A Loss-of-Function Mutation in the Integrin Alpha L ( Itgal ) Gene Contributes to Susceptibility to Salmonella enterica Serovar Typhimurium Infection in Collaborative Cross Strain CC042
| Autor: | Jing Zhang, Rachel Meade, Megan Teh, Danielle Malo, Anastasia Nijnik, Jean Jaubert, Xavier Montagutelli, Megan M. Eva, Jamie Kim, Romain Cayrol |
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| Přispěvatelé: | Génétique de la souris - Mouse Genetics, Institut Pasteur [Paris] (IP), McGill University Research Centre on Complex Traits [Montreal] (MRCCT), McGill University = Université McGill [Montréal, Canada], Université de Montréal (UdeM), D.M. is the recipient of a Canadian Institutes of Health Research (CIHR) project grant (grant MOP133700) and a Natural Sciences and Engineering Research Council (NSERC) discovery grant (grant RGPIN-2017-04717). A.N. is a Canada Research Chair Tier II in Hematopoiesis and Lymphocyte Differentiation and the recipient of CIHR project grant PJT-153016 and NSERC discovery grant RGPIN-2016-05657. Funding had been provided to M.T. by an NSERC Undergraduate Student Research Award and the Fonds de Recherche du Québec Nature et Technologies and to J.K. by the McGill Faculty of Medicine Solvay Fellowship. The flow cytometry work/cell sorting was performed in the Flow Cytometry Core Facility for flow cytometry and single cell analysis of the Life Science Complex (McGill University) and was supported by funding from the Canadian Foundation for Innovation. This study was also supported by AgroParisTech (France) through a Ph.D. fellowship to J.Z., We thank Line Larivière and Hyejin Park for technical assistance and Patricia D’Arcy (McGill University) and Isabelle Lanctin and Tommy Penel (DTPS/C2RA-Central Animal Facility, Institut Pasteur) for mouse breeding and screening., Institut Pasteur [Paris] |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
QTL mapping Salmonella MESH: Spleen Immunology Integrin Alpha-L MESH: Lymphocyte Subsets Spleen MESH: CD11a Antigen medicine.disease_cause MESH: Bacterial Load Microbiology host resistance 03 medical and health sciences 0302 clinical medicine immunophenotyping MESH: Mice Inbred C57BL medicine Splenocyte MESH: Animals MESH: Bacteremia Gene MESH: Mice [SDV.GEN]Life Sciences [q-bio]/Genetics MESH: Salmonella Infections biology MESH: Genetic Predisposition to Disease MESH: Salmonella typhimurium MESH: Loss of Function Mutation MESH: Serogroup MESH: Thymus Gland biology.organism_classification MESH: Genes 3. Good health Complementation 030104 developmental biology Infectious Diseases medicine.anatomical_structure Salmonella enterica MESH: Survival Analysis Parasitology MESH: Bone Marrow MESH: Disease Models Animal CD8 030215 immunology |
| Zdroj: | Infection and Immunity Infection and Immunity, 2019, 88 (1), pp.e00656-19. ⟨10.1128/IAI.00656-19⟩ Infection and Immunity, American Society for Microbiology, 2019, 88 (1), pp.e00656-19. ⟨10.1128/IAI.00656-19⟩ |
| ISSN: | 0019-9567 1098-5522 |
| DOI: | 10.1128/IAI.00656-19⟩ |
| Popis: | International audience; Salmonella is an intracellular bacterium found in the gastrointestinal tract of mammalian, avian, and reptilian hosts. Mouse models have been extensively used to model in vivo distinct aspects of human Salmonella infections and have led to the identification of several host susceptibility genes. We have investigated the susceptibility of Collaborative Cross strains to intravenous infection with Salmonella enterica serovar Typhimurium as a model of human systemic invasive infection. In this model, strain CC042/GeniUnc (CC042) mice displayed extreme susceptibility with very high bacterial loads and mortality. CC042 mice showed lower spleen weights and decreased splenocyte numbers before and after infection, affecting mostly CD8+ T cells, B cells, and all myeloid cell populations, compared with control C57BL/6J mice. CC042 mice also had lower thymus weights with a reduced total number of thymocytes and double-negative and double-positive (CD4+, CD8+) thymocytes compared to C57BL/6J mice. Analysis of bone marrow-resident hematopoietic progenitors showed a strong bias against lymphoid-primed multipotent progenitors. An F2 cross between CC042 and C57BL/6N mice identified two loci on chromosome 7 (Stsl6 and Stsl7) associated with differences in bacterial loads. In the Stsl7 region, CC042 carried a loss-of-function variant, unique to this strain, in the integrin alpha L (Itgal) gene, the causative role of which was confirmed by a quantitative complementation test. Notably, Itgal loss of function increased the susceptibility to S. Typhimurium in a (C57BL/6J × CC042)F1 mouse background but not in a C57BL/6J mouse inbred background. These results further emphasize the utility of the Collaborative Cross to identify new host genetic variants controlling susceptibility to infections and improve our understanding of the function of the Itgal gene. |
| Databáze: | OpenAIRE |
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