General Background

Viral tissue tropism and pathogenesis are highly dependent on well-orchestrated and defined interactions that occur between the viral pathogen and its host. The single-stranded Parvoviridae infect a broad range of natural hosts that include invertebrates and mammals, and pathogenic members cause serious disease in the young and immunocompromised adults. However, disparities in tissue tropism and in vivo pathogenicity can be observed between highly homologous strains for several members of the Parvoviridae. The combination of molecular analysis with disease outcomes for a number of strains of the Aleutian mink disease parvovirus (AMDV), canine parvovirus, and feline panleukopenia virus (FPV), and for porcine parvovirus (PPV), has provided models for probing the determinants of parvovirus tissue tropism and pathogenicity. In the parvovirus minute virus of mice (MVM) model adopted in this study, the prototype strain (MVMp) replicates in vitro in mouse fibroblast cell lines, while the immunosuppressive strain (MVMi) replicates in mouse T lymphocytes and mouse hematopoietic precursors. In vivo, MVMp infection of newborn mice is asymptomatic, while MVMi infection of newborn mice as well as of adult mice with severe combined immunodeficiency syndrome (SCID) is lethal.


Parvovirus capsids are ~260 Ĺ in diameter and contain 60 copies (in total) of viral protein 1 (VP1) to VP4, in a T=1 icosahedral capsid arrangement, with the smallest VP, depending on the virus member, being the major capsid viral protein. The number of capsid VP species per virion differs among parvoviruses. For example, the AMDV capsid contains only two polypeptides, VP1 and VP2; MVM has three, VP1 to VP3; and members of the subfamily Densovirinae have four, VP1 to VP4. The VPs are overlapping, with the entire sequence of VP4 contained within VP3; VP3 is contained in VP2, which is in turn contained within VP1; VP1 has a unique N-terminal domain. The VPs are translated from the same mRNA or result from posttranslational cleavage. For example, in MVM, VP3 is formed by postassembly cleavage of approximately 18 to 20 amino acids from the N terminus of VP2 in full (DNA containing) infectious virions. This cleavage event is not seen in empty (no DNA) particles digested in vitro with trypsin, unless exposure of VP2 is induced by heat. The molecular sizes of the MVM proteins are 83,000, 64,000, and 61,000 Da for VP1, VP2, and VP3, respectively. The 3-dimensional structures of several parvoviruses, adenoassociated virus serotype 2 (AAV2), human parvovirus B19 (B19), CPV, Galleria mellonella densovirus (GmDNV), FPV, MVMi, and PPV, have been determined using X-ray crystallography. Crystal structures of host range and antigenic mutants of CPV, as well as of CPV and FPV under various pH and ionic conditions, have also been determined. The structures of AMDV strain G (AMDV-G), AAV2, AAV4, AAV5, B19-globoside receptor complex, CPV-Fab complex, and Junonia coenia densovirus (JcDNV) have been determined by cryoelectron microscopy and image reconstruction. The parvovirus capsid VP topology is highly conserved, even for members that are only ~20% identical at the amino acid sequence level, such as AAV2 and B19, with variations localized to surface loop regions between strands of a core b-barrel domain. The characteristic parvovirus capsid surface features include protrusions at or surrounding the icosahedral threefold axes and depressions at the icosahedral twofold axes and around the fivefold axes. Exceptions to this general surface topology are seen in the smoother GmDNV and JcDNV capsids as a result of smaller loop insertions between their b-strands. Structural mapping of amino acids reported to control tissue tropism and pathogenicity onto the capsid proteins of AMDV-G, CPV, FPV, MVMi, and PPV localize these regions on or close to variable capsid surface loops.

Our Focus

Our lab in conjunction with the Almendral Lab study how the MVM capsid structure plays a role in controlling the tropism and pathogenicity of this family of viruses.

Selected Recent Publications

López-Bueno, A., M. P. Rubio, N. Bryant, R. McKenna, M. Agbandje-McKenna, J. M. Almendral. 2006. Host selection of subtle topological changes at the sialic acid binding pocket of the parvovirus capsid modulating cell binding affinity drastically determine virulence. J. Virol., 80:1563-1573.
López-Bueno 2006

Kontou, K., L. Govindasamy, H-J Nam, N. Bryant, A. L. Llamas-Saiz, C. Foces-Foces, E. Hernando, M.-P. Rubio, R. McKenna, J.M. Almendral, M. Agbandje-McKenna. 2005. Structural determinants of tissue tropism and in vivo pathogenicity for the parvovirus minute virus of mice. J. of Virology, 79:10931-10943.
Kontou 2005

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