title: Role of the aryl hydrocarbon receptor in the immune response profile and development of pathology during Plasmodium berghei Anka infection.
abstract: Infection with Plasmodium falciparum may result in severe disease affecting various organs, including liver, spleen, and brain, resulting in high morbidity and mortality. Plasmodium berghei Anka infection of mice recapitulates many features of severe human malaria. The aryl hydrocarbon receptor (AhR) is an intracellular receptor activated by ligands important in the modulation of the inflammatory response. We found that AhR-knockout (KO) mice infected with P. berghei Anka displayed increased parasitemia, earlier mortality, enhanced leukocyte-endothelial cell interactions in the brain microvasculature, and increased inflammation in brain (interleukin-17 [IL-17] and IL-6) and liver (gamma interferon [IFN-γ] and tumor necrosis factor alpha [TNF-α]) compared to infected wild-type (WT) mice. Infected AhR-KO mice also displayed a reduction in cytokines required for host resistance, including TNF-α, IL-1β, and IFN-γ, in the brain and spleen. Infection of AhR-KO mice resulted in an increase in T regulatory cells and transforming growth factor β, IL-6, and IL-17 in the brain. AhR modulated the basal expression of SOCS3 in spleen and brain, and P. berghei Anka infection resulted in enhanced expression of SOCS3 in brain, which was absent in infected AhR-KO mice. These data suggest that AhR-mediated control of SOCS3 expression is probably involved in the phenotype seen in infected AhR-KO mice. This is, to our knowledge, the first demonstration of a role for AhR in the pathogenesis of malaria.
authors.affiliation: Program in Health Sciences, Infectious Diseases and Tropical Medicine/Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil Department of Biochemistry and Immunology, Institute of Biological Science, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Fatima
authors.initials: F
authors.lastname: Brant
authors.affiliation: Program in Health Sciences, Infectious Diseases and Tropical Medicine/Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil Department of Biochemistry and Immunology, Institute of Biological Science, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Aline S
authors.initials: AS
authors.lastname: Miranda
authors.affiliation: Program in Health Sciences, Infectious Diseases and Tropical Medicine/Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil Department of Biochemistry and Immunology, Institute of Biological Science, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Lisia
authors.initials: L
authors.lastname: Esper
authors.affiliation: Department of Biochemistry and Immunology, Institute of Biological Science, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: David Henrique
authors.initials: DH
authors.lastname: Rodrigues
authors.affiliation: Department of Physiology and Biophysics, Institute of Biological Science, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Lucas Miranda
authors.initials: LM
authors.lastname: Kangussu
authors.affiliation: Department of Physiology and Biophysics, Institute of Biological Science, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Daniella
authors.initials: D
authors.lastname: Bonaventura
authors.affiliation: Department of General Biology, Institute of Biological Science, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Frederico Marianetti
authors.initials: FM
authors.lastname: Soriani
authors.affiliation: Department of Morphology, Institute of Biological Science, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Pinho
authors.affiliation: Department of Microbiology, Institute of Biological Science, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Danielle G
authors.initials: DG
authors.lastname: Souza
authors.affiliation: Department of Pathology, Institute of Biological Science, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Milene Alvarenga
authors.initials: MA
authors.lastname: Rachid
authors.affiliation: Departments of Pathology and Medicine, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Weiss
authors.affiliation: Departments of Pathology and Medicine, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Herbert B
authors.initials: HB
authors.lastname: Tanowitz
authors.affiliation: Program in Health Sciences, Infectious Diseases and Tropical Medicine/Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil Department of Biochemistry and Immunology, Institute of Biological Science, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Mauro Martins
authors.initials: MM
authors.lastname: Teixeira
authors.affiliation: Program in Health Sciences, Infectious Diseases and Tropical Medicine/Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil Department of Biochemistry and Immunology, Institute of Biological Science, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Antônio Lucio
authors.initials: AL
authors.lastname: Teixeira
authors.affiliation: Program in Health Sciences, Infectious Diseases and Tropical Medicine/Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil Department of Biochemistry and Immunology, Institute of Biological Science, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil machadofs@icb.ufmg.br.
authors.forename: Fabiana Simão
authors.initials: FS
authors.lastname: Machado
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D001921:Brain / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D017353:Gene Deletion; D006801:Humans; D008099:Liver / Q000276:immunology / Q000473:pathology; D008288:Malaria / Q000276:immunology* / Q000469:parasitology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010962:Plasmodium berghei / Q000276:immunology*; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D013154:Spleen / Q000276:immunology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000276:immunology* / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D016207:Cytokines; D018336:Receptors, Aryl Hydrocarbon; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C484722:Ahr protein, mouse; C491411:Socs3 protein, mouse