title: Maladjusted host immune responses induce experimental cerebral malaria-like pathology in a murine Borrelia and Plasmodium co-infection model.
abstract: In the Plasmodium infected host, a balance between pro- and anti-inflammatory responses is required to clear the parasites without inducing major host pathology. Clinical reports suggest that bacterial infection in conjunction with malaria aggravates disease and raises both mortality and morbidity in these patients. In this study, we investigated the immune responses in BALB/c mice, co-infected with Plasmodium berghei NK65 parasites and the relapsing fever bacterium Borrelia duttonii. In contrast to single infections, we identified in the co-infected mice a reduction of L-Arginine levels in the serum. It indicated diminished bioavailability of NO, which argued for a dysfunctional endothelium. Consistent with this, we observed increased sequestration of CD8+ cells in the brain as well over expression of ICAM-1 and VCAM by brain endothelial cells. Co-infected mice further showed an increased inflammatory response through IL-1β and TNF-α, as well as inability to down regulate the same through IL-10. In addition we found loss of synchronicity of pro- and anti-inflammatory signals seen in dendritic cells and macrophages, as well as increased numbers of regulatory T-cells. Our study shows that a situation mimicking experimental cerebral malaria (ECM) is induced in co-infected mice due to loss of timing and control over regulatory mechanisms in antigen presenting cells.
authors: Department of Molecular Biology, Umeå University, Umeå, Sweden; Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Umeå, Sweden; Umeå Center for Microbial Research, Umeå University, Umeå, Sweden; Division of Infectious diseases, Department of Clinical Microbiology, Umeå University, Umeå, Sweden.
authors: Johan
authors: J
authors: Normark
authors: Department of Molecular Biology, Umeå University, Umeå, Sweden; Umeå Center for Microbial Research, Umeå University, Umeå, Sweden.
authors: Maria
authors: M
authors: Nelson
authors: Department of Molecular Biology, Umeå University, Umeå, Sweden; Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Umeå, Sweden; Umeå Center for Microbial Research, Umeå University, Umeå, Sweden; Department of Molecular and Cell Biology, University of California, Berkeley, California, United States of America.
authors: Patrik
authors: P
authors: Engström
authors: Department of Molecular Biology, Umeå University, Umeå, Sweden.
authors: Marie
authors: M
authors: Andersson
authors: Department of Mathematics and Mathematical Statistics, Umeå University, Umeå, Sweden.
authors: Rafael
authors: R
authors: Björk
authors: Umeå Plant Science Centre (UPSC), Swedish University of Agricultural Sciences (SLU), Umeå, Sweden.
authors: Thomas
authors: T
authors: Moritz
authors: Department of Molecular Biology, Umeå University, Umeå, Sweden; Umeå Center for Microbial Research, Umeå University, Umeå, Sweden.
authors: Anna
authors: A
authors: Fahlgren
authors: Department of Molecular Biology, Umeå University, Umeå, Sweden; Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Umeå, Sweden; Umeå Center for Microbial Research, Umeå University, Umeå, Sweden.
authors: Sven
authors: S
authors: Bergström
mesh_terms: D000818:Animals; D001120:Arginine / Q000097:blood; D001898:Borrelia / Q000276:immunology*; D001899:Borrelia Infections / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D060085:Coinfection; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004727:Endothelium / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D054884:Host-Pathogen Interactions / Q000276:immunology*; D016753:Interleukin-10 / Q000378:metabolism; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D016779:Malaria, Cerebral / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology / Q000473:pathology; D051379:Mice; D010961:Plasmodium / Q000276:immunology*; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D000949:Histocompatibility Antigens Class II; D016753:Interleukin-10; D001120:Arginine