COLLABORATION OF ANTIBODY AND INFLAMMATION IN CLEARANCE OF RABIES VIRUS FROM THE CENTRAL-NERVOUS-SYSTEM

To investigate the involvement of various cellular and humoral aspects of immunity in the clearance of rabies virus from the central nervous system, (CNS), we studied the development of clinical signs and virus clearance from the CNS in knockout mice lacking either B and T cells, CD8(+) cytotoxic T cells, B cells, alpha/beta interferon (IFN-alpha/b eta) receptors, IFN-gamma receptors, or complement components C3 and C 4. Following intranasal infection with the attenuated rabies virus CVS -F3, normal adult mice of different genetic backgrounds developed a tr ansient disease characterized by loss of body weight and appetite depr ession which peaked at 13 days post-infection (p.i.). While these anim als had completely recovered by day 21 p.i., mice lacking either B and T cells or B cells alone developed a progressive disease and succumbe d to infection. Mice lacking either CD8(+) T cells, IFN receptors, or complement components C3 and C4 showed no, significant differences in the development of clinical signs by comparison with intact counterpar ts having the same genetic background. However, while infectious virus and viral RNA could be detected in normal control mice only until day 8 p.i., in all of the gene knockout mice studied except those lacking C3 and C4, virus infection persisted through day 21 p.i. Analysis of rabies virus-specific antibody production together with histological a ssessment of brain inflammation in infected animals revealed that clea rance of CVS-F3 by 21 days p.i. correlated with both a strong inflamma tory response in the CNS early in the infection (day 8 p.i.), and the rapid (day 10 p.i.) production of significant levels of virus-neutrali zing antibody (VNA), These studies confirm that rabies VNA is an absol ute requirement for clearance of an established rabies virus infection . However, for the latter to occur in a timely fashion, collaboration between VNA and inflammatory mechanisms is necessary.