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Malaria and relapsing fever Borrelia: interactions and potential therapy
Umeå universitet, Medicinsk fakultet, Molekylärbiologi (Medicinska fakulteten). (Cathrine Persson)
2009 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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

Ort, förlag, år, upplaga, sidor
Umeå: Institutionen för molekylärbiologi , 2009. , s. 84
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1258
Nyckelord [en]
Malaria, Plasmodium, relapsing fever, Borrelia, persistent, concomitant infections, polyamines
Nationell ämneskategori
Cell- och molekylärbiologi Mikrobiologi inom det medicinska området
Forskningsämne
molekylär bioteknik (inst f molekylärbiologi); infektionssjukdomar
Identifikatorer
URN: urn:nbn:se:umu:diva-21845ISBN: 978-91-7264-768-8 (tryckt)OAI: oai:DiVA.org:umu-21845DiVA, id: diva2:211971
Disputation
2009-05-15, Major groove, Umeå Universitet, Byggnad 6L, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2009-04-29 Skapad: 2009-04-20 Senast uppdaterad: 2018-06-08Bibliografiskt granskad
Delarbeten
1. Residual brain infection in murine relapsing fever borreliosis can be successfully treated with ceftriaxone
Öppna denna publikation i ny flik eller fönster >>Residual brain infection in murine relapsing fever borreliosis can be successfully treated with ceftriaxone
2008 (Engelska)Ingår i: Microbial Pathogenesis, ISSN 0882-4010, E-ISSN 1096-1208, Vol. 44, nr 3, s. 262-264Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
Elsevier, 2008
Nyckelord
Latent, Persistent, Ceftriaxone, Antibiotics, CNS infections, Meningitis
Nationell ämneskategori
Infektionsmedicin Mikrobiologi inom det medicinska området
Identifikatorer
urn:nbn:se:umu:diva-20789 (URN)10.1016/j.micpath.2007.11.002 (DOI)18083325 (PubMedID)2-s2.0-38549102587 (Scopus ID)
Tillgänglig från: 2009-03-25 Skapad: 2009-03-25 Senast uppdaterad: 2023-03-23Bibliografiskt granskad
2. Mixed infection decreases malaria burden and escalate relapsing fever
Öppna denna publikation i ny flik eller fönster >>Mixed infection decreases malaria burden and escalate relapsing fever
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(Engelska)Manuskript (Övrigt vetenskapligt)
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.

Nyckelord
Malaria, Plasmodium, Relapsing fever Borrelia, and mixed infections
Nationell ämneskategori
Cell- och molekylärbiologi
Forskningsämne
infektionssjukdomar
Identifikatorer
urn:nbn:se:umu:diva-21815 (URN)
Tillgänglig från: 2009-04-20 Skapad: 2009-04-20 Senast uppdaterad: 2018-06-08Bibliografiskt granskad
3. An in vivo study of the antimalarial effect of polyamine synthesis inhibitors in Plasmodium berghei
Öppna denna publikation i ny flik eller fönster >>An in vivo study of the antimalarial effect of polyamine synthesis inhibitors in Plasmodium berghei
Visa övriga...
(Engelska)Manuskript (Övrigt vetenskapligt)
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.

Nyckelord
Malaria, Plasmodium, polyamine inhibitors, 4MCHA, DFMO, AdoDATO
Nationell ämneskategori
Biokemi och molekylärbiologi
Forskningsämne
infektionssjukdomar
Identifikatorer
urn:nbn:se:umu:diva-21828 (URN)
Tillgänglig från: 2009-04-20 Skapad: 2009-04-20 Senast uppdaterad: 2019-01-21

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