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Malaria impairs resistance to Salmonella through heme- and heme oxygenase–dependent dysfunctional granulocyte mobilization

Nature Medicine volume 18, pages 120–127 (2012)Cite this article

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Abstract

In sub-Saharan Africa, invasive nontyphoid Salmonella (NTS) infection is a common and often fatal complication of Plasmodium falciparum infection. Induction of heme oxygenase-1 (HO-1) mediates tolerance to the cytotoxic effects of heme during malarial hemolysis but might impair resistance to NTS by limiting production of bactericidal reactive oxygen species. We show that co-infection of mice with Plasmodium yoelii 17XNL (Py17XNL) and Salmonella enterica serovar Typhimurium 12023 (Salmonella typhimurium) causes acute, fatal bacteremia with high bacterial load, features reproduced by phenylhydrazine-induced hemolysis or hemin administration. S. typhimurium localized predominantly in granulocytes. Py17XNL, phenylhydrazine and hemin caused premature mobilization of granulocytes from bone marrow with a quantitative defect in the oxidative burst. Inhibition of HO by tin protoporphyrin abrogated the impairment of resistance to S. typhimurium by hemolysis. Thus, a mechanism of tolerance to one infection, malaria, impairs resistance to another, NTS. Furthermore, HO inhibitors may be useful adjunctive therapy for NTS infection in the context of hemolysis.

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Figure 1: Hemolysis and heme are associated with impaired resistance to S. typhimurium.
Figure 2: S. typhimurium localize in granulocytes after hemolysis and hemin treatment.
Figure 3: Hemolysis and heme cause dysfunctional granulocyte mobilization.
Figure 4: HO-1 induction in bone marrow.
Figure 5: Impaired resistance to S. typhimurium is abrogated by inhibition of heme oxygenase.
Figure 6: Proposed mechanism to explain how hemolysis impairs resistance to S. typhimurium through heme- and heme oxygenase-dependent dysfunctional granulocyte mobilization.

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  • 31 January 2012

     In the version of this article initially published, the received date was incorrect. The correct date is 25 July 2011. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

This work was supported by a UK Medical Research Council Clinical Research Training Fellowship (G0701427) and a small grant award from the European Society for Pediatric Infectious Diseases awarded to A.J.C. We wish to thank D. Holden (Imperial College, London) for providing GFP-expressing S. typhimurium and R. Motterlini, S. Baines, H. Kaur, L. King, C. Stanley, R. Gregory, L. McCarthy, K. Couper, J. Hafalla, E. Findlay and D. Blount for technical advice and assistance.

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Author notes

  1. Michael Walther

    Present address: Current address: Immune Regulation Section, Laboratory of Malaria Immunology and Vaccinology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Rockville, Maryland, USA.,

Authors and Affiliations

  1. Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK

    Aubrey J Cunnington, J Brian de Souza & Eleanor M Riley

  2. Division of Infection and Immunity, University College London Medical School, London, UK

    J Brian de Souza

  3. Medical Research Council Laboratories, Banjul, The Gambia

    Michael Walther

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Contributions

A.J.C. and J.B.d.S. conducted the experiments. A.J.C. and E.M.R. wrote the manuscript. All authors contributed to the conception and planning of the experiments, and to critical revision of the manuscript. M.W. and E.M.R. supervised the project.

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Correspondence to Eleanor M Riley.

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Cunnington, A., de Souza, J., Walther, M. et al. Malaria impairs resistance to Salmonella through heme- and heme oxygenase–dependent dysfunctional granulocyte mobilization. Nat Med 18, 120–127 (2012). https://doi.org/10.1038/nm.2601

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