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Persistent brain infection and disease reactivation in relapsing fever borreliosis
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). (Bergström)
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). (Bergström)
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). (Bergström)
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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. Vol. 8, no 8, 2213-2219 p.
Keyword [en]
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: urn:nbn:se:umu:diva-12903DOI: 10.1016/j.micinf.2006.04.007PubMedID: 16782384OAI: oai:DiVA.org:umu-12903DiVA: diva2:152574
Available from: 2008-01-12 Created: 2008-01-12 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Pathobiology of African relapsing fever Borrelia
Open this publication in new window or tab >>Pathobiology of African relapsing fever Borrelia
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Relapsing fever (RF) is a disease caused by tick- or louse-transmitted bacteria of the genus Borrelia. It occurs worldwide but is most common in Africa where it is one of the most prevalent bacterial diseases. The main manifestation is a recurring fever which coincides with massive numbers of bacteria in the blood. Severity ranges from asymptomatic to fatal.

RF is usually considered a transient disease. In contrast, B. duttonii causes a persistent, residual brain infection in C57BL/6 mice which remains long time after the bacteria are cleared from the blood. The host gene expression pattern is indistinguishable from that of uninfected animals, indicating that persistent bacteria are not recognized by the immune system nor do they cause noticeable tissue damage. This is probably due to the quite low number of bacteria residing in the brain. The silent infection can be reactivated by immunosuppression allowing bacteria to re-enter the blood. To investigate if the residual infection is in a quiescent state or if the bacteria are actively dividing, mice with residual brain infection were treated with the cell-wall disrupting antibiotic ceftriaxone, which is only active against dividing bacteria. Since all mice were cured by ceftriaxone we conclude that the bacteria are actively growing in the brain rather than being in a latent, dormant state. The brain is used as an immunoprivileged site to escape host immune defence and probably as a reservoir for bacteria.

RF is a common cause of pregnancy complications, miscarriage and neonatal death in sub-Saharan Africa. We established a murine model of gestational relapsing fever to study the pathological development of these complications. B. duttonii infection during pregnancy results in intrauterine growth retardation as well as placental damage and inflammation. Spirochetes cross the maternal-foetal barrier, resulting in congenital infection. Further, pregnancy has a protective effect, resulting in milder disease during pregnancy.

A clinic-based study to investigate the presence of RF in Togo was performed. Blood from patients with fever were examined for RF by microscopy, GlpQ ELISA and PCR. About 10% of the patients were positive by PCR and 13% had antibodies to GlpQ. Many RF patients originally had a misdiagnosis of malaria, which resulted in ineffective treatment. The inability of microscopic analysis to detect spirochetes demonstrates the need for tests with greater sensitivity. To provide simple, fast, cheap and sensitive diagnostics using equipment available in small health centres, a method based on enrichment of bacteria by centrifugation and detection by Giemsa staining was developed which detects <10 spirochetes/ml.

To study the phylogeny of RF, IGS and glpQ were sequenced and neighbor joining trees were constructed. B. persica and B. hispanica were distant from the other species iswhereas B. crocidurae appeared to be a heterogeneous species. B. duttonii is polyphyletic in relation to B. recurrentis suggesting that the two species may in fact be the same or have a polyphyletic origin.

Place, publisher, year, edition, pages
Umeå: Molekylärbiologi (Medicinska fakulteten), 2007. 92 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1137
Keyword
borrelia, persistence, meningitis, pregnancy, latency, immune privileged sites
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-1452 (URN)978-91-7264-430-4 (ISBN)
Public defence
2007-12-14, Major Groove, 6L, Inst. Molekylärbiologi, UMEÅ, 09:00 (English)
Opponent
Supervisors
Available from: 2007-11-26 Created: 2007-11-26 Last updated: 2009-05-27Bibliographically approved
2. Immunopathogenesis of relapsing fever borreliosis
Open this publication in new window or tab >>Immunopathogenesis of relapsing fever borreliosis
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
Relapsing fever, Borrelia, mouse models, biological barriers, pathology, chemokines, cytokines, pregnancy
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-1968 (URN)978-91-7264-710-7 (ISBN)
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

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Larsson, ChristerAndersson, MarieGuo, BettyNordstrand, AnnikaBergström, Sven
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