ppat.1012907