Disrupted Iron Metabolism and Mortality during Co-infection with Malaria and an Intestinal Gram-Negative Extracellular Pathogen
Luara Isabela dos Santos,
Thais Abdala Torres,
Suelen Queiroz Diniz,
Ricardo Gonçalves,
Gustavo Caballero-Flores,
Gabriel Núñez,
Ricardo Tostes Gazzinelli,
Kevin Joseph Maloy,
Lis Ribeiro do V. Antonelli
Affiliations
Luara Isabela dos Santos
Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte 30190-009, Minas Gerais, Brazil; Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK
Thais Abdala Torres
Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte 30190-009, Minas Gerais, Brazil; Instituto de Ciências Biológicas, Departamento de Bioquimica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Minas Gerais, Brazil
Suelen Queiroz Diniz
Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte 30190-009, Minas Gerais, Brazil; Instituto de Ciências Biológicas, Departamento de Bioquimica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Minas Gerais, Brazil
Ricardo Gonçalves
Departamento de Patologia Geral, ICB, Universidade Federal de Minas Gerais, Belo Horizonte, Minhas Gerais, Brazil
Gustavo Caballero-Flores
Department of Pathology and Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Gabriel Núñez
Department of Pathology and Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Ricardo Tostes Gazzinelli
Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte 30190-009, Minas Gerais, Brazil; Instituto de Ciências Biológicas, Departamento de Bioquimica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Minas Gerais, Brazil; University of Massachusetts Medical School, Worcester, MA 01605-2324, USA
Kevin Joseph Maloy
Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK; Institute of Infection, Immunity and Inflammation, University of Glasgow, Sir Graeme Davies Building, 120 University Place, Glasgow G12 8TA, Scotland; Corresponding author
Lis Ribeiro do V. Antonelli
Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte 30190-009, Minas Gerais, Brazil; Corresponding author
Summary: 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.
