title: Behavioural and neurological symptoms accompanied by cellular neuroinflammation in IL-10-deficient mice infected with Plasmodium chabaudi.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  These studies demonstrate exacerbated neuroinflammation concurrent with development of behavioural symptoms in P. chabaudi infection of IL-10(-/-) animals.
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, 77555, USA.
authors.forename: Kyle D
authors.identifier: 0000-0003-0710-0808
authors.initials: KD
authors.lastname: Wilson
authors.affiliation: Mitchell Center for Neurodegenerative Diseases, Center for Addiction Research, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, 77555, USA.
authors.forename: Sonja J
authors.initials: SJ
authors.lastname: Stutz
authors.affiliation: Center for Biomedical Engineering, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, 77555, USA.
authors.forename: Lorenzo F
authors.initials: LF
authors.lastname: Ochoa
authors.affiliation: Department of Pathology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, 77555, USA.|Institute for Human Infections and Immunity, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, 77555, USA.
authors.forename: Gustavo A
authors.initials: GA
authors.lastname: Valbuena
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, 77555, USA.
authors.forename: Petra D
authors.initials: PD
authors.lastname: Cravens
authors.affiliation: Mitchell Center for Neurodegenerative Diseases, Center for Addiction Research, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, 77555, USA.|Department of Neurology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, 77555, USA.
authors.forename: Kelly T
authors.initials: KT
authors.lastname: Dineley
authors.affiliation: Center for Biomedical Engineering, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, 77555, USA.|Department of Neuroscience and Cell Biology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, 77555, USA.|Institute for Human Infections and Immunity, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, 77555, USA.
authors.forename: Gracie
authors.initials: G
authors.lastname: Vargas
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, 77555, USA. rostephe@utmb.edu.|Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, 77555, USA. rostephe@utmb.edu.|Institute for Human Infections and Immunity, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, 77555, USA. rostephe@utmb.edu.
authors.forename: Robin
authors.initials: R
authors.lastname: Stephens
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D016753:Interleukin-10 / Q000172:deficiency*; D007962:Leukocytes / Q000276:immunology; D016779:Malaria, Cerebral / Q000150:complications* / Q000469:parasitology / Q000473:pathology*; D008297:Male; D001523:Mental Disorders / Q000209:etiology*; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D016788:Plasmodium chabaudi / Q000254:growth & development*
chemical_list: C556062:IL10 protein, mouse; D016753:Interleukin-10
keywords: Brain; Malaria; Monocyte; Mouse; Neuroinflammation; T cell