title: Malaria impairs resistance to Salmonella through heme- and heme oxygenase-dependent dysfunctional granulocyte mobilization.
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.
authors.affiliation: Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: Aubrey J
authors.initials: AJ
authors.lastname: Cunnington
authors.forename: J Brian
authors.initials: JB
authors.lastname: de Souza
authors.forename: Michael
authors.initials: M
authors.lastname: Walther
authors.forename: Eleanor M
authors.initials: EM
authors.lastname: Riley
mesh_terms: D000818:Animals; D016470:Bacteremia / Q000209:etiology / Q000276:immunology*; D002465:Cell Movement; D060085:Coinfection / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D060467:Disease Resistance / Q000235:genetics; D015870:Gene Expression; D006098:Granulocytes / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology; D006418:Heme / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000235:genetics; D006427:Hemin / Q000494:pharmacology; D006461:Hemolysis / Q000276:immunology; D006801:Humans; D008288:Malaria / Q000150:complications / Q000235:genetics / Q000276:immunology*; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D010659:Phenylhydrazines / Q000494:pharmacology; D010967:Plasmodium yoelii; D016897:Respiratory Burst; D012480:Salmonella Infections / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D012486:Salmonella typhimurium
chemical_list: D008565:Membrane Proteins; D010659:Phenylhydrazines; C030299:phenylhydrazine; D006418:Heme; D006427:Hemin; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse