Article provided by David G. Besselsen, DVM, PhD, University of Arizona
Murine parvovirus induced pathology
The pathogenesis of minute virus of mice (MVM) has been investigated in several strains and ages of mice, with emphasis upon the pathogenesis of MVMi in neonatal BALB/c mice. MVMi induces runting in neonatal BALB/c mice beginning at 7 days post infection (p.i.) (10), and sudden death in neonatal BALB/c, SWR, SJL, CBA, C3H, or DBA/2 mice, but not neonatal C57BL/6 mice, by 12 days p.i. (2, 10, 19). Death in susceptible strains is apparently due to small intestinal hemorrhage (DBA/2) or bilateral renal papillary necrosis (other strains), and susceptible mouse strains are resistant to lethal infections if inoculated after 24 hours of age. MVMi can also induce motor disabilities and intention tremors in neonatal BALB/c mice by 6 days p.i. that are due to infection of the post-migratory internal granular layer neurons of the cerebellum, and infects other major germinal centers in the cerebrum (18). Neonatal mice inoculated with MVMp by combined intracranial/intraperitoneal route display runting and lesions in the external germinal layer of the cerebellum, although without clinical ataxia (9). In addition, MVMi can infect primitive hematopoietic stem cells and erythroid and granulocyte-macrophage precursors in vitro (21), and when inoculated into neonatal BALB/c mice MVMi decreases femoral and splenic hematopoiesis by 10 days p.i.(19). Disruption of hepatic erythropoiesis is also observed in C3H but not C57BL/6 mice infected with MVMi, though anemia is not observed (2). Adult C.B-17 scid mice infected with MVMi intranasally results in persistent infection with ruffled fur and hunched posture by 40 days p.i. and death at 100 days p.i. (11, 20). Severe leucopenia is observed in these mice due to MVMi infection of the granulocyte-macrophage lineage. Erythroid and megakaryocytic precursor cells are also infected, though anemia and thrombocytopenia are not observed, presumably due to increased production at more mature stages in these lineages as suggested by a 5-fold elevation in reticulocyte counts. Finally, a recent report indicates that B-cell deficient mice naturally infected with MVM display runting, decreased fecundity, anemia, leucopenia, and premature death (16). Collectively, these studies indicate that MVM infections can induce runting, sudden or premature death, cerebellar hypoplasia, and/or disruption of hematopoiesis in a mouse strain and age dependent manner. No pathology has been observed in mice experimentally or naturally infected with MPV.
Adverse research effects associated with murine parvovirus infection
Although MVM is capable of inducing clinical disease and death, the predominant adverse research effects associated with murine parvovirus infections are immunomodulation, hematopoetic disruption, tumor suppression, and contamination of cultured cell lines. MVMi inhibits lymphocyte proliferation, generation of cytolytic T cell activity, and antibody response to foreign antigen in vitro, while MVMp has no such effects (1, 15). Although it has been stated that MVMi does not have immunomodulatory effects in vivo, the only reported investigation of this actually provides evidence that MVMi decreases delayed type hypersensivity in BALB/c mice infected as neonates (10), suggesting that MVM can potentially affect immune function in vivo. The immunomodulatory effects of MPV have been more thoroughly investigated. MPV-1 induces poor growth of CD8+, CD4+, and g/d T cell clones in vitro, and inhibits the proliferative response of CD8+ and CD4+ (particularly Th0 and Th1) T cell clones in response to IL-2 in vitro, (12). However, cytolytic T cell activity in primary mixed lymphocyte cultures is not affected by MPV-1 in vitro, thereby exhibiting a different phenotype than MVMi. In contrast, the cytolytic activity of T cells obtained from spleen, peripheral lymph node, and mesenteric lymph node obtained from MPV-1a infected BALB/c mice is reduced for at least one month after MPV-induced immunomodulation caused sarcoma cell regression in the same mice (14). Interestingly, CD4+ cells obtained from spleen and peripheral lymph node of these mice did not proliferate as well as control cells obtained from uninfected mice, while CD4+ cells obtained from the mesenteric lymph node of infected mice displayed increased proliferation as compared to controls. MPV-1a also potentiates rejection of allogeneic and syngeneic skin grafts in BALB/c mice by altering the T-cell dependent immune response, thereby allowing recognition and response to self antigens (13, 14). Interestingly, C3H/HeSn and C57BL/6 mice infected with MPV-1a under the same experimental conditions did not reject syngeneic skin grafts, indicating that genetic factors unique to BALB/c mice are involved in rejection of syngeneic skin grafts. Collectively these data indicate MPV-1 significantly and chronically alters the in vivo immune response, and that these effects can significantly differ among different mouse strains and indeed different lymphoid tissues within the same mouse. Hematopoietic disruption in MVMi infected neonatal BALB/c and adult C.B-17 scid mice was previously discussed in the pathogenesis section. Tumor suppression has been demonstrated for a mastocytoma cell line by MVMp or MVMi (10), ascites tumor cells by MVMp (8), a melanoma cell line by MVMp (7) and hybridoma and sarcoma cells by MPV-1a (12, 14). Tumor suppression by murine parvoviruses is thought to occur by either lytic viral infection of susceptible tumor cells or by enhanced immunity to tumor cells. Finally, MVM and MPV can potentially contaminate cell cultures and tissues of mouse origin (1, 3-6, 12, 17). In conclusion, murine parvoviruses can significantly alter research data generated through the use of infected mice, particularly in the areas of immunology, transplantation, hematopoiesis, and oncology, and can effectively shut down research progress within entire laboratories by contaminating cell cultures and tissues of mouse origin.
