부산대학교 도서관

The protozoan parasite Leishmania donovani (L. donovani) causes visceral leishmaniasis, a chronic infection which is fatal when untreated. Herein, we investigated whether in addition to altering transcription, L. donovani modulates host mRNA translation to establish a successful infection. Polysome-profiling revealed that one third of protein-coding mRNAs expressed in primary mouse macrophages are differentially translated upon infection with L. donovani promastigotes or amastigotes. Gene ontology analysis identified key biological processes enriched for translationally regulated mRNAs and were predicted to be either activated (e.g. chromatin remodeling and RNA metabolism) or inhibited (e.g. intracellular trafficking and antigen presentation) upon infection. Mechanistic in silico and biochemical analyses showed selective activation mTOR- and eIF4A-dependent mRNA translation, including transcripts encoding central regulators of mRNA turnover and inflammation (i.e. PABPC1, EIF2AK2, and TGF-β). L. donovani survival within macrophages was favored under mTOR inhibition but was dampened by pharmacological blockade of eIF4A. Overall, this study uncovers a vast yet selective reprogramming of the host cell translational landscape early during L. donovani infection, and suggests that some of these changes are involved in host defense mechanisms while others are part of parasite-driven survival strategies. Further in vitro and in vivo investigation will shed light on the contribution of mTOR- and eIF4A-dependent translational programs to the outcome of visceral leishmaniasis. Author summary: Protozoan parasites of the genus Leishmania are the causative agents of leishmaniases, a group of diseases that range from cutaneous to potentially lethal visceral forms. Unfortunately, no efficient vaccine has been developed yet and drug resistance is rapidly increasing. Hence, the current situation reflects an urgent need for a better understanding of the molecular underpinnings of the interactions between Leishmania and its host in order to identify novel regulatory nodes for therapeutic intervention. During infectious diseases, fine-tuning the efficiency of mRNA translation into proteins allows cells to tailor their anti-microbial responses but can also be exploited by the invading pathogen. Using a global-scale translatome-based approach in macrophages, herein we report a profound perturbation in host mRNA translation during L. donovani infection. Our computational analyses reveal that subsets of host mRNAs encoding functionally related proteins share the same directionality of translational regulation, suggesting that key metabolic and microbicidal functions are hijacked by L. donovani via modulation of mRNA translation. We also show enrichment of reported mTOR- and eIF4A-sensitive mRNAs in the translationally activated dataset, including several immune-related transcripts. Finally, we report that in contrast to mTOR blockade, pharmacological inhibition of eIF4A hinders intramacrophage L. donovani survival. Thus, our study warrants further investigation on the potential of targeting eIF4A-dependent host mRNA translation to treat L. donovani infections. [ABSTRACT FROM AUTHOR]