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Host responses to malaria and bacterial co-­infections
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
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. 

Place, publisher, year, edition, pages
Umeå Universitet: Umeå universitet , 2015. , 59 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1720
Keyword [en]
Plasmodium, Malaria, Borrelia, S. pneumoniae, Co-infection, Immunology, Metabolomics
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-102795ISBN: 978-91-7601-276-5 (print)OAI: oai:DiVA.org:umu-102795DiVA: diva2:809976
Public defence
2015-05-29, Major Grove, Building J1, Department of Molecular Biology, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2015-05-08 Created: 2015-05-05 Last updated: 2015-05-08Bibliographically approved
List of papers
1. Concomitant Infection Decreases the Malaria Burden but Escalates Relapsing Fever Borreliosis
Open this publication in new window or tab >>Concomitant Infection Decreases the Malaria Burden but Escalates Relapsing Fever Borreliosis
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2010 (English)In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 78, no 5, 1924-1930 p.Article in journal (Refereed) Published
Abstract [en]

About 500 million cases of malaria occur annually. However, a substantial number of patients who actually have relapsing fever (RF) Borrelia can be misdiagnosed with malaria due to similar manifestations and geographic distribution of the two diseases. More alarmingly, high prevalence of concomitant infections with malaria and RF Borrelia has been reported. Therefore, we used a mouse model to study the effects of such mixed infection. We observed a 21-fold increase in spirochete titers, whereas the numbers of parasitized erythrocytes were reduced 15-fold. This may be explained by polarization of the host immune response towards the intracellular malaria parasite, resulting in unaffected extracellular spirochetes and hosts that succumb to sepsis. Mixed infection also resulted in severe malaria anemia with low hemoglobin levels, even though the parasite counts were low. Overall, co-infected animals had higher fatality rate and shorter time to death than both malaria and RF single infection. Furthermore, secondary malaria infection reactivated a quiescent RF brain infection, which is the first evidence of a clinically and biologically relevant cue for reactivation of RF Borrelia infection. Our study highlights the importance of investigating concomitant infections in vivo to elucidate the immune responses that are involved in the clinical outcome.

Place, publisher, year, edition, pages
American Society for Microbiology, 2010
National Category
Immunology in the medical area Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-32816 (URN)10.1128/IAI.01082-09 (DOI)000276778700013 ()20145098 (PubMedID)
Available from: 2010-03-29 Created: 2010-03-26 Last updated: 2017-12-12Bibliographically approved
2. Maladjusted Host Immune Responses Induce Experimental Cerebral Malaria-Like Pathology in a Murine Borrelia and Plasmodium Co-Infection Model
Open this publication in new window or tab >>Maladjusted Host Immune Responses Induce Experimental Cerebral Malaria-Like Pathology in a Murine Borrelia and Plasmodium Co-Infection Model
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2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 7, e103295Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
PLOS ONE, 2014
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-92942 (URN)10.1371/journal.pone.0103295 (DOI)000340028800036 ()
Available from: 2014-09-17 Created: 2014-09-09 Last updated: 2017-12-05Bibliographically approved
3. Malaria-enhanced Neutrophil Dependent Clearance of S. pneumoniae in an in vivo Co-infection Model
Open this publication in new window or tab >>Malaria-enhanced Neutrophil Dependent Clearance of S. pneumoniae in an in vivo Co-infection Model
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(English)Manuscript (preprint) (Other (popular science, discussion, etc.))
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-102818 (URN)
Note

Orifinally published with the title: Malaria-induced alteration of neutrophils to clear S. pneumoniae in vivo

Available from: 2015-05-05 Created: 2015-05-05 Last updated: 2015-05-06
4. Metabolic signature profiling as a diagnostic and prognostic tool in paediatric Plasmodium falciparum malaria
Open this publication in new window or tab >>Metabolic signature profiling as a diagnostic and prognostic tool in paediatric Plasmodium falciparum malaria
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2015 (English)In: Open Forum Infectious Diseases, ISSN 2328-8957, Vol. 2, no 2Article in journal (Refereed) Published
Abstract [en]

Background: Accuracy in malaria diagnosis and staging is vital in order to reduce mortality and post infectious sequelae. Herein we present a metabolomics approach to diagnostic staging of malaria infection, specifically Plasmodium falciparum infection in children. Methods: A group of 421 patients between six months and six years of age with mild and severe states of malaria with age-matched controls were included in the study, 107, 192 and 122 individuals respectively. A multivariate design was used as basis for representative selection of twenty patients in each category. Patient plasma was subjected to Gas Chromatography-Mass Spectrometry analysis and a full metabolite profile was produced from each patient. In addition, a proof-of-concept model was tested in a Plasmodium berghei in-vivo model where metabolic profiles were discernible over time of infection. Results: A two-component principal component analysis (PCA) revealed that the patients could be separated into disease categories according to metabolite profiles, independently of any clinical information. Furthermore, two sub-groups could be identified in the mild malaria cohort who we believe represent patients with divergent prognoses. Conclusion: Metabolite signature profiling could be used both for decision support in disease staging and prognostication.

Place, publisher, year, edition, pages
Oxford University Press, 2015
Keyword
disease staging, malaria, metabolomics
National Category
Bioinformatics (Computational Biology) Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-102800 (URN)10.1093/ofid/ofv062 (DOI)000365786200047 ()
Available from: 2015-05-05 Created: 2015-05-05 Last updated: 2015-12-28Bibliographically approved

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