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Malaria and relapsing fever Borrelia: interactions and potential therapy
Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine). (Cathrine Persson)
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Infectious diseases such as malaria and relapsing fever borreliosis (RF), cause severe human mortality and morbidity in developing countries. Malaria, caused by Plasmodium spp. parasites, is estimated by the World Health Organization to cause 1.5-2.7 million deaths annually. RF, caused by Borrelia spirochetes, has the highest prevalence described for any bacterial disease in Africa, with infection outcomes ranging from asymptomatic to fatal. RF borreliosis manifests in humans as a recurring fever and with other symptoms very similar to those of malaria.

RF borreliosis has been regarded as a transient infection of the blood. However, B. duttonii exploits the brain as an immunoprivileged site escaping the host immune response while spirochetes in the blood are cleared. To investigate whether residual bacteria are dormant or actively dividing, mice with residual brain infection were administered ceftriaxone, a β-lactam antibiotic interfering with cell wall synthesis. Hence, it only affects actively dividing bacteria. Ceftriaxone eradicated brain RF infection in all treated mice, demonstrating that the bacteria are actively multiplying rather than in a dormant state. The findings support the therapeutic use of ceftriaxone for RF neuroborreliosis since penetration into cerebrospinal fluid is greater for ceftriaxone than for the often recommended doxycycline.

The clinical features of malaria and RF are similar and diagnosis is further complicated by the frequently occurring concomitant malaria-RF infections. Therefore, we established a mouse model to study the pathogenesis and immunological response to Plasmodium/Borrelia mixed infection. Interestingly, malaria was suppressed in the co-infected animals whereas spirochete numbers were elevated 21-fold. The immune response in the concomitantly infected mice was polarized towards malaria leaving the spirochetes unharmed. Mice with co-infections also exhibited severe anemia and internal damages, probably attributed to escalating spirochete numbers. A secondary malaria infection reactivated the residual brain RF infection in 60% of the mice. This highlights the importance of co-infections as diagnostic pitfalls as well as the need for novel treatment strategies.

Currently there is no commercial malaria vaccine and increasing drug resistance presents an urgent need for new malaria chemotherapeutics. Blood-stage malaria parasites are rapidly growing with high metabolic and biosynthetic activity, making them highly sensitive to limitations in polyamine supply. Disrupting polyamine synthesis in vivo with trans-4-methylcyclohexylamine (4MCHA) eradicated the malaria infection gradually, resulting in protective immunity. This leads the way for further biochemical and pharmacological development of the polyamine inhibitor 4MCHA and similar compounds as antimalarial drugs

Place, publisher, year, edition, pages
Umeå: Institutionen för molekylärbiologi , 2009. , 84 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1258
Keyword [en]
Malaria, Plasmodium, relapsing fever, Borrelia, persistent, concomitant infections, polyamines
National Category
Cell and Molecular Biology Microbiology in the medical area
Research subject
Molecular Biotechnology; Infectious Diseases
Identifiers
URN: urn:nbn:se:umu:diva-21845ISBN: 978-91-7264-768-8 (print)OAI: oai:DiVA.org:umu-21845DiVA: diva2:211971
Public defence
2009-05-15, Major groove, Umeå Universitet, Byggnad 6L, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2009-04-29 Created: 2009-04-20 Last updated: 2009-04-29Bibliographically approved
List of papers
1. 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: 2013-11-20Bibliographically approved
2. Mixed infection decreases malaria burden and escalate relapsing fever
Open this publication in new window or tab >>Mixed infection decreases malaria burden and escalate relapsing fever
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(English)Manuscript (Other academic)
Abstract [en]

About 500 million cases of malaria occur annually. However, a substantial number of patients who actually have relapsing fever (RF) Borrelia are misdiagnosed with malaria due to similar manifestation and geographic distribution of the two diseases. More alarmingly, high prevalence of mixed infections with malaria and RF Borrelia has been reported. Therefore, we developed a mouse model to study the effects of such mixed infection. We observed a 21-fold increase in spirochete titers, whereas parasitemia decreased 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 succumb to sepsis. Furthermore, secondary malaria infection can reactivate a quiescent RF brain infection, which is the first evidence of a clinically and biologically relevant cue for reactivation of dormant RF Borrelia infection. Mixed infection also resulted in severe anemia even though the parasite counts were low. Our study highlights the importance of investigating mixed infections in vivo to elucidate the immune responses that are involved in the clinical outcome, and it also emphasizes the urgent need for improved diagnostics of malaria and other infectious diseases such as RF Borrelia.

Keyword
Malaria, Plasmodium, Relapsing fever Borrelia, and mixed infections
National Category
Cell and Molecular Biology
Research subject
Infectious Diseases
Identifiers
urn:nbn:se:umu:diva-21815 (URN)
Available from: 2009-04-20 Created: 2009-04-20 Last updated: 2010-01-14Bibliographically approved
3. An in vivo study of the antimalarial effect of polyamine synthesis inhibitors in Plasmodium berghei
Open this publication in new window or tab >>An in vivo study of the antimalarial effect of polyamine synthesis inhibitors in Plasmodium berghei
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(English)Manuscript (Other academic)
Abstract [en]

Malaria is one of the most devastating diseases of the developing world responsible for approximately two million deaths annually. The high mortality together with the fact that resistance to available antimalarial drugs has increased, highlights the necessity of finding new chemotherapeutics against the parasite. Polyamines play a critical role in the regulation of cell proliferation and differentiation in most organisms including the malaria parasite. Therefore, targeting enzymes in the polyamine synthesis could be a possible approach to combat malaria. In order to evaluate the curative potential of the polyamine biosynthesis inhibitors S-adenosyl-3-thio-1,8-diaminooctane (AdoDATO) and trans-4-methylcyclohexylamine (4MCHA), which both target spermidine synthase, we took the advantage of an accessible mouse model using the rodent malaria parasite, P. berghei. Despite the promising inhibitory potential of AdoDATO, this drug was inefficient against malaria infection in mice. In contrast, 4MCHA restrained the parasite infection, which subsequently led to clearance within 24 days. This curative effect was not synergistically enhanced by combination treatment with the ornithine decarboxylase inhibitor, α-difluoromethylornithine (DFMO) and neither did a prophylactic treatment of 4MCHA increase the antimalarial effect. Interestingly, mice that received 4MCHA treatment gained a protective immunity towards malaria infection. The nature of this protective immunity is not established.

Keyword
Malaria, Plasmodium, polyamine inhibitors, 4MCHA, DFMO, AdoDATO
National Category
Biochemistry and Molecular Biology
Research subject
Infectious Diseases
Identifiers
urn:nbn:se:umu:diva-21828 (URN)
Available from: 2009-04-20 Created: 2009-04-20 Last updated: 2011-09-06Bibliographically approved

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Lundqvist, Jenny

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