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Mixed infection decreases malaria burden and escalate relapsing fever
Umeå universitet, Medicinsk fakultet, Molekylärbiologi (Medicinska fakulteten). (Cathrine Persson)
Umeå universitet, Medicinsk fakultet, Molekylärbiologi (Medicinska fakulteten). (Sven Bergström)
Umeå universitet, Medicinsk fakultet, Molekylärbiologi (Medicinska fakulteten). (Cathrine Persson)
Umeå universitet, Medicinsk fakultet, Molekylärbiologi (Medicinska fakulteten). (Sven Bergström)
Vise andre og tillknytning
(engelsk)Manuskript (Annet vitenskapelig)
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.

Emneord [en]
Malaria, Plasmodium, Relapsing fever Borrelia, and mixed infections
HSV kategori
Forskningsprogram
infektionssjukdomar
Identifikatorer
URN: urn:nbn:se:umu:diva-21815OAI: oai:DiVA.org:umu-21815DiVA, id: diva2:211913
Tilgjengelig fra: 2009-04-20 Laget: 2009-04-20 Sist oppdatert: 2018-06-08bibliografisk kontrollert
Inngår i avhandling
1. Malaria and relapsing fever Borrelia: interactions and potential therapy
Åpne denne publikasjonen i ny fane eller vindu >>Malaria and relapsing fever Borrelia: interactions and potential therapy
2009 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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

sted, utgiver, år, opplag, sider
Umeå: Institutionen för molekylärbiologi, 2009. s. 84
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1258
Emneord
Malaria, Plasmodium, relapsing fever, Borrelia, persistent, concomitant infections, polyamines
HSV kategori
Forskningsprogram
molekylär bioteknik (inst f molekylärbiologi); infektionssjukdomar
Identifikatorer
urn:nbn:se:umu:diva-21845 (URN)978-91-7264-768-8 (ISBN)
Disputas
2009-05-15, Major groove, Umeå Universitet, Byggnad 6L, Umeå, 09:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2009-04-29 Laget: 2009-04-20 Sist oppdatert: 2018-06-08bibliografisk kontrollert

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