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Maladjusted Host Immune Responses Induce Experimental Cerebral Malaria-Like Pathology in a Murine Borrelia and Plasmodium Co-Infection Model
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Department of Molecular and Cell Biology, University of California, Berkeley, California, United States of America.
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
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2014 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 7, artikel-id e103295Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

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-1 beta and TNF-alpha, 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.

Ort, förlag, år, upplaga, sidor
PLOS ONE , 2014. Vol. 9, nr 7, artikel-id e103295
Nationell ämneskategori
Cell- och molekylärbiologi
Identifikatorer
URN: urn:nbn:se:umu:diva-92942DOI: 10.1371/journal.pone.0103295ISI: 000340028800036OAI: oai:DiVA.org:umu-92942DiVA, id: diva2:747797
Tillgänglig från: 2014-09-17 Skapad: 2014-09-09 Senast uppdaterad: 2018-06-07Bibliografiskt granskad
Ingår i avhandling
1. Host responses to malaria and bacterial co-­infections
Öppna denna publikation i ny flik eller fönster >>Host responses to malaria and bacterial co-­infections
2015 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

The two main causes of child mortality and morbidity in Africa are malaria and invasive bacterial diseases. In addition, co-infections in sub-Saharan Africa are the rule rather than the exception. However, not much is known about the host-pathogen interaction during a concomitant infection or how it affects the outcome of disease.

In order to study the immunological responses during malaria and bacterial co-infections, we established a co-infection mouse model. In these studies we used two pathogenic bacteria found in malaria co-infected patients: Streptococcus pneumoniae and Relapsing fever Borrelia duttonii.

Hosts co-infected with malaria and Borrelia showed greatly increased spirochetal growth but low parasite densities. In addition, the co-infected hosts presented symptoms of experimental-cerebral malaria, in an otherwise unsusceptible mouse model. This was found to be a consequence of a dysregulated immune response due to loss of timing and control over regulatory mechanisms in antigen presenting cells thus locking the host in an inflammatory response. This results in inflammation, severe anemia, internal organ damage and pathology of experimental cerebral malaria.

On the other hand, in the malaria - S. pneumoniae co-infection model we found that co-infected hosts cleared the bacterium much more efficiently than the single infected counterpart. This efficiency of clearance showed to be neutrophil dependent. Furthermore, in vitro studies revealed that neutrophils isolated from malaria-infected hosts present an altered migratory effect together with a significantly increased capacity to kill S. pneumoniae. This suggests that a malaria infection primes neutrophils to kill S. pneumoniae more efficiently.

Furthermore, a study was carried out on plasma samples from Rwandan children under the age of five, on which a full metabolomics profile was performed. We showed that these children could be divided in different disease categories based on their metabolomics profile and independent of clinical information. Additionally, the mild malaria group could further be divided in two sub-groups, in which one had a metabolomic profile resembling that of severe malaria infected patients. Based on this, metabolite profiling could be used as a diagnostic tool to determine the distinct phase, or severity of a malaria infection, identify risk patients and provide helpful and correct therapy. 

Ort, förlag, år, upplaga, sidor
Umeå Universitet: Umeå universitet, 2015. s. 59
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1720
Nyckelord
Plasmodium, Malaria, Borrelia, S. pneumoniae, Co-infection, Immunology, Metabolomics
Nationell ämneskategori
Cell- och molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-102795 (URN)978-91-7601-276-5 (ISBN)
Disputation
2015-05-29, Major Grove, Building J1, Department of Molecular Biology, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2015-05-08 Skapad: 2015-05-05 Senast uppdaterad: 2018-06-07Bibliografiskt granskad

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Normark, JohanNelson, MariaEngström, PatrikBjörk, RafaelMoritz, ThomasFahlgren, AnnaBergström, Sven

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Institutionen för molekylärbiologi (Medicinska fakulteten)Molekylär Infektionsmedicin, Sverige (MIMS)Umeå Centre for Microbial Research (UCMR)Institutionen för klinisk mikrobiologiInstitutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet)Institutionen för matematik och matematisk statistik
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