title: Suppressor of cytokine signaling 2 modulates the immune response profile and development of experimental cerebral malaria.
abstract: Plasmodium falciparum infection results in severe malaria in humans, affecting various organs, including the liver, spleen and brain, and resulting in high morbidity and mortality. The Plasmodium berghei ANKA (PbA) infection in mice closely recapitulates many aspects of human cerebral malaria (CM); thus, this model has been used to investigate the pathogenesis of CM. Suppressor of cytokine signaling 2 (SOCS2), an intracellular protein induced by cytokines and hormones, modulates the immune response, neural development, neurogenesis and neurotrophic pathways. However, the role of SOCS2 during CM remains unknown. SOCS2 knockout (SOCS2(-/-)) mice infected with PbA show an initial resistance to infection with reduced parasitemia and production of TNF, TGF-β, IL-12 and IL-17 in the brain. Interestingly, in the late phase of infection, SOCS2(-/-) mice display increased parasitemia and reduced Treg cell infiltration, associated with enhanced levels of Th1 and Th17 cells and related cytokines IL-17, IL-6, and TGF-β in the brain. A significant reduction in protective neurotrophic factors, such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), was also observed. Moreover, the molecular alterations in the brain of infected SOCS2(-/-) mice were associated with anxiety-related behaviors and cognition impairment. Mechanistically, these results revealed enhanced nitric oxide (NO) production in PbA-infected SOCS2(-/-) mice, and the inhibition of NO synthesis through l-NAME led to a marked decrease in survival, the disruption of parasitemia control and more pronounced anxiety-like behavior. Treatment with l-NAME also shifted the levels of Th1, Th7 and Treg cells in the brains of infected SOCS2(-/-) mice to the background levels observed in infected WT, with remarkable exception of increased CD8(+)IFN(+) T cells and inflammatory monocytes. These results indicate that SOCS2 plays a dual role during PbA infection, being detrimental in the control of the parasite replication but crucial in the regulation of the immune response and production of neurotrophic factors. Here, we provided strong evidence of a critical relationship between SOCS2 and NO in the orchestration of the immune response and development of CM during PbA infection.
authors.affiliation: Program in Health Sciences: Infectious Diseases and Tropical Medicine, School 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, School 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, School 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: Melisa
authors.initials: M
authors.lastname: Gualdrón-López
authors.affiliation: Department of Microbiology, Institute of Biological Science, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Daniel
authors.initials: D
authors.lastname: Cisalpino
authors.affiliation: Department of Microbiology, Institute of Biological Science, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Danielle da Gloria
authors.initials: DDG
authors.lastname: de 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: Department of Pathology and Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Herbert B
authors.initials: HB
authors.lastname: Tanowitz
authors.affiliation: Program in Health Sciences: Infectious Diseases and Tropical Medicine, School 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, School 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, School 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. Electronic address: machadofs@icb.ufmg.br.
authors.forename: Fabiana Simão
authors.initials: FS
authors.lastname: Machado
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D016779:Malaria, Cerebral / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009414:Nerve Growth Factors / Q000378:metabolism; D010962:Plasmodium berghei / Q000302:isolation & purification; D013154:Spleen / Q000378:metabolism; D050826:Suppressor of Cytokine Signaling Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism; D058504:Th17 Cells / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D016207:Cytokines; D009414:Nerve Growth Factors; C491409:Socs2 protein, mouse; D050826:Suppressor of Cytokine Signaling Proteins; D016212:Transforming Growth Factor beta
keywords: BDNF; Cerebral malaria; GDNF; Immune regulation; Neuroimmune response; Neuroinflammation; Neurotrophic factors; Nitric oxide; SOCS2; l-NAME