1991 Fiscal Year Final Research Report Summary
Experimental Analysis of Pathogenicity of Cytomegalovirus with The Attenuated Mutants.
| Project/Area Number |
02807051
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Virology
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| Research Institution | Miyazaki Medical College |
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Principal Investigator |
MINAMISHIMA Yoichi Miyazaki Medical College, Professor, 医学部, 教授 (80041284)
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| Co-Investigator(Kenkyū-buntansha) |
KUMURA Keiko Miyazaki Medical College, Research Instructor, 医学部, 助手 (50186475)
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| Project Period (FY) |
1990 – 1991
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| Keywords | Cytomegalovirus / Murine cytomegalovirus (MCMV) / Temperature-sensitive mutation / Attenuation mutation / Virus replication in the target organs / Organ damage / Virulence factor |
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| Research Abstract |
Human cytomegalovirus (HCMV) causes congenital infections and serious diseases in immunocompromised hosts including organ transplant recipients and patients with acquired immunodeficiency syndrome (AIDS). Because of species-specificity, mechanisms of infection and pathogenesis of HCMV has been studied with animal models. We employed murine cytomegalovirus (MCMV) as a model for HCMV.
Temperature-sensitive mutants of MCMV were isolated from the Smith strain (wild type; wt) for the purpose of obtaining mutant strains with reduced pathogenicity. One of them, ts21, lacks the ability to synthesize DNA at 39ﾟC and showed the reduced ability to cause lethal infection in newborn mice. Back cross of ts21 with wt resulted in production of a recombinant (rec21w) which were temperature-insensitive but still attenuated for mice. These results suggest that ts21 harbors two independent mutations: a mutation(s) responsible for temperature sensitivity (ts), and a mutation(s) responsible for attenuation (
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att). Genotypes of these mutants were proposed as follows: ts21 (ts, att), and rec21w (ts^+, att).
The effect of each mutation on in vivo virus replication and pathogenicity was investigated. A genetical difference between wt and rec21w exists in the att gene. Virus titer in the target organs of rec21w-infected mice was almost as same as that of wt-infected mice, but rec21w produced less organ damage and less intraperitoneal hemorrhage than wt. Thus att reduces the capacity of MCMV to induce clinicopathological changes without affecting the capacity to replicate in the target organs. Therefore, lethal infection of MCMV requires a factor(s) responsible for clinicopathological changes. A genetical difference between rec21w and ts21 exists in the ts gene. Replication of ts21 was almost completely restricted in the organs of infected mice and little clinicopathological change was observed in the organs of ts21-infected rniee. The in vivo and in vitro result suggest that ts is a temperature-sensitive mutation(s) which occurred in a gene(s) essential for virus replication in cells, and the reduced pathogenicity of ts21 is directly attributable to lack of virus multiplication in the target organs whose temperature is nonpermissive for virus growth. Less
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