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Immunopathogenesis of relapsing fever borreliosis
Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Relapsing fever (RF) is caused by different species of Borrelia transmitted by soft ticks or by the human body louse. Illness is characterized by reappearing peaks of high concentrations of spirochetes in blood, concordant with fever peaks separated by asymptomatic periods. Neuroborreliosis is one of the most severe manifestations of RF borreliosis. To understand the immune response during early RF, we analyzed immune cells in brain and kidney of mice infected with B. crocidurae during the acute infection. Our results indicate that brain defense is comprised primarily of innate immune cells. Despite the infiltration of innate immune cells, Borrelia was not completely eradicated. A failure of the host brain to clear the bacteria may give the pathogen a niche where it can persist. Using our mouse model, we revealed that Borrelia duttonii could persist in the mouse brain for up to 270 days, without being present in the circulation. The infection was silent with no change in host gene expression, and the spirochetes could re-enter the circulation after immunosuppression. We propose that the brain is used by the pathogen to evade host immunity and serves as a possible natural reservoir for B. duttonii, a spirochete that has rarely been found in any mammalian host other than man. Borrelia-induced complications during pregnancy have been reported, and are especially common in RF. In our established mouse model of gestational RF, we could show that the fetuses suffered from severe pathology and growth retardation, probably as a consequence of placental destruction. We could also show trans-placental transmission of the bacteria leading to neonatal RF. Surprisingly, pregnant dams had a lower bacterial load and less severe disease, showing that pregnancy has a protective effect during RF. We have used the gestational RF model to investigate host factors favoring disease resolution. Because the spleen is the primary organ responsible for trapping and removing blood-borne pathogens, we have compared temporal changes in spleen immune cell populations and cytokine/chemokine induction during the infection. Spleens of pregnant mice had earlier neutrophil infiltration, as well as faster and higher production of pro-inflammatory mediators. This rapid, robust response suggests a more effective host defense. Thus, an enhanced pro-inflammatory response during pregnancy imparts a distinct advantage in controlling the severity of relapsing fever infection.

Place, publisher, year, edition, pages
Umeå: Molekylärbiologi (Medicinska fakulteten) , 2008. , 102 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1236
Keyword [en]
Relapsing fever, Borrelia, mouse models, biological barriers, pathology, chemokines, cytokines, pregnancy
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-1968ISBN: 978-91-7264-710-7 (print)OAI: oai:DiVA.org:umu-1968DiVA: diva2:142595
Public defence
2009-01-16, Major Groove, Byggnad 6L, Institutionen för Molekylärbiologi, Umeå Universitet, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2009-01-21 Created: 2009-01-21 Last updated: 2010-02-23Bibliographically approved
List of papers
1. In situ immune response in brain and kidney during early relapsing fever borreliosis.
Open this publication in new window or tab >>In situ immune response in brain and kidney during early relapsing fever borreliosis.
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2007 (English)In: Journal of Neuroimmunology, ISSN 0165-5728, Vol. 183, no 1-2, 26-32 p.Article in journal (Refereed) Published
Keyword
Animals, Antigens, Differentiation/metabolism, Borrelia Infections/*complications/immunology, Brain/*immunology, Immunohistochemistry/methods, Kidney/*immunology, Macrophages/metabolism, Mice, Mice; Inbred BALB C, Mice; Inbred C57BL, Neuropil/metabolism, Relapsing Fever/*etiology/*immunology, Spirochaetales/isolation & purification, Time Factors
Identifiers
urn:nbn:se:umu:diva-12889 (URN)10.1016/j.jneuroim.2006.11.004 (DOI)17184846 (PubMedID)
Available from: 2007-10-03 Created: 2007-10-03Bibliographically approved
2. Persistent brain infection and disease reactivation in relapsing fever borreliosis
Open this publication in new window or tab >>Persistent brain infection and disease reactivation in relapsing fever borreliosis
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2006 (English)In: Microbes and infection, ISSN 1286-4579, E-ISSN 1769-714X, Vol. 8, no 8, 2213-2219 p.Article in journal (Refereed) Published
Abstract [en]

