Pathogenesis of Type 1 Dengue Virus Infection in Suckling, Weanling and Adult Mice

Interrelationships between age of host and degree of adaptation of virus were studied by measuring lethality, virus production, antibody formation and interferon production. Low, medium, and high mouse-passaged lines (MP-3, MP-33, and MP-125) of type 1 dengue virus were inoculated intracerebrally into suckling, weanling, and adult mice. Each line multiplied to the highest titer in suckling mice and caused a rapidly fatal infection before the development of detectable circulating antibodies. Peak virus titers were lower in older mice, and marked dissimilarities appeared in the neurologic manifestation of disease as well as in mortality patterns. Weanling mice remained uniformly susceptible to the MP-125 and MP-33 lines but approximately 60 per cent survived infection with MP-3 virus. More pronounced differences occurred in adults. While MP-125 virus was still uniformly lethal, 95 and 10 per cent survived infections with MP-3 and MP-33 lines, respectively. In such cases irregular symptomatology and abortive CNS disease were not infrequent and recovery could be correlated with the development of an immune response and the elimination of virus from the brain. Exogenous interferon, passively administered to suckling animals prior to the inoculation of a lethal dose of any of the three virus lines, was capable of preventing mortality in a significant number. However, under the conditions of experimental infection with all nine virus-host combinations, detectable levels of actively induced interferon appeared in the brain only after virus titers reached approximately 105 per gram of brain and thereafter were directly related to virus titer. Such a relationship indicated that 1) interferon had little or no effect on the outcome of infection, 2) the differences in virulence between virus lines were not determined by their relative abilities to induce or respond to interferon and 3) the amount of interferon produced was not influenced by age.