Unraveling the role of host kinase PIM1 in Toxoplasma gondii infection: Implications for therapies

TL;DR

This study shows that the host kinase PIM1 helps Toxoplasma gondii multiply by preventing cell death, and inhibiting PIM1 reduces parasite load, suggesting a new therapeutic approach.

Contribution

The study identifies PIM1 as a novel host factor promoting T. gondii proliferation and validates its inhibition as a potential therapeutic strategy.

Findings

PIM1 enhances T. gondii proliferation by suppressing host cell apoptosis.

Inhibiting PIM1 with AZD1208 reduces parasite load and increases apoptosis in infected cells.

PIM1 inhibition bolsters the host immune response against T. gondii in murine models.

Abstract

Toxoplasma gondii, a widespread intracellular protozoan parasite, infects a significant portion of the global human population. Restricted to an acute-infection model, this study elucidates the role of the host protein PIM1, a serine/threonine protein kinase, in facilitating T. gondii proliferation and its potential as a therapeutic target. Employing both in vitro and in vivo models, we establish that PIM1 enhances the intracellular proliferation of T. gondii by suppressing host cell apoptosis. Our findings underscore the necessity of PIM1’s kinase activity in this process, as evidenced by the significant reduction in T. gondii proliferation upon treatment with either a kinase-dead PIM1 mutant or the PIM1 inhibitor AZD1208. In murine models, AZD1208 treatment resulted in decreased T. gondii load and elevated pro-apoptotic markers in tissues, indicating that PIM1 inhibition bolsters the host’s immune response against the parasite. Since the role of PIM1 in chronic infection remains unexplored, follow-up studies using chronic models are essential. Collectively, our findings illuminate host–parasite interplay during acute toxoplasmosis and position PIM1 as a promising target for anti-T. gondii therapeutics.

PIM1 functions as a regulator that suppresses apoptosis and, consequently, fosters the proliferation of T. gondii. This promotion of T. gondii proliferation by PIM1 is contingent upon its kinase activity, and the inhibition of PIM1 has been shown to induce increased apoptosis in host cells across both in vitro and in vivo studies. The potential therapeutic application of AZD1208, a PIM1 small molecule inhibitor, in treating toxoplasmosis has been brought to light by these findings. AZD1208 has demonstrated the ability to eliminate T. gondii-infected cells and decrease the overall parasite load by inhibiting PIM1. Collectively, the research emphasizes the role of PIM1 in the proliferation of T. gondii during infection and highlights the therapeutic potential of PIM1 inhibition in the fight against toxoplasmosis. The study’s findings propose that targeting PIM1 may offer a viable strategy for the development of innovative treatments aimed at this intracellular parasite.

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