Behavioural and neurological symptoms accompanied by cellular neuroinflammation in IL-10-deficient mice infected with Plasmodium chabaudi

Kyle D. Wilson, Sonja J. Stutz, Lorenzo F. Ochoa, Gustavo A. Valbuena, Petra D. Cravens, Kelly Dineley, Gracie Vargas, Robin Stephens

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Background: Cerebral malaria is one of the most severe complications of Plasmodium falciparum infection and occurs mostly in young African children. This syndrome results from a combination of high levels of parasitaemia and inflammation. Although parasite sequestration in the brain is a feature of the human syndrome, sequestering strains do not uniformly cause severe malaria, suggesting interplay with other factors. Host genetic factors such as mutations in the promoters of the cytokines IL-10 and TNF are also clearly linked to severe disease. Plasmodium chabaudi, a rodent malaria parasite, leads to mild illness in wildtype animals. However, IL-10-/- mice respond to parasite with increased levels of pro-inflammatory cytokines IFN-γ and TNF, leading to lethal disease in the absence of sequestration in the brain. These mice also exhibit cerebral symptoms including gross cerebral oedema and haemorrhage, allowing study of these critical features of disease without the influence of sequestration. Methods: The neurological consequences of P. chabaudi infection were investigated by performing a general behavioural screen (SHIRPA). The immune cell populations found in the brain during infection were also analysed using flow cytometry and confocal microscopy. Results: IL-10-/- mice suffer significant declines in behavioural and physical capacities during infection compared to wildtype. In addition, grip strength and pain sensitivity were affected, suggestive of neurological involvement. Several immune cell populations were identified in the perfused brain on day 7 post-infection, suggesting that they are tightly adherent to the vascular endothelium, or potentially located within the brain parenchyma. There was an increase in both inflammatory monocyte and resident macrophage (CD11bhi, CD45+, MHCII+, Ly6C+/-) numbers in IL-10-/- compared to wildtype animals. In addition, the activation state of all monocytes and microglia (CD11bint, CD45-, MHC-II+) were increased. T cells making IFN-γ were also identified in the brain, but were localized within the vasculature, and not the parenchyma. Conclusions: These studies demonstrate exacerbated neuroinflammation concurrent with development of behavioural symptoms in P. chabaudi infection of IL-10-/- animals.

Original languageEnglish (US)
Article number428
JournalMalaria Journal
Volume15
Issue number1
DOIs
StatePublished - Aug 24 2016

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Plasmodium chabaudi
Behavioral Symptoms
Interleukin-10
Malaria
Brain
Parasites
Monocytes
Infection
Cytokines
Cerebral Malaria
Parasitemia
Brain Edema
Vascular Endothelium
Cerebral Hemorrhage
Microglia
Hand Strength
Plasmodium falciparum
Confocal Microscopy
Population
Rodentia

Keywords

  • Brain
  • Malaria
  • Monocyte
  • Mouse
  • Neuroinflammation
  • T cell

ASJC Scopus subject areas

  • Parasitology
  • Infectious Diseases

Cite this

Behavioural and neurological symptoms accompanied by cellular neuroinflammation in IL-10-deficient mice infected with Plasmodium chabaudi. / Wilson, Kyle D.; Stutz, Sonja J.; Ochoa, Lorenzo F.; Valbuena, Gustavo A.; Cravens, Petra D.; Dineley, Kelly; Vargas, Gracie; Stephens, Robin.

In: Malaria Journal, Vol. 15, No. 1, 428, 24.08.2016.

Research output: Contribution to journalArticle

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title = "Behavioural and neurological symptoms accompanied by cellular neuroinflammation in IL-10-deficient mice infected with Plasmodium chabaudi",
abstract = "Background: Cerebral malaria is one of the most severe complications of Plasmodium falciparum infection and occurs mostly in young African children. This syndrome results from a combination of high levels of parasitaemia and inflammation. Although parasite sequestration in the brain is a feature of the human syndrome, sequestering strains do not uniformly cause severe malaria, suggesting interplay with other factors. Host genetic factors such as mutations in the promoters of the cytokines IL-10 and TNF are also clearly linked to severe disease. Plasmodium chabaudi, a rodent malaria parasite, leads to mild illness in wildtype animals. However, IL-10-/- mice respond to parasite with increased levels of pro-inflammatory cytokines IFN-γ and TNF, leading to lethal disease in the absence of sequestration in the brain. These mice also exhibit cerebral symptoms including gross cerebral oedema and haemorrhage, allowing study of these critical features of disease without the influence of sequestration. Methods: The neurological consequences of P. chabaudi infection were investigated by performing a general behavioural screen (SHIRPA). The immune cell populations found in the brain during infection were also analysed using flow cytometry and confocal microscopy. Results: IL-10-/- mice suffer significant declines in behavioural and physical capacities during infection compared to wildtype. In addition, grip strength and pain sensitivity were affected, suggestive of neurological involvement. Several immune cell populations were identified in the perfused brain on day 7 post-infection, suggesting that they are tightly adherent to the vascular endothelium, or potentially located within the brain parenchyma. There was an increase in both inflammatory monocyte and resident macrophage (CD11bhi, CD45+, MHCII+, Ly6C+/-) numbers in IL-10-/- compared to wildtype animals. In addition, the activation state of all monocytes and microglia (CD11bint, CD45-, MHC-II+) were increased. T cells making IFN-γ were also identified in the brain, but were localized within the vasculature, and not the parenchyma. Conclusions: These studies demonstrate exacerbated neuroinflammation concurrent with development of behavioural symptoms in P. chabaudi infection of IL-10-/- animals.",
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T1 - Behavioural and neurological symptoms accompanied by cellular neuroinflammation in IL-10-deficient mice infected with Plasmodium chabaudi

AU - Wilson, Kyle D.

