THE PATHOGENESIS OF HERPES VIRUS ENCEPHALITIS II. A CELLULAR BASIS POlZ THE DEVELOPMENT OF RESISTANCE WITH AGE

The development of resistance to disease with increasing age is recognized in many viral infections of man and experimental animals (see reviews by Blmaet, reference 1, and Sigel, reference 2). Metabolic and hormonal changes, antibody response, inhibitory substances, anatomical developments, and interferon production have all been suggested to explain this development of resistance (2, 3). Resistance to viruses causing encephalitis often develops only to virus inoculated extraneurally, and the adult remains susceptible to intracerebral inoculation (4-6). The elusive "blood-brain barrier" has been invoked to explain this selective resistance. The most extensive study of the development of resistance to encephalitis with age was carried out with vesicular stomatitis virus in mice and guinea pigs by Sabin and Olitsky (7-10). They concluded that "barriers" developed with age and that these were located in the anterior olfactory region of the brain and at the myoneural junction. Extending their studies to Eastern and Western equine encephalitis viruses, they suggested barriers at the level of blood vessels (11, 12). Precisely which cells constituted the barriers, however, could not be determined with the methods employed. In herpes simplex virus infection age is an important host determinant in the development of encephalitis. Andervont (13) first showed in mice that resistance to herpetic encephalitis developed only to extraneurally inoculated virus, and his finding has been confirmed by others (5, 14, 15). Since fluorescent antibody staining proved successful in demonstrating the pathogenesis of herpes virus encephalitis in the suckling mouse (16), the present study was undertaken to determine at what cellular level the spread of extraneural infection was arrested in the adult. With this method the location of the "age barrier" was deter-