1. Bonnard, G. D., E. K. Manders, D. A. Campbell, Jr., R. B. Herberman, and M. J. Collins, Jr. 1976. Immunosuppressive activity of a subline of the mouse EL-4 lymphoma. Evidence for minute virus of mice causing the inhibition. Journal of Experimental Medicine. 143:187-205.
2. Brownstein, D. G., A. L. Smith, R. O. Jacoby, E. A. Johnson, G. Hansen, and P. Tattersall. 1991. Pathogenesis of infection with a virulent allotropic variant of minute virus of mice and regulation by host genotype. Laboratory Investigation. 65:357-64.
3. Collins, M. J., Jr., and J. C. Parker. 1972. Murine virus contaminants of leukemia viruses and transplantable tumors. Journal of the National Cancer Institute 49:1139-43.
4. Crawford, L. V., E. A. Follett, M. G. Burdon, and D. J. McGeoch. 1969. The DNA of a minute virus of mice. Journal of General Virology 4:37-46.
5. Garnick, R. L. 1996. Experience with viral contamination in cell culture. Developments in Biological Standardization 88:49-56.
6. Garnick, R. L. 1998. Raw materials as a source of contamination in large-scale cell culture. Developments in Biological Standardization 93:21-9.
7. Giese, N. A., S. Lang, Z. Raykov, J. Rommelaere, C. Dinsart, and J. J. Cornelis. 2000. Oncosuppressive effects of wild-type MVMp and recombinant derivates in immunocompetent mice. Infectious Disease Review 2:153-154.
8. Guetta, E., Y. Graziani, and J. Tal. 1986. Suppression of Ehrlich ascites tumors in mice by minute virus of mice. Journal of the National Cancer Institute 76:1177-80.
9. Kilham, L., and G. Margolis. 1970. Pathogenicity of minute virus of mice (MVM) for rats, mice, and hamsters. Proceedings of the Society for Experimental Biology & Medicine 133:1447-52.
10. Kimsey, P. B., H. D. Engers, B. Hirt, and C. V. Jongeneel. 1986. Pathogenicity of fibroblast- and lymphocyte-specific variants of minute virus of mice. Journal of Virology. 59:8-13.
11. Lamana, M. L., B. Albella, J. A. Bueren, and J. C. Segovia. 2001. In vitro and in vivo susceptibility of mouse megakaryocytic progenitors to strain i of parvovirus minute virus of mice. Experimental Hematology. 29:1303-9.
12. McKisic, M. D., D. W. Lancki, G. Otto, P. Padrid, S. Snook, D. C. Cronin, P. D. Lohmar, T. Wong, and F. W. Fitch. 1993. Identification and propagation of a putative immunosuppressive orphan parvovirus in cloned T cells. Journal of Immunology 150:419-28.
13. McKisic, M. D., J. D. Macy, Jr., M. L. Delano, R. O. Jacoby, F. X. Paturzo, and A. L. Smith. 1998. Mouse parvovirus infection potentiates allogeneic skin graft rejection and induces syngeneic graft rejection. Transplantation. 65:1436-46.
14. McKisic, M. D., F. X. Paturzo, and A. L. Smith. 1996. Mouse parvovirus infection potentiates rejection of tumor allografts and modulates T cell effector functions. Transplantation 61:292-9.
15. McMaster, G. K., P. Beard, H. D. Engers, and B. Hirt. 1981. Characterization of an immunosuppressive parvovirus related to the minute virus of mice. Journal of Virology. 38:317-26.
16. Naugler, S. L., M. H. Myles, B. A. Bauer, M. J. Kennett, and C. L. Besch-Williford. 2001. Reduced fecundity and death associated with parvovirus infection in B-lymphocyte deficient mice. Contemporary Topics in Laboratory Animal Science 40:66.
17. Nicklas, W., V. Kraft, and B. Meyer. 1993. Contamination of transplantable tumors, cell lines, and monoclonal antibodies with rodent viruses. Laboratory Animal Science 43:296-300.
18. Ramirez, J. C., A. Fairen, and J. M. Almendral. 1996. Parvovirus minute virus of mice strain i multiplication and pathogenesis in the newborn mouse brain are restricted to proliferative areas and to migratory cerebellar young neurons. Journal of Virology 70:8109-16.
19. Segovia, J. C., J. A. Bueren, and J. M. Almendral. 1995. Myeloid depression follows infection of susceptible newborn mice with the parvovirus minute virus of mice (strain i). Journal of Virology. 69:3229-32.
20. Segovia, J. C., J. M. Gallego, J. A. Bueren, and J. M. Almendral. 1999. Severe leukopenia and dysregulated erythropoiesis in SCID mice persistently infected with the parvovirus minute virus of mice. Journal of Virology. 73:1774-84.
21. Segovia, J. C., A. Real, J. A. Bueren, and J. M. Almendral. 1991. In vitro myelosuppressive effects of the parvovirus minute virus of mice (MVMi) on hematopoietic stem and committed progenitor cells. Blood. 77:980-8.