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: Fatima Brant, Aline S Miranda, Lisia Esper, David Henrique Rodrigues, Lucas Miranda Kangussu, Daniella Bonaventura, Frederico Marianetti Soriani, Vanessa Pinho, Danielle G Souza, Milene Alvarenga Rachid, Louis M Weiss, Herbert B Tanowitz, Mauro Martins Teixeira, Antônio Lucio Teixeira, Fabiana Simão Machado
• Journal: Infection and immunity (Infect Immun) Vol. 82 Issue 8 Pg. 3127-40 (Aug 2014) ISSN: 1098-5522 [Electronic] United States
• PMID: 24818665 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Chemical References

• Ahr protein, mouse
• Basic Helix-Loop-Helix Transcription Factors
• Cytokines
• Receptors, Aryl Hydrocarbon
• Socs3 protein, mouse
• Suppressor of Cytokine Signaling 3 Protein
• Suppressor of Cytokine Signaling Proteins

Topics

• Animals
• Basic Helix-Loop-Helix Transcription Factors (genetics, immunology, metabolism)
• Brain (immunology, pathology)
• Cytokines (immunology, metabolism)
• Gene Deletion
• Humans
• Liver (immunology, pathology)
• Malaria (immunology, parasitology, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Plasmodium berghei (immunology)
• Receptors, Aryl Hydrocarbon (genetics, immunology, metabolism)
• Spleen (immunology)
• Suppressor of Cytokine Signaling 3 Protein
• Suppressor of Cytokine Signaling Proteins (immunology, metabolism)