Article | Published:

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

Nature Medicine volume 18, pages 120127 (2012) | Download Citation

This article has been updated

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Change history

  • 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.

References

  1. 1.

    , & Invasive non-Typhi Salmonella disease in Africa. Clin. Infect. Dis. 49, 606–611 (2009).

  2. 2.

    et al. HIV infection, malnutrition and invasive bacterial infection among children with severe malaria. Clin. Infect. Dis. 49, 336–343 (2009).

  3. 3.

    , & Plasmodium falciparum malaria and Salmonella infections in Gambian children. J. Infect. Dis. 155, 1319–1321 (1987).

  4. 4.

    et al. Bacteremia in Malawian children with severe malaria: prevalence, etiology, HIV coinfection and outcome. J. Infect. Dis. 195, 895–904 (2007).

  5. 5.

    , & Septicemia caused by Salmonella infection: an overlooked complication of sickle cell disease. J. Pediatr. 130, 394–399 (1997).

  6. 6.

    , & Influence of Plasmodium berghei infection on susceptibility to Salmonella infection. Proc. Soc. Exp. Biol. Med. 120, 810–813 (1965).

  7. 7.

    Host defenses in murine malaria: analysis of plasmodial infection–caused defects in macrophage microbicidal capacities. Infect. Immun. 31, 396–407 (1981).

  8. 8.

    et al. Both hemolytic anemia and malaria parasite-specific factors increase susceptibility to nontyphoidal Salmonella enterica serovar Typhimurium infection in mice. Infect. Immun. 78, 1520–1527 (2010).

  9. 9.

    & The influence of hemolysis or blood loss on susceptibility to infection. J. Immunol. 91, 65–75 (1963).

  10. 10.

    & The influence of hemolysis on susceptibility to Salmonella infection: additional observations. J. Immunol. 91, 518–527 (1963).

  11. 11.

    et al. Pyruvate kinase deficiency confers susceptibility to Salmonella typhimurium infection in mice. J. Exp. Med. 204, 2949–2961 (2007).

  12. 12.

    , & Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications. Physiol. Rev. 86, 583–650 (2006).

  13. 13.

    , & Microsomal heme oxygenase. Characterization of the enzyme. J. Biol. Chem. 244, 6388–6394 (1969).

  14. 14.

    et al. Heme is a potent inducer of inflammation in mice and is counteracted by heme oxygenase. Blood 98, 1802–1811 (2001).

  15. 15.

    , , , & Neutrophil activation by heme: implications for inflammatory processes. Blood 99, 4160–4165 (2002).

  16. 16.

    et al. Heme induces neutrophil migration and reactive oxygen species generation through signaling pathways characteristic of chemotactic receptors. J. Biol. Chem. 282, 24430–24436 (2007).

  17. 17.

    , & Mechanisms of cell protection by heme oxygenase-1. Annu. Rev. Pharmacol. Toxicol. 50, 323–354 (2010).

  18. 18.

    & Heme oxygenase 1 is required for mammalian iron reutilization. Proc. Natl. Acad. Sci. USA 94, 10919–10924 (1997).

  19. 19.

    & Reduced stress defense in heme oxygenase 1–deficient cells. Proc. Natl. Acad. Sci. USA 94, 10925–10930 (1997).

  20. 20.

    et al. Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. J. Clin. Invest. 103, 129–135 (1999).

  21. 21.

    & Heme oxygenase-1: from biology to therapeutic potential. Trends Mol. Med. 15, 50–58 (2009).

  22. 22.

    , , , & Cerebral malaria and the hemolysis/methemoglobin/heme hypothesis: shedding new light on an old disease. Int. J. Biochem. Cell Biol. 41, 711–716 (2009).

  23. 23.

    et al. Heme oxygenase-1 is a modulator of inflammation and vaso-occlusion in transgenic sickle mice. J. Clin. Invest. 116, 808–816 (2006).

  24. 24.

    et al. Heme oxygenase-1 and carbon monoxide suppress the pathogenesis of experimental cerebral malaria. Nat. Med. 13, 703–710 (2007).

  25. 25.

    et al. Heme oxygenase-1 affords protection against noncerebral forms of severe malaria. Proc. Natl. Acad. Sci. USA 106, 15837–15842 (2009).

  26. 26.

    et al. Sickle hemoglobin confers tolerance to Plasmodium infection. Cell 145, 398–409 (2011).

  27. 27.

    et al. A central role for free heme in the pathogenesis of severe sepsis. Sci. Transl. Med. 2, 51ra71 (2010).

  28. 28.

    et al. Antimicrobial actions of the NADPH phagocyte oxidase and inducible nitric oxide synthase in experimental salmonellosis. II. Effects on microbial proliferation and host survival in vivo. J. Exp. Med. 192, 237–248 (2000).

  29. 29.

    et al. Characterization and regulation of RB6–8C5 antigen expression on murine bone marrow cells. J. Immunol. 147, 22–28 (1991).

  30. 30.

    et al. Heme oxygenase-1 expression inhibits dendritic cell maturation and proinflammatory function but conserves IL-10 expression. Blood 106, 1694–1702 (2005).

  31. 31.

    , & Leishmania pifanoi amastigotes avoid macrophage production of superoxide by inducing heme degradation. Infect. Immun. 73, 8322–8333 (2005).

  32. 32.

    et al. Induction of heme oxygenase-1 in vivo suppresses NADPH oxidase derived oxidative stress. Hypertension 50, 636–642 (2007).

