Disrupted Iron Metabolism and Mortality during Co-infection with Malaria and an Intestinal Gram-Negative Extracellular Pathogen

• Published in: Cell reports (Cambridge) Vol. 34; no. 2; p. 108613
• Main Authors: dos Santos, Luara Isabela, Torres, Thais Abdala, Diniz, Suelen Queiroz, Gonçalves, Ricardo, Caballero-Flores, Gustavo, Núñez, Gabriel, Gazzinelli, Ricardo Tostes, Maloy, Kevin Joseph, Ribeiro do V. Antonelli, Lis
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12-01-2021; Cell Press; Elsevier
• Subjects: Animals; Citrobacter rodentium; co-infection; Coinfection; Enterobacteriaceae Infections - immunology; Gram-negative bacteria; heme; hemolysis; Humans; Intestines - physiopathology; iron; Iron - metabolism; malaria; Malaria - immunology; Malaria - mortality; Mice; mortality; Plasmodium; Survival Analysis; Plasmodium; co-infection; heme; mortality; iron; Gram-negative bacteria; Citrobacter rodentium; malaria; hemolysis
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.108613

Individuals with malaria exhibit increased morbidity and mortality when infected with Gram-negative (Gr−) bacteria. To explore this experimentally, we performed co-infection of mice with Plasmodium chabaudi and Citrobacter rodentium, an extracellular Gr− bacterial pathogen that infects the large intestine. While single infections are controlled effectively, co-infection results in enhanced virulence that is characterized by prolonged systemic bacterial persistence and high mortality. Mortality in co-infected mice is associated with disrupted iron metabolism, elevated levels of plasma heme, and increased mitochondrial reactive oxygen species (ROS) production by phagocytes. In addition, iron acquisition by the bacterium plays a key role in pathogenesis because co-infection with a mutant C. rodentium strain lacking a critical iron acquisition pathway does not cause mortality. These results indicate that disrupted iron metabolism may drive mortality during co-infection with C. rodentium and P. chabaudi by both altering host immune responses and facilitating bacterial persistence.
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•Co-infection with malaria and a Gram-negative bacterial pathogen leads to high mortality•Co-infection leads to elevated plasma heme and systemic bacterial persistence•Iron acquisition is critical for bacterial persistence and mortality
Mortality of individuals with malaria and bacteremia is higher than with malaria alone. dos Santos et al. report that co-infection with Citrobacter rodentium and Plasmodium chabaudi results in high mortality that is associated with increased plasma heme, sustained bacterial persistence, and altered host immunity.