STUDIES OF THE PATHOGENESIS OF WILD-TYPE VIRUS AND 6 TEMPERATURE-SENSITIVE MUTANTS OF MOUSE CYTOMEGALOVIRUS

A comparison of six temperature-sensitive (ts) mutants with the parent al wild-type (wt) virus showed that, when 1-week-old BALB/c mice were inoculated intraperitoneally with 300 pfu of mouse passaged virus, the viruses could be broadly categorized into two groups. Two viruses (wt and tsm6) were lethal at this dose (10 and 2 LD(50) respectively); an imals died within 4-6 days of inoculation and the virus became general ized infecting heart, lung, liver, spleen, kidney, and salivary glands to high titre (>4.3 log(10) pfu/ g). In contrast, for viruses (tsm1, tsm3, and tsm4) not lethal at this dose (300 pfu = 0.1 to 0.25 LD(50)) , viral replication was poor (<3.4 log(10) pfu/g) except in the saliva ry glands (5.6 to 7.5 log(10) pfu/g). Mutant tsm5 failed to replicate in any tissue while mutant tsm2, lethal at this dose (300 pfu = 1 LD(5 0)), produced levels of virus similar to those found with tsm1, tsm3, and tsm4. Comparison of all viruses at sub-lethal doses (0.1 to 0.25 L D(50)) did show minor differences in their replication in heart, and i n levels of virus and duration of infection in kidney and salivary gla nds. More marked differences were evident between the viruses in their ability to be reactivated from the latent state during immunosuppress ion. Wild-type virus was most easily reactivated in that 67% of animal s exhibited virus in salivary glands, heart, lung, spleen, and kidney. Mutants tsm1, tsm2, tsm3 and tsm6 could be reactivated but from fewer animals (33%, 33%, 18%, and 38% respectively) and fewer tissues. Muta nts tsm4 and tsm5 could not be reactivated. Differences in the ability of the viruses to replicate in the lungs and to cause penumonitis in intranasally-inoculated immunosuppressed mice were also seen. Although immunosuppression was necessary for the induction of severe pneumonit is, differences in severity of pneumonitis resulted from differences i n the ability of the mutants to replicate in the lung in vivo. These d ifferent mutants should prove useful for examining the viral and host factors involved in CMV-induced pneumonitis, and for examining mechani sms involved in latency and reactivation. (C) 1994 Wiley-Liss, Inc.