4.4 Article

Malaria Parasite-Mediated Alteration of Macrophage Function and Increased Iron Availability Predispose to Disseminated Nontyphoidal Salmonella Infection

Journal

INFECTION AND IMMUNITY
Volume 86, Issue 9, Pages -

Publisher

AMER SOC MICROBIOLOGY
DOI: 10.1128/IAI.00301-18

Keywords

Salmonella; coinfection; iron; macrophage; malaria

Funding

  1. USPHS [AI098078, AI126860, T32AI060555, UL1 TR001860, TL1 TR001861]
  2. American Heart Association [15PRE21420011]
  3. [RR12088-01]

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Disseminated infections with nontyphoidal Salmonella (NTS) are a significant cause of child mortality in sub-Saharan Africa. NTS infection in children is clinically associated with malaria, suggesting that malaria compromises the control of disseminated NTS infection. To study the mechanistic basis for increased NTS susceptibility, we utilized a model of concurrent infection with Salmonella enterica serotype Typhimurium and Plasmodium yoelii nigeriensis (P. yoelii). Underlying malaria blunted monocyte expression of Ly6C, a marker for inflammatory activation, and impaired recruitment of inflammatory cells to the liver. Hepatic mononuclear phagocytes expressed lower levels of inducible nitric oxide synthase, tumor necrosis factor alpha, and granulocyte-macrophage colony-stimulating factor and showed increased levels of production of interleukin-10 and heme oxygenase-1, indicating that the underlying malaria modifies the activation state and inflammatory response of mononuclear phagocytes to NTS. P. yoelii infection also increased intracellular iron levels in liver mononuclear cells, as evidenced by elevated levels of ferritin and by the rescue of an S. Typhimurium ton13 feo8 mutant defective for iron uptake. In addition, concurrent P. yoelii infection partially rescued the systemic colonization defect of an S. Typhimurium spi8 mutant defective for type Ill secretion system 2 (T35S-2), indicating that the ability of phagocytic cells to limit the spread of S. Typhimurium is impaired during concurrent P. yoelii infection. These results show that concurrent malaria increases susceptibility to disseminated NTS infection by blunting macrophage bactericidal mechanisms and providing an essential nutrient that enhances bacterial growth.

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