PMID- 37187743 OWN - NLM STAT- MEDLINE DCOM- 20230517 LR - 20230525 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 14 DP - 2023 TI - Host M-CSF induced gene expression drives changes in susceptible and resistant mice-derived BMdMs upon Leishmania major infection. PG - 1111072 LID - 10.3389/fimmu.2023.1111072 [doi] LID - 1111072 AB - Leishmaniases are a group of diseases with different clinical manifestations. Macrophage-Leishmania interactions are central to the course of the infection. The outcome of the disease depends not only on the pathogenicity and virulence of the parasite, but also on the activation state, the genetic background, and the underlying complex interaction networks operative in the host macrophages. Mouse models, with mice strains having contrasting behavior in response to parasite infection, have been very helpful in exploring the mechanisms underlying differences in disease progression. We here analyzed previously generated dynamic transcriptome data obtained from Leishmania major (L. major) infected bone marrow derived macrophages (BMdMs) from resistant and susceptible mouse. We first identified differentially expressed genes (DEGs) between the M-CSF differentiated macrophages derived from the two hosts, and found a differential basal transcriptome profile independent of Leishmania infection. These host signatures, in which 75% of the genes are directly or indirectly related to the immune system, may account for the differences in the immune response to infection between the two strains. To gain further insights into the underlying biological processes induced by L. major infection driven by the M-CSF DEGs, we mapped the time-resolved expression profiles onto a large protein-protein interaction (PPI) network and performed network propagation to identify modules of interacting proteins that agglomerate infection response signals for each strain. This analysis revealed profound differences in the resulting responses networks related to immune signaling and metabolism that were validated by qRT-PCR time series experiments leading to plausible and provable hypotheses for the differences in disease pathophysiology. In summary, we demonstrate that the host's gene expression background determines to a large degree its response to L. major infection, and that the gene expression analysis combined with network propagation is an effective approach to help identifying dynamically altered mouse strain-specific networks that hold mechanistic information about these contrasting responses to infection. CI - Copyright (c) 2023 Bouabid, Rabhi, Thedinga, Barel, Tnani, Rabhi, Benkahla, Herwig and Guizani-Tabbane. FAU - Bouabid, Cyrine AU - Bouabid C AD - Laboratory of Medical Parasitology, Biotechnology and Biomolecules (PMBB), Institut Pasteur de Tunis, Tunis, Tunisia. AD - Faculty of Sciences of Tunis, Universite de Tunis El Manar, Tunis, Tunisia. FAU - Rabhi, Sameh AU - Rabhi S AD - Laboratory of Medical Parasitology, Biotechnology and Biomolecules (PMBB), Institut Pasteur de Tunis, Tunis, Tunisia. FAU - Thedinga, Kristina AU - Thedinga K AD - Department Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany. FAU - Barel, Gal AU - Barel G AD - Department Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany. FAU - Tnani, Hedia AU - Tnani H AD - Laboratory de BioInformatic, BioMathematic and BioStatistic (BIMS), Institut Pasteur de Tunis, Tunis, Tunisia. FAU - Rabhi, Imen AU - Rabhi I AD - Laboratory of Medical Parasitology, Biotechnology and Biomolecules (PMBB), Institut Pasteur de Tunis, Tunis, Tunisia. AD - Higher Institute of Biotechnology at Sidi-Thabet (ISBST), Biotechnopole Sidi-Thabet- University of Manouba, Sidi-Thabet, Tunisia. FAU - Benkahla, Alia AU - Benkahla A AD - Laboratory de BioInformatic, BioMathematic and BioStatistic (BIMS), Institut Pasteur de Tunis, Tunis, Tunisia. FAU - Herwig, Ralf AU - Herwig R AD - Department Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany. FAU - Guizani-Tabbane, Lamia AU - Guizani-Tabbane L AD - Laboratory of Medical Parasitology, Biotechnology and Biomolecules (PMBB), Institut Pasteur de Tunis, Tunis, Tunisia. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230428 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 81627-83-0 (Macrophage Colony-Stimulating Factor) SB - IM MH - Animals MH - Mice MH - *Leishmania major/physiology MH - Macrophage Colony-Stimulating Factor/metabolism MH - *Leishmaniasis MH - Macrophages MH - Transcriptome MH - Disease Susceptibility/metabolism PMC - PMC10175952 OTO - NOTNLM OT - Leishmania OT - M-CSF OT - Resistance OT - host background OT - macrophages OT - network propagation OT - susceptibility OT - transcriptome COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2023/05/16 01:09 MHDA- 2023/05/17 06:42 PMCR- 2023/01/01 CRDT- 2023/05/15 19:30 PHST- 2022/11/29 00:00 [received] PHST- 2023/04/11 00:00 [accepted] PHST- 2023/05/17 06:42 [medline] PHST- 2023/05/16 01:09 [pubmed] PHST- 2023/05/15 19:30 [entrez] PHST- 2023/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2023.1111072 [doi] PST - epublish SO - Front Immunol. 2023 Apr 28;14:1111072. doi: 10.3389/fimmu.2023.1111072. eCollection 2023.