Suppressor of cytokine signaling 2 modulates the immune response profile and development of experimental cerebral malaria

Fatima Brant, Aline S. Miranda, Lisia Esper, Melisa Gualdrón-López, Daniel Cisalpino, Danielle da Gloria de Souza, Milene Alvarenga Rachid, Herbert B. Tanowitz, Mauro Martins Teixeira, Antônio Lucio Teixeira, Fabiana Simão Machado

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish (US)
JournalBrain, Behavior, and Immunity
DOIs
StateAccepted/In press - Sep 17 2015

Fingerprint

Cerebral Malaria
Cytokines
Plasmodium berghei
Parasitemia
Brain
Infection
Nitric Oxide
Th1 Cells
Interleukin-17
Nerve Growth Factors
Regulatory T-Lymphocytes
Malaria
Intracellular Signaling Peptides and Proteins
Anxiety
Communicable Disease Control
Glial Cell Line-Derived Neurotrophic Factor
Th17 Cells
Brain-Derived Neurotrophic Factor
Neurogenesis
Plasmodium falciparum

Keywords

  • BDNF
  • Cerebral malaria
  • GDNF
  • Immune regulation
  • l-NAME
  • Neuroimmune response
  • Neuroinflammation
  • Neurotrophic factors
  • Nitric oxide
  • SOCS2

ASJC Scopus subject areas

  • Immunology
  • Behavioral Neuroscience
  • Endocrine and Autonomic Systems

Cite this

Brant, F., Miranda, A. S., Esper, L., Gualdrón-López, M., Cisalpino, D., de Souza, D. D. G., ... Machado, F. S. (Accepted/In press). Suppressor of cytokine signaling 2 modulates the immune response profile and development of experimental cerebral malaria. Brain, Behavior, and Immunity. https://doi.org/10.1016/j.bbi.2016.01.002

Suppressor of cytokine signaling 2 modulates the immune response profile and development of experimental cerebral malaria. / Brant, Fatima; Miranda, Aline S.; Esper, Lisia; Gualdrón-López, Melisa; Cisalpino, Daniel; de Souza, Danielle da Gloria; Rachid, Milene Alvarenga; Tanowitz, Herbert B.; Teixeira, Mauro Martins; Teixeira, Antônio Lucio; Machado, Fabiana Simão.

In: Brain, Behavior, and Immunity, 17.09.2015.

Research output: Contribution to journalArticle

Brant, F, Miranda, AS, Esper, L, Gualdrón-López, M, Cisalpino, D, de Souza, DDG, Rachid, MA, Tanowitz, HB, Teixeira, MM, Teixeira, AL & Machado, FS 2015, 'Suppressor of cytokine signaling 2 modulates the immune response profile and development of experimental cerebral malaria', Brain, Behavior, and Immunity. https://doi.org/10.1016/j.bbi.2016.01.002
Brant, Fatima ; Miranda, Aline S. ; Esper, Lisia ; Gualdrón-López, Melisa ; Cisalpino, Daniel ; de Souza, Danielle da Gloria ; Rachid, Milene Alvarenga ; Tanowitz, Herbert B. ; Teixeira, Mauro Martins ; Teixeira, Antônio Lucio ; Machado, Fabiana Simão. / Suppressor of cytokine signaling 2 modulates the immune response profile and development of experimental cerebral malaria. In: Brain, Behavior, and Immunity. 2015.
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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.",
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AU - Cisalpino, Daniel

AU - de Souza, Danielle da Gloria

AU - Rachid, Milene Alvarenga

AU - Tanowitz, Herbert B.

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