The RBC-Substituted SCID Mouse Model for Intraerythrocytic Protozoan Parasites.

Abstract

In vivo studies for hemoparasitic protozoan diseases of man and domestic animals will be greatly facilitated if experimental infections can be done with small laboratory animals, such as mice and rats. We have developed an innovative experimental system which makes mice susceptible to intraerythocytic protozoan parasites that are, in nature, not infectious to mice. A key of our experimental system is the use of a mutant strain of mice having severe combined immunodeficiency (SCID mice; C.B-17 scid) . Owing to the inability to generate specific immune responses, the red blood cells (RBCs) circulating in SCID mice can be substituted with RBCs of other animal species.The RBC-substitution of SCID mice was demonstrated the best with bovine (bo) RBCs. We were able to create SCID mice having bo-RBCs by giving repetitive transfusions of bo-RBCs into SCID mice. The bo-RBC-SCID mice became susceptible to intraerythocytic parasites of cattle, such as Theileriia sergenti and Babesia bovis, and developed high levels of parasitemia as long as bo-RBC transfusions were continued. This mouse model was found to be useful to evaluate efficacy of antiprotozoal drugs and to examine ability of antibodies against parasites to inhibit parasite growth. The bo-RBC-SCID mice infected with Babesia parasites exhibited clinical symptoms and, thus, should serve as an useful model system to study mechanisms of hemoparasitic protozoan diseases, particularly in cerebral babesiosis caused by B. bovis.Although the principle of our experimental system is applicable to human malaria, substitution of SCID mice with human (hu) RBC is found to be difficult. In SCID mice, hu-RBCs are cleared from the blood circulation much more rapidly than bo-RBCs. The rapid hu-RBC clearance in SCID mice appeared to be caused by avid phagocytosis of hu-RBCs by reticuloen-dothelial macrophages as well as deposition of complement C3 on the surface of hu-RBCs. Human serum and some carbohydrate compounds, such as yeast mannan, SCM-chitin and lactof errin, were found to decelerate the clearance of hu-RBCs in SCID mice. We were able to elaborate hu-RBC-substituted SCID mice by giving hu-RBC transfusions together with administration of human serum. Following infection with Plasmodium falciparum, parasitemia was observed in the hu-RBC-SCID mice for as long as 2 weeks, indicating a possible growth of P. falciprum in the mice.