Bc1-2 protects mice against fatal alphavirus encephalitis.
Virus-induced apoptosis has been well characterized in vitro, but the role of apoptosis in viral pathogenesis is not well understood. The suicide of a cell in response to viral infection is postulated to be an important host defense for the organism, leading to a reduction in its total viral burden. However, virus-induced death of nonregenerating cells in the central nervous system may be detrimental to the host. Therefore, to investigate the role of apoptosis in the pathogenesis of fatal encephalitis, we constructed a recombinant alphavirus chimera that expresses the antiapoptotic gene, bcl-2, in virally infected neural cells. Infection of neonatal mice with the alphavirus chimera expressing human bcl-2 [Sindbis virus (SIN)/bcl-2] resulted in a significantly lower mortality rate (7.5%) as compared with infection with control chimeric viruses containing a chloramphenicol acetyltransferase (CAT) reporter gene (SIN/CAT) (78.1%) or bcl-2 containing a premature stop codon (SIN/bcl-2stop) (72.1%) (P < 0.001). Viral titers were reduced 5-fold 1 day after infection and 10-fold 6 days after infection in the brains of SIN/bcl-2-infected mice as compared to SIN/CAT or SIN/bcl-2stop-infected mice. In situ end labeling to detect apoptotic nuclei demonstrated a reduction in the number of foci of apoptotic cells in the brains of mice infected with SIN/bcl-2 as compared with SIN/bcl-2stop. The reduction in apoptosis was associated with a reduction in the number of foci of cells expressing alphavirus RNA. Thus, the antiapoptotic gene, bcl-2, suppresses viral replication and protects against a lethal viral disease, suggesting an interaction between cellular genetic control of viral replication and cell death.
Levine
B
B
Department of Medicine, Columbia University College of Physicians and Surgeons, New York, 10032, USA.
Goldman
J E
JE
Jiang
H H
HH
Griffin
D E
DE
Hardwick
J M
JM
D018354:Alphavirus Infections / Q000209:etiology / Q000517:prevention & control*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000235:genetics*; D001921:Brain / Q000473:pathology / Q000821:virology; D002678:Chimera / Q000235:genetics; D018792:Encephalitis, Viral / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D015870:Gene Expression; D006801:Humans; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2; D012845:Sindbis Virus / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology; D014779:Virus Replication / Q000187:drug effects
D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2