Disrupted iron metabolism and mortality during co-infection with malaria and an intestinal gram-negative extracellular pathogen

dos Santos, L. I., Torres, T. A., DIniz, S. Q., Gonçalves, R., Caballero-Flores, G., Núñez, G., Gazzinelli, R. T., Maloy, K. J. and Antonelli, L. R. d. V. (2021) Disrupted iron metabolism and mortality during co-infection with malaria and an intestinal gram-negative extracellular pathogen. Cell Reports, 34(2), 108613. (doi: 10.1016/j.celrep.2020.108613) (PMID:33440153) (PMCID:PMC8655499)

Abstract

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Maloy, Professor Kevin
• Authors: dos Santos, L. I., Torres, T. A., DIniz, S. Q., Gonçalves, R., Caballero-Flores, G., Núñez, G., Gazzinelli, R. T., Maloy, K. J., and Antonelli, L. R. d. V.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Research Centre: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology
• Journal Name: Cell Reports
• Publisher: Elsevier (Cell Press)
• ISSN: 2211-1247
• ISSN (Online): 2211-1247
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Cell Reports 34(2):108613
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
313264		Regulation of intestinal immune homeostasis by NOD-like receptors	Kevin Maloy	Wellcome Trust (WELLCOTR)	N/A	III - Immunology