Azathioprine favourably influences the course of malaria.
BACKGROUND
Azathioprine triggers suicidal erythrocyte death or eryptosis, characterized by cell shrinkage and exposure of phosphatidylserine at the erythrocyte surface. Eryptosis may accelerate the clearance of Plasmodium-infected erythrocytes. The present study thus explored whether azathioprine influences eryptosis of Plasmodium-infected erythrocytes, development of parasitaemia and thus the course of malaria.


METHODS
Human erythrocytes were infected in vitro with Plasmodium falciparum (P. falciparum) (strain BinH) in the absence and presence of azathioprine (0.001 - 10 microM), parasitaemia determined utilizing Syto16, phosphatidylserine exposure estimated from annexin V-binding and cell volume from forward scatter in FACS analysis. Mice were infected with Plasmodium berghei (P. berghei) ANKA by injecting parasitized murine erythrocytes (1 x 106) intraperitoneally. Where indicated azathioprine (5 mg/kg b.w.) was administered subcutaneously from the eighth day of infection.


RESULTS
In vitro infection of human erythrocytes with P. falciparum increased annexin V-binding and initially decreased forward scatter, effects significantly augmented by azathioprine. At higher concentrations azathioprine significantly decreased intraerythrocytic DNA/RNA content (>or= 1 microM) and in vitro parasitaemia (>or= 1 microM). Administration of azathioprine significantly decreased the parasitaemia of circulating erythrocytes and increased the survival of P. berghei-infected mice (from 0% to 77% 22 days after infection).


CONCLUSIONS
Azathioprine inhibits intraerythrocytic growth of P. falciparum, enhances suicidal death of infected erythrocytes, decreases parasitaemia and fosters host survival during malaria.
Bobbala
Diwakar
D
Department of Physiology, University of Tübingen, Tübingen, Germany. diwakarmpharm@gmail.com
Koka
Saisudha
S
Geiger
Corinna
C
Föller
Michael
M
Huber
Stephan M
SM
Lang
Florian
F
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001379:Azathioprine / Q000378:metabolism / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects* / Q000469:parasitology; D005434:Flow Cytometry; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D021141:Nucleic Acid Amplification Techniques; D018512:Parasitemia / Q000469:parasitology* / Q000517:prevention & control; D010718:Phosphatidylserines / Q000378:metabolism; D010962:Plasmodium berghei / Q000187:drug effects* / Q000254:growth & development; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development
D007166:Immunosuppressive Agents; D010718:Phosphatidylserines; D001379:Azathioprine