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An in vivo study of the antimalarial effect of polyamine synthesis inhibitors in Plasmodium berghei
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Biology. (Cathrine Persson)
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Biology. (Cathrine Persson)
Umeå University, Faculty of Medicine, Molecular Biology. (Jonas Nilsson)
Umeå University, Faculty of Medicine, Molecular Biology. (Jonas Nilsson)
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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 [en]
Malaria, Plasmodium, polyamine inhibitors, 4MCHA, DFMO, AdoDATO
National Category
Biochemistry and Molecular Biology
Research subject
Infectious Diseases
Identifiers
URN: urn:nbn:se:umu:diva-21828OAI: oai:DiVA.org:umu-21828DiVA: diva2:211920
Available from: 2009-04-20 Created: 2009-04-20 Last updated: 2011-09-06Bibliographically approved
In thesis
1. Malaria and relapsing fever Borrelia: interactions and potential therapy
Open this publication in new window or tab >>Malaria and relapsing fever Borrelia: interactions and potential therapy
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
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:nbn:se:umu:diva-21845 (URN)978-91-7264-768-8 (ISBN)
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

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