The Journal of Experimental Medicine
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Published online November 12, 2007
doi:10.1084/jem.20062606
The Journal of Experimental Medicine, Vol. 204, No. 12, 2949-2961
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Roy et al.
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ARTICLE

 Pyruvate kinase deficiency confers susceptibility to Salmonella typhimurium infection in mice

Marie-France Roy1,2, Noémie Riendeau2, Christian Bédard5, Pierre Hélie5, Gundula Min-Oo2,3, Karine Turcotte2,3, Philippe Gros2,3, François Canonne-Hergaux6, and Danielle Malo1,2,4

1 Department of Human Genetics, 2 Center for the Study of Host Resistance, 3 Department of Biochemistry, 4 Department of Medicine, McGill University Health Center, Montréal, Québec, H3G 1A4, Canada
5 Département de Pathologie et de Microbiologie, Faculté de Médecine Vétérinaire, Université de Montréal, St-Hyacinthe, Québec, J2S 2M2, Canada
6 Institut National de la Santé et de la Recherche Médicale, U656, Fer et Synthèse d'Hème, Génétique, Physiologie et Pathologie, Faculté de Médecine Xavier Bichat, Paris, 75870, France

CORRESPONDENCE Danielle Malo:danielle.malo{at}mcgill.ca

The mouse response to acute Salmonella typhimurium infection is complex, and it is under the influence of several genes, as well as environmental factors. In a previous study, we identified two novel Salmonella susceptibility loci, Ity4 and Ity5, in a (AcB61 x 129S6)F2 cross. The peak logarithm of odds score associated with Ity4 maps to the region of the liver and red blood cell (RBC)–specific pyruvate kinase (Pklr) gene, which was previously shown to be mutated in AcB61. During Plasmodium chabaudi infection, the Pklr mutation protects the mice against this parasite, as indicated by improved survival and lower peak parasitemia. Given that RBC defects have previously been associated with resistance to malaria and susceptibility to Salmonella, we hypothesized that Pklr is the gene underlying Ity4 and that it confers susceptibility to acute S. typhimurium infection in mice. Using a fine mapping approach combined with complementation studies, comparative studies, and functional analysis, we show that Pklr is the gene underlying Ity4 and that it confers susceptibility to acute S. typhimurium infection in mice through its effect on the RBC turnover and iron metabolism.

Abbreviations used: BMDM, BM-derived macrophages; LOD, logarithm of odds; Nramp, Natural resistance-associated macrophage protein; PHZ, phenylhydrazine; PK, pyruvate kinase; RBC, red blood cell; RCS, recombinant congenic strain; RES, reticuloendothelial system; Tlr, Toll-like receptor.


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