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Pathobiology of African relapsing fever Borrelia
Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
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 [en]
borrelia, persistence, meningitis, pregnancy, latency, immune privileged sites
National Category
Microbiology in the medical area
Identifiers
URN: urn:nbn:se:umu:diva-1452ISBN: 978-91-7264-430-4 (print)OAI: oai:DiVA.org:umu-1452DiVA: diva2:141122
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
List of papers
1. 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: 2017-12-14Bibliographically approved
2. Residual brain infection in murine relapsing fever borreliosis can be successfully treated with ceftriaxone
Open this publication in new window or tab >>Residual brain infection in murine relapsing fever borreliosis can be successfully treated with ceftriaxone
2008 (English)In: Microbial Pathogenesis, ISSN 0882-4010, E-ISSN 1096-1208, Vol. 44, no 3, 262-264 p.Article in journal (Refereed) Published
Abstract [en]

Like several other spirochetes, relapsing fever Borrelia can cause persistent infection of the central nervous system (CNS). By treating mice harboring residual Borrelia duttonii brain infection with the bacteriocidal, cell wall inhibiting antibiotic ceftriaxone, bacteria were cleared from the brain. This shows that the residual infection is not latent but actively growing.

Place, publisher, year, edition, pages
Elsevier, 2008
Keyword
Latent, Persistent, Ceftriaxone, Antibiotics, CNS infections, Meningitis
National Category
Infectious Medicine Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-20789 (URN)10.1016/j.micpath.2007.11.002 (DOI)18083325 (PubMedID)
Available from: 2009-03-25 Created: 2009-03-25 Last updated: 2017-12-13Bibliographically 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, E-ISSN 1537-6613, 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: 2017-12-14Bibliographically approved
4. Tickborne relapsing fever diagnosis obscured by malaria, Togo.
Open this publication in new window or tab >>Tickborne relapsing fever diagnosis obscured by malaria, Togo.
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2007 (English)In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 13, no 1, 117-123 p.Article in journal (Refereed) Published
Abstract [en]

Given the prevalence of relapsing fever (RF) in Senegal, this disease may cause illness and death in other areas of West Africa. We performed a cross-sectional, clinic-based study to investigate the presence of RF in Togo during 2002-2004. Blood samples from patients with fever were examined for RF spirochetes by microscopy, PCR, and DNA sequencing of amplicons and for antibodies to the glycerophosphodiester phosphodiesterase antigen. Although no spirochetes were seen in blood smears, approximately 10% of the patients were positive by PCR and approximately 13% were seropositive for spirochetes. DNA sequencing demonstrated that Borrelia crocidurae and B. duttonii were present. Most patients were treated for malaria whether or not plasmodia were observed. Thus, many RF patients originally had a misdiagnosis of malaria, which resulted in ineffective treatment. The inability of microscopic analysis to detect spirochetes compared with PCR demonstrates the need for tests with greater sensitivity.

Keyword
Adolescent, Adult, Anti-Bacterial Agents/therapeutic use, Antimalarials/therapeutic use, Child, Child; Preschool, Female, Humans, Infant, Malaria/*complications/drug therapy/*epidemiology, Male, Relapsing Fever/*complications/*diagnosis/drug therapy/epidemiology, Togo/epidemiology
Identifiers
urn:nbn:se:umu:diva-12891 (URN)17370524 (PubMedID)
Available from: 2007-10-03 Created: 2007-10-03 Last updated: 2017-12-14Bibliographically approved
5. Diagnostics and treatment of relapsing fever Borrelia
Open this publication in new window or tab >>Diagnostics and treatment of relapsing fever Borrelia
Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-2832 (URN)
Available from: 2007-11-26 Created: 2007-11-26 Last updated: 2010-01-13Bibliographically approved
6. Phylogeny of new world relapsing fever Borrelia
Open this publication in new window or tab >>Phylogeny of new world relapsing fever Borrelia
Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-2833 (URN)
Available from: 2007-11-26 Created: 2007-11-26 Last updated: 2010-01-13Bibliographically approved

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