IAI Accepts, published online ahead of print on 11 August 2008

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Infect. Immun. doi:10.1128/IAI.00612-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Increased susceptibility to Mycobacterium avium in HFE-deficient mice

Sandra Gomes-Pereira, Pedro Nuno Rodrigues, Rui Appelberg, and Maria Salomé Gomes^*

Laboratory of Microbiology and Immunology of Infection, & Iron Genes and the Immune System, IBMC- Instituto de Biologia Molecular e Celular, Universidade do Porto (UP), Porto, Portugal; ICBAS-Instituto de Ciências Biomédicas de Abel Salazar, UP, Porto, Portugal, Escola Superior de Tecnologia da Saúde do Porto, Instituto Politécnico do Porto, Porto, Portugal
Laboratory of Microbiology and Immunology of Infectiony, & Iron Genes and the Immune System, IBMC- Instituto de Biologia Molecular e Celular, Universidade do Porto (UP), Porto, Portugal; ICBAS-Instituto de Ciências Biomédicas de Abel Salazar, UP, Porto, Portugal, Escola Superior de Tecnologia da Saúde do Porto, Instituto Politécnico do Porto, Porto, Portugal

^* To whom correspondence should be addressed. Email: sgomes{at}ibmc.up.pt.

Mycobacterium avium is an opportunistic infectious agent in immunocompromised patients, living inside macrophage phagosomes. As for other mycobacterial species, iron availability is a critical factor for M. avium survival and multiplication. Indeed, an association between host secondary iron overload and increased susceptibility to these mycobacteria is generally acknowledged. However, studies on the impact of primary iron-overload on M. avium infection have not been performed. In this work, we used animal models of primary iron-overload that mimic the human disease hereditary hemochromatosis. This pathology is characterized by increased serum transferrin saturation with iron deposition in parenchymal cells, mainly in the liver, and is most often associated with mutations in the gene encoding the molecule HFE. In this paper we demonstrate that mice of two genetically-determined primary iron-overload phenotypes, Hfe^-/- and 2m^-/-, show an increased susceptibility to experimental infection with M. avium and that during infection these animals accumulate iron inside granuloma macrophages. 2m^-/- mice were found to be more susceptible than Hfe^-/- mice, but depleting Hfe^-/- mice of CD8⁺ cells had no effect on resistance to infection. Overall, our results suggest that serum iron, rather than total liver iron levels have a considerable impact on the susceptibility to Mycobacterium avium infection.