  33. 33.

    , , & Heme oxygenase-1 protects against neutrophil-mediated intestinal damage by down-regulation of neutrophil p47phox and p67phox activity and O2 production in a two-hit model of alcohol intoxication and burn injury. J. Immunol. 180, 6933–6940 (2008).

  34. 34.

    , , & A simple flow cytometry assay using dihydrorhodamine for the measurement of the neutrophil respiratory burst in whole blood: comparison with the quantitative nitrobluetetrazolium test. J. Immunol. Methods 219, 187–193 (1998).

  35. 35.

    et al. Granulocyte colony-stimulating factor administration to healthy volunteers: analysis of the immediate activating effects on circulating neutrophils. Blood 84, 3885–3894 (1994).

  36. 36.

    & Functional differentiation of normal human neutrophils. Blood 69, 937–944 (1987).

  37. 37.

    et al. Migrating monocytes recruited to the spleen play an important role in control of blood stage malaria. Blood 114, 5522–5531 (2009).

  38. 38.

    et al. Structural organization of the neutrophil NADPH oxidase: phosphorylation and translocation during priming and activation. J. Leukoc. Biol. 78, 1025–1042 (2005).

  39. 39.

    et al. Heme oxygenase and carbon monoxide initiate homeostatic signaling. J. Mol. Med. 86, 267–279 (2008).

  40. 40.

    & Phenylhydrazine-mediated induction of haem oxygenase activity in rat liver and kidney and development of hyperbilirubinaemia. Inhibition by zinc-protoporphyrin. Biochem. J. 217, 409–417 (1984).

  41. 41.

    et al. Induction of an IL7-R+c-Kithi myelolymphoid progenitor critically dependent on IFN-γ signaling during acute malaria. Nat. Immunol. 11, 477–485 (2010).

  42. 42.

    , , & A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature 404, 193–197 (2000).

  43. 43.

    , , & Role of Bach1 and Nrf2 in up-regulation of the heme oxygenase-1 gene by cobalt protoporphyrin. FASEB J. 20, 2651–2653 (2006).

  44. 44.

    et al. Processing and maturation of flavocytochrome b558 include incorporation of heme as a prerequisite for heterodimer assembly. J. Biol. Chem. 275, 13986–13993 (2000).

  45. 45.

    et al. The co-ordinated regulation of iron homeostasis in murine macrophages limits the availability of iron for intracellular Salmonella typhimurium. Cell. Microbiol. 9, 2126–2140 (2007).

  46. 46.

    et al. Cytoprotective function of heme oxygenase 1 induced by a nitrated cyclic nucleotide formed during murine salmonellosis. J. Immunol. 182, 3746–3756 (2009).

  47. 47.

    , , & A dynamic view of the spread and intracellular distribution of Salmonella enterica. Nat. Rev. Microbiol. 7, 73–80 (2009).

  48. 48.

    , & Animal defenses against infectious agents: is damage control more important than pathogen control. PLoS Biol. 6, e4 (2008).

  49. 49.

    & Two ways to survive infection: what resistance and tolerance can teach us about treating infectious diseases. Nat. Rev. Immunol. 8, 889–895 (2008).

  50. 50.

    et al. Heme oxygenase-1 is an anti-inflammatory host factor that promotes murine plasmodium liver infection. Cell Host Microbe 3, 331–338 (2008).

  51. 51.

    & The role of anorexia in resistance and tolerance to infections in Drosophila. PLoS Biol. 7, e1000150 (2009).

  52. 52.

    & Inhibition of pulmonary antibacterial defense by interferon-gamma during recovery from influenza infection. Nat. Med. 14, 558–564 (2008).

  53. 53.

    & Heme oxygenase-1/carbon monoxide: from metabolism to molecular therapy. Am. J. Respir. Cell Mol. Biol. 41, 251–260 (2009).

  54. 54.

    The evolution of carbon monoxide into medicine. Respir. Care 54, 925–932 (2009).

  55. 55.

    , , , & Sn-protoporphyrin use in the management of hyperbilirubinemia in term newborns with direct Coombs-positive ABO incompatibility. Pediatrics 81, 485–497 (1988).

  56. 56.

    et al. Cobalt protoporphyrine IX–mediated heme oxygenase-I induction alters the inflammatory cytokine response, but not antigen presentation after experimental allogeneic bone marrow transplantation. Int. J. Mol. Med. 20, 301–308 (2007).

  57. 57.

    & Hematin–studies on protein complexes and determination in human plasma. Am. J. Clin. Pathol. 40, 113–122 (1963).

  58. 58.

    , & An evaluation of a spectrophotometric scanning technique for measurement of plasma hemoglobin. Ann. Clin. Lab. Sci. 11, 126–131 (1981).

  59. 59.

    , , & Thiol compounds interact with nitric oxide in regulating heme oxygenase-1 induction in endothelial cells. Involvement of superoxide and peroxynitrite anions. J. Biol. Chem. 272, 18411–18417 (1997).

Download references

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.

Author information

Author notes

    • Michael Walther

    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.

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

Authors

  1. Search for Aubrey J Cunnington in:

  2. Search for J Brian de Souza in:

  3. Search for Michael Walther in:

  4. Search for Eleanor M Riley in:

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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Eleanor M Riley.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–7 and Supplementary Methods

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nm.2601

Further reading