Relapsing fever, an infection caused by Borrelia spirochetes, is generally considered a transient, self-limiting disease in humans. The present study reveals that murine infection by Borrelia duttonii can be reactivated after an extended time as a silent infection in the brain, with no bacteria appearing in the blood and spirochete load comparable to the numbers in an infected tick. The host cerebral gene expression pattern is indistinguishable from that of uninfected animals, indicating that persistent bacteria are not recognized by the immune system nor cause noticeable tissue damage. Silent infection can be reactivated by immunosuppression, inducing spirochetemia comparable to that of initial densities. B. duttonii has never been found in any host except man and the tick vector. We therefore propose the brain to be a possible natural reservoir of the spirochete. The view of relapsing fever as an acute disease should be extended to include in some cases prolonged persistence, a feature characteristic of the related spirochetal infections Lyme disease and syphilis.

Place, publisher, year, edition, pages
Elsevier, 2006
Keyword
Animals, Bacteremia, Borrelia/classification/*isolation & purification, Brain/*microbiology, Brain Chemistry, Brain Diseases/*microbiology, Colony Count; Microbial, Disease Models; Animal, Gene Expression Profiling, Immunosuppression, Male, Mice, Mice; Inbred C57BL, Relapsing Fever/*microbiology, Serotyping
National Category
Infectious Medicine Microbiology in the medical area Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-12903 (URN)10.1016/j.micinf.2006.04.007 (DOI)16782384 (PubMedID)
Available from: 2008-01-12 Created: 2008-01-12 Last updated: 2013-11-20Bibliographically approved
3. Complications of pregnancy and transplacental transmission of relapsing-fever borreliosis
Open this publication in new window or tab >>Complications of pregnancy and transplacental transmission of relapsing-fever borreliosis
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2006 (English)In: Journal of Infectious Diseases, ISSN 0022-1899, Vol. 194, no 10, 1367-1374 p.Article in journal (Refereed) Published
Abstract [en]

Relapsing-fever borreliosis caused by Borrelia duttonii is a common cause of complications of pregnancy, miscarriage, and neonatal death in sub-Saharan Africa. We established a murine model of gestational relapsing fever infection for the study of the pathological development of these complications. We demonstrate that B. duttonii infection during pregnancy results in intrauterine growth retardation, as well as placental damage and inflammation, impaired fetal circulation, and decreased maternal hemoglobin levels. We show that spirochetes frequently cross the maternal-fetal barrier, resulting in congenital infection. Furthermore, we compared the severity of infection in pregnant and nonpregnant mice and show that pregnancy has a protective effect. This model closely parallels the consequences of human gestational infection, and our results provide insight into the mechanisms behind the complications of pregnancy that have been reported in human relapsing-fever infection.

Keyword
Animals, Bacteremia, Borrelia, Disease Models; Animal, Disease Transmission; Vertical, Female, Fetal Diseases/*microbiology/pathology, Fetal Growth Retardation, Fetal Weight, Hemoglobins/analysis, Histocytochemistry, Mice, Mice; Inbred C3H, Placenta/*microbiology/pathology, Placental Circulation, Pregnancy, Pregnancy Complications; Infectious/microbiology/pathology, Relapsing Fever/microbiology/pathology/*transmission
National Category
Microbiology in the medical area Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-12901 (URN)10.1086/508425 (DOI)17054065 (PubMedID)
Available from: 2008-02-11 Created: 2008-02-11 Last updated: 2013-11-20Bibliographically approved
4. Enhanced inflammatory response to relapsing fever during pregnancy
Open this publication in new window or tab >>Enhanced inflammatory response to relapsing fever during pregnancy
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Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-3749 (URN)
Available from: 2009-01-21 Created: 2009-01-21 Last updated: 2010-01-13Bibliographically approved

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