Translational profiling of macrophages infected with Leishmania donovani identifies mTOR- and eIF4A-sensitive immune-related transcripts


Autoři: Visnu Chaparro aff001;  Louis-Philippe Leroux aff001;  Laia Masvidal aff002;  Julie Lorent aff002;  Tyson E. Graber aff003;  Aude Zimmermann aff001;  Guillermo Arango Duque aff001;  Albert Descoteaux aff001;  Tommy Alain aff003;  Ola Larsson aff002;  Maritza Jaramillo aff001
Působiště autorů: Institut National de la Recherche Scientifique (INRS)–Centre Armand-Frappier Santé Biotechnologie (CAFSB), Laval, Quebec, Canada aff001;  Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden aff002;  Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada aff003;  Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada aff004
Vyšlo v časopise: Translational profiling of macrophages infected with Leishmania donovani identifies mTOR- and eIF4A-sensitive immune-related transcripts. PLoS Pathog 16(6): e32767. doi:10.1371/journal.ppat.1008291
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008291

Souhrn

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.

Klíčová slova:

Amastigotes – Leishmania donovani – Macrophages – Messenger RNA – Parasitic diseases – Protein translation – Protozoan infections – Promastigotes


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