EVALUATION OF THE SEVERE COMBINED IMMUNODEFICIENT (SCID) MOUSE AS AN ANIMAL-MODEL FOR DENGUE VIRAL-INFECTION

Severe combined immunodeficient (SCID) mice reconstituted with human p eripheral blood lymphocytes (hu-PBL) were evaluated as an animal model for demonstrating dengue (DEN) viral infection. Reconstituted mice (h u-PBL-SCID) that demonstrated successful engraftment by the presence o f serum titers of human immunoglobulin (Ig) were inoculated intraperit oneally with DEN virus serotype 1 (DEN-1). Serial blood samples were t aken postinoculation and assayed for virus in C6/36 cells. The identit y of all viral isolates was confirmed by an immunofluorescence antibod y assay using DEN-1 monoclonal antibody. A total of six experiments we re performed using different procedures of reconstitution and infectio n, and in three of these experiments, DEN-1 virus was recovered from t he hu-PBL-SCID mice. In the first successful experiment, DEN-1 virus w as recovered on postinoculation day (PID) 24 from blood, spleen, thymu s, and lung tissues of one of eight hu-PBL-SCID mice. A second group o f eight hu-PBL-SCID mice were inoculated with human monocytes infected in vitro with DEN-1 virus. Virus was recovered from the blood of mice between PID 15 and 23, and from lung tissue of one of these mice. In a third experiment, seven SCID mice were treated initially with anti-a sialo GM1 antibody to eliminate natural killer cells, and then were in jected simultaneously with a mixture of hu-PBL and DEN-1 virus. Virus was demonstrated in the blood of one mouse on PID 38, and in another m ouse on PID 8, 12, 20, 24, and 36. Virus was recovered from lung tissu e of the first mouse on PID 85 and from all tissues tested from the se cond mouse on PID 50. Tissues from the second mouse also were tested b y immunostaining, and DEN viral antigen was detected in liver, spleen, kidney and lune sections; human B cells were detected in spleen and l ung tissues, and human T cells were detected in lung and brain. The DE N virus-positive mice from all three experiments had been reconstitute d with lymphoid cells from the same human donor. None of the 16 nonrec onstituted SCID mice inoculated with DEN-1 virus as controls for these three experiments had detectable virus in any tissues. Attempts to de tect evidence of DEN-1 virus infection of hu-PBL-SCID mice in three ad ditional experiments using other human donors were unsuccessful. Data derived from these experiments show that hu-PBL-SCID mice can be infec ted with DEN-1 virus, but the frequency of infection was low. Further studies need to be conducted to better define and control the factors responsible for susceptibility to DEN virus infection in the hu-PBL-SC ID mouse before it will be useful as a laboratory model.