AU - Stutz, Sonja J.

AU - Ochoa, Lorenzo F.

AU - Valbuena, Gustavo A.

AU - Cravens, Petra D.

AU - Dineley, Kelly

AU - Vargas, Gracie

AU - Stephens, Robin

PY - 2016/8/24

Y1 - 2016/8/24

N2 - Background: Cerebral malaria is one of the most severe complications of Plasmodium falciparum infection and occurs mostly in young African children. This syndrome results from a combination of high levels of parasitaemia and inflammation. Although parasite sequestration in the brain is a feature of the human syndrome, sequestering strains do not uniformly cause severe malaria, suggesting interplay with other factors. Host genetic factors such as mutations in the promoters of the cytokines IL-10 and TNF are also clearly linked to severe disease. Plasmodium chabaudi, a rodent malaria parasite, leads to mild illness in wildtype animals. However, IL-10-/- mice respond to parasite with increased levels of pro-inflammatory cytokines IFN-γ and TNF, leading to lethal disease in the absence of sequestration in the brain. These mice also exhibit cerebral symptoms including gross cerebral oedema and haemorrhage, allowing study of these critical features of disease without the influence of sequestration. Methods: The neurological consequences of P. chabaudi infection were investigated by performing a general behavioural screen (SHIRPA). The immune cell populations found in the brain during infection were also analysed using flow cytometry and confocal microscopy. Results: IL-10-/- mice suffer significant declines in behavioural and physical capacities during infection compared to wildtype. In addition, grip strength and pain sensitivity were affected, suggestive of neurological involvement. Several immune cell populations were identified in the perfused brain on day 7 post-infection, suggesting that they are tightly adherent to the vascular endothelium, or potentially located within the brain parenchyma. There was an increase in both inflammatory monocyte and resident macrophage (CD11bhi, CD45+, MHCII+, Ly6C+/-) numbers in IL-10-/- compared to wildtype animals. In addition, the activation state of all monocytes and microglia (CD11bint, CD45-, MHC-II+) were increased. T cells making IFN-γ were also identified in the brain, but were localized within the vasculature, and not the parenchyma. Conclusions: These studies demonstrate exacerbated neuroinflammation concurrent with development of behavioural symptoms in P. chabaudi infection of IL-10-/- animals.

AB - Background: Cerebral malaria is one of the most severe complications of Plasmodium falciparum infection and occurs mostly in young African children. This syndrome results from a combination of high levels of parasitaemia and inflammation. Although parasite sequestration in the brain is a feature of the human syndrome, sequestering strains do not uniformly cause severe malaria, suggesting interplay with other factors. Host genetic factors such as mutations in the promoters of the cytokines IL-10 and TNF are also clearly linked to severe disease. Plasmodium chabaudi, a rodent malaria parasite, leads to mild illness in wildtype animals. However, IL-10-/- mice respond to parasite with increased levels of pro-inflammatory cytokines IFN-γ and TNF, leading to lethal disease in the absence of sequestration in the brain. These mice also exhibit cerebral symptoms including gross cerebral oedema and haemorrhage, allowing study of these critical features of disease without the influence of sequestration. Methods: The neurological consequences of P. chabaudi infection were investigated by performing a general behavioural screen (SHIRPA). The immune cell populations found in the brain during infection were also analysed using flow cytometry and confocal microscopy. Results: IL-10-/- mice suffer significant declines in behavioural and physical capacities during infection compared to wildtype. In addition, grip strength and pain sensitivity were affected, suggestive of neurological involvement. Several immune cell populations were identified in the perfused brain on day 7 post-infection, suggesting that they are tightly adherent to the vascular endothelium, or potentially located within the brain parenchyma. There was an increase in both inflammatory monocyte and resident macrophage (CD11bhi, CD45+, MHCII+, Ly6C+/-) numbers in IL-10-/- compared to wildtype animals. In addition, the activation state of all monocytes and microglia (CD11bint, CD45-, MHC-II+) were increased. T cells making IFN-γ were also identified in the brain, but were localized within the vasculature, and not the parenchyma. Conclusions: These studies demonstrate exacerbated neuroinflammation concurrent with development of behavioural symptoms in P. chabaudi infection of IL-10-/- animals.

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KW - Malaria

KW - Monocyte

KW - Mouse

KW - Neuroinflammation

KW - T cell

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