Tumor necrosis factor alpha is a determinant of pathogenesis and disease progression in mycobacterial infection in the central nervous system

The pathogenesis of tuberculous meningitis, a devastating complication of t uberculosis in man, is poorly understood. We previously reported that rabbi ts with experimental tuberculous meningitis were protected from death by a combination of antibiotics and thalidomide therapy. Survival was associated with inhibition of tumor necrosis factor alpha (TNF-alpha) production by t halidomide, To test whether cerebrospinal fluid (CSF) levels of TNF-alpha c orrelated with pathogenesis, the response of rabbits infected in the centra l nervous system (CNS) with various mycobacterial strains was studied. CNS infection with Mycobacterium bovis Ravenel, nl. bovis bacillus Calmette-Gue rin (BCG) Pasteur, and M. bovis BCG Montreal were compared. M. bovis Ravene l induced the highest levels of TNF-alpha in the CSF in association with hi gh leukocytosis, protein accumulation, and severe meningeal inflammation. B CG Pasteur had intermediate effects, and BCG Montreal was the least virulen t. In addition, M. bovis Ravenel numbers were highest in the brain and CSF and the bacilli also disseminated more efficiently to distant organs, compa red with BCG Pasteur and BCG Montreal. In subsequent experiments, rabbits w ere infected with either recombinant M. bovis BCG Montreal (vector), or BCG Montreal expressing the murine gene for TNF-alpha (BCG mTNF-alpha), BCG Mo ntreal was rendered virulent by the expression of murine TNF-alpha, as demo nstrated by high CSF leukocytosis, high protein accumulation, severe mening eal inflammation, persistent bacillary load, and progressive clinical deter ioration, Taken together, these results demonstrate that the level of TNF-a lpha produced during mycobacterial CNS infection determines, at least in pa rt, the extent of pathogenesis.