Parvovirus Minute Virus of Mice (MVM)

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The Parvoviridae is a family of small non-enveloped ssDNA viruses with a broad range of natural vertebrate and invertebrate hosts, including humans, monkeys, dogs, cats, mice, and insects. Pathogenic members cause severe disease in the young and immunocompromised adults. As examples, the newly discovered human bocavirus causes respiratory tract infections and gastroenteritis in young children and human parvovirus B19, which causes a mild rash in children infects, can cause acute severe or chronic anemia. Severe anemia due to B19 infection of an unborn baby can result in miscarriage in ~5% of pregnant women who are not immune to the virus. Non-pathogenic members, such as the Adeno-associated viruses (AAVs), are being developed for therapeutic gene deliver applications.

The ssDNA parvovirus genome, ~5000 bases, is packaged into a T=1 capsid that is ~260 Å in diameter[1]. The capsid is assembled from 60 copies (in total) of the common C-terminal region (~520 aa) of two to four overlapping capsid viral proteins (VPs), depending on the family member, with the larger proteins having N-terminal extensions which are not required for capsid assembly, but perform other functions in the life cycle, including a PLA2 domain required for endosomal escape during cellular trafficking. Thus these capsids are assembled from essentially one protein which is responsible for performing the multitude of functions required for successful host infection, including host cell receptor attachment, an essential first step in the life cycle[2]. While the cell surface receptors are not known for the majority of the Parvoviridae, recognition of cell surface glycans, in the context of proteins or lipids, have been reported to be an important first step in infection. This glycan recognition also plays a role in (I) tissue tropism and pathogenicity differences between highly homologous strains for several pathogenic members and (II) tissue tropism and transduction efficiency in viral gene delivery vectors. Thus characterizing the interaction(s) of these viruses with their receptors is important for understanding the capsid determinants of tissue tropism and pathogenicity, and for manipulating the capsids for improved efficacy in corrective gene delivery applications. Minute Virus of Mice (MVM), is assembled from three VPs, VP1, VP2, and VP3, with the entire sequence of the smallest VP3 contained within VP2 which is in turn contained with VP1; VP1 has a unique N-terminal PLA2 region. VP3, which is only generated from VP2 following genome packaging, forms the majority of the capsid protein content, at ~90%, and contains the receptor recognition site. Significantly, this receptor-recognition site is only created in the assembled capsid with amino acid contributions from icosahedral symmetry related VPs[3].

The parvoviruses provide an excellent example of genomic economy in the coding of a “single” viral protein which assembles a multifunctional capsid, including a receptor recognition site. MVM has proved to be an ideal model for studying the capsid determinant of tissue tropism, pathogenicity, and host range adaption dictated by glycan receptor interaction(s) for this family. Interaction with cell surface sialic acid, in the context of a glycoprotein, is an essential first step in cellular recognition and tropism by MVM[4][5]. Two homologous MVM strains (MVMp, the prototype non-pathogenic strain and MVMi, the immunosuppressive pathogenic strain) that are 97% identical have pronounced differences in tissue tropism and in vivo pathogenesis[6][7][8][9][10]. Their phenotypes are associated with one or two VP amino acid differences resulting in local structural variations that alter MVM – infectious sialic acid receptor interactions and utilization[11][5]. Studies of the MVMp, in which virulent mutations were observed, also provided information on capsid adaptations, associated with altered receptor affinity, which confer a pathogenic phenotype[11]. In addition, MVM has served as a model for studying capsid adaptations, involving the sialic acid receptor recognition site, which enables the infection of a new host[12]. While it is known that a limited number of amino acids differences can also dictate tropism and pathogenicity disparities between homologous strains of other Parvoviridae members, unlike MVM, these have not been extensively studied with respect to the contribution of glycans interactions in dictating these differences.

Contents

CFG Participating Investigators contributing to the understanding of this paradigm

  • CFG Participating Investigators (PIs) contributing to the understanding of MVM include: Mavis McKenna
  • CFG PIs contributing to the understanding of AAV capsid include: Aravind Asokan, Regine Heilbronn

Progress toward understanding this GBP paradigm

Carbohydrate ligands

MVM interacts with cell surface sialic acid, in the context of a glycoprotein[4][5]. This glycan is also recognized by several members of the Parvoviridae, including H1 (rat parvovirus) and members of the AAV[13] (and unpublished data).

Cellular expression of GBP and ligands

MVM is a member of the Parvoviridae, a group of small non-enveloped ssDNA family of viruses with a T=1 icosahedral capsid. Members of this family infect a broad range of vertebrate and invertebrate hosts, including humans, dogs, cats, mice, and insects and have tropism for different tissues and organs In vitro MVM strains grow in mouse fibroblasts, T lymphocytes, and hematopoietic precursors. In vivo MVM replicates in many organs, including the kidneys, liver, and the brain (for MVM strain i)

Biosynthesis of ligands

Sialylated glycoproteins recognized by MVM are synthesized by host cells. The enzyme required for biosynthesis of the type 2 poly N-acetyllactosamine chains and modification with sialic acid or with sialic acid and fucose, creating the Lewisx epitope, have been defined (poly N-acetyllactosamine extension biosynthesis). Gangliosides, sialylated oligosaccharides, are synthesized by the host by well defined pathways (Glucosylceramide biosynthesis).

Structure

MVM is assembled from three VPs, VP1, VