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

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...

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Autores principales: Wilson, Kyle D., Stutz, Sonja J., Ochoa, Lorenzo F., Valbuena, Gustavo A., Cravens, Petra D., Dineley, Kelly T., Vargas, Gracie, Stephens, Robin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4995805/
https://www.ncbi.nlm.nih.gov/pubmed/27557867
http://dx.doi.org/10.1186/s12936-016-1477-1
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author Wilson, Kyle D.
Stutz, Sonja J.
Ochoa, Lorenzo F.
Valbuena, Gustavo A.
Cravens, Petra D.
Dineley, Kelly T.
Vargas, Gracie
Stephens, Robin
author_facet Wilson, Kyle D.
Stutz, Sonja J.
Ochoa, Lorenzo F.
Valbuena, Gustavo A.
Cravens, Petra D.
Dineley, Kelly T.
Vargas, Gracie
Stephens, Robin
author_sort Wilson, Kyle D.
collection PubMed
description 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 (CD11b(hi), CD45(+), MHCII(+), Ly6C(+/−)) numbers in IL-10(−/−) compared to wildtype animals. In addition, the activation state of all monocytes and microglia (CD11b(int), 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12936-016-1477-1) contains supplementary material, which is available to authorized users.
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spelling pubmed-49958052016-08-25 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 T. Vargas, Gracie Stephens, Robin Malar J Research 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 (CD11b(hi), CD45(+), MHCII(+), Ly6C(+/−)) numbers in IL-10(−/−) compared to wildtype animals. In addition, the activation state of all monocytes and microglia (CD11b(int), 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12936-016-1477-1) contains supplementary material, which is available to authorized users. BioMed Central 2016-08-24 /pmc/articles/PMC4995805/ /pubmed/27557867 http://dx.doi.org/10.1186/s12936-016-1477-1 Text en © The Author(s) 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Wilson, Kyle D.
Stutz, Sonja J.
Ochoa, Lorenzo F.
Valbuena, Gustavo A.
Cravens, Petra D.
Dineley, Kelly T.
Vargas, Gracie
Stephens, Robin
Behavioural and neurological symptoms accompanied by cellular neuroinflammation in IL-10-deficient mice infected with Plasmodium chabaudi
title Behavioural and neurological symptoms accompanied by cellular neuroinflammation in IL-10-deficient mice infected with Plasmodium chabaudi
title_full Behavioural and neurological symptoms accompanied by cellular neuroinflammation in IL-10-deficient mice infected with Plasmodium chabaudi
title_fullStr Behavioural and neurological symptoms accompanied by cellular neuroinflammation in IL-10-deficient mice infected with Plasmodium chabaudi
title_full_unstemmed Behavioural and neurological symptoms accompanied by cellular neuroinflammation in IL-10-deficient mice infected with Plasmodium chabaudi
title_short Behavioural and neurological symptoms accompanied by cellular neuroinflammation in IL-10-deficient mice infected with Plasmodium chabaudi
title_sort behavioural and neurological symptoms accompanied by cellular neuroinflammation in il-10-deficient mice infected with plasmodium chabaudi
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4995805/
https://www.ncbi.nlm.nih.gov/pubmed/27557867
http://dx.doi.org/10.1186/s12936-016-1477-1
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