4-Hydroxybenzaldehyde Restricts the Intracellular Growth of Toxoplasma gondii by Inducing SIRT1-Mediated Autophagy in Macrophages

Abstract

<i>Toxoplasma gondii</i> is an intracellular protozoan parasite that infects approximately one third of the human popu- lation worldwide. Considering the toxicity and side effects of anti-toxoplasma medications, it is important to develop effec- tive drug alternatives with fewer and less severe off-target effects. In this study, we found that 4-hydroxybenzaldehyde (4- HBA) induced autophagy and the expression of NAD-dependent protein deacetylase sirtuin-1 (SIRT1) in primary murine bone marrow-derived macrophages (BMDMs). Interestingly, treatment of BMDMs with 4-HBA significantly reduced the number of macrophages infected with <i>T. gondii</i> and the proliferation of <i>T. gondii</i> in infected cells. This effect was impaired by pretreating the macrophages with 3-methyladenine or wortmannin (selective autophagy inhibitors) or with sirtinol or EX527 (SIRT1 inhibitors). Moreover, we found that pharmacological inhibition of SIRT1 prevented 4-HBA-mediated expres- sion of LC3-phosphatidylethanolamine conjugate (LC3-II) and the colocalization of <i>T. gondii</i> parasitophorous vacuoles with autophagosomes in BMDMs. These data suggest that 4-HBA promotes antiparasitic host responses by activating SIRT1- mediated autophagy, and 4-HBA might be a promising therapeutic alternative for the treatment of toxoplasmosis.

Recent Advances in the Roles of Autophagy and Autophagy Proteins in Host Cells During Toxoplasma gondii Infection and Potential Therapeutic Implications

“…More recent studies evaluated 4-hydroxybenzaldehyde (4-HBA) ( Lee et al, 2020 ). 4-HBA-induced anti- T. gondii activity in BMDM seemed to be mediated by autophagy ( Lee et al, 2020 ).…”

“…More recent studies evaluated 4-hydroxybenzaldehyde (4-HBA) ( Lee et al, 2020 ). 4-HBA-induced anti- T. gondii activity in BMDM seemed to be mediated by autophagy ( Lee et al, 2020 ). 4-HBA seems to act via sirtuin-1 (SIRT1), a nicotine adenine dinucleotide-dependent protein deacetylase that can stimulate autophagy ( Lee et al, 2020 ).…”

“…4-HBA-induced anti- T. gondii activity in BMDM seemed to be mediated by autophagy ( Lee et al, 2020 ). 4-HBA seems to act via sirtuin-1 (SIRT1), a nicotine adenine dinucleotide-dependent protein deacetylase that can stimulate autophagy ( Lee et al, 2020 ). 4-HBA upregulated SIRT1 protein levels, and SIRT1 inhibitors impaired the anti- T. gondii activity induced by 4-HBA.…”

The Surface Antigen 1(SAG1) of Toxoplasma Gondii Interacts With RACK1 Inducing Autophagy and Maintaining The Viability of Host Cells

“…Based on the mechanism by which autophagy is initiated, it can be divided into the canonical autophagy and the non-canonical autophagy [10]. It has been reported that T. gondii infection could induce autophagy in many mammalian cells including Hela cells and murine bone marrow derived macrophages(BMDMs), suggesting the critical role of autophagy in antiparasitic responses of host cells [11]. For example, IFN-γ could induce non-canonical autophagy by recruitment of γ-aminobutyric acid (GABA) receptor-associated protein-like 2 (GABARAPL2), causing growth restriction of T.gondii in Hela cells [12].…”

The Host Autophagy During Toxoplasma Infection

“…Moreover, autophagy is thought to be an integral component of the innate immune response, targeting intracellular parasites, and parasites in damaged vacuoles and phagosomes, limiting their growth (Huang and Brumell, 2014). Recent study has shown that 4-Hydroxybenzaldehyde restricts the intracellular growth of Toxoplasma by activating SIRT1-mediated autophagy in macrophages (Lee et al, 2020). However, intracellular pathogens have also evolved diverse mechanisms to avoid autophagy (Steele et al, 2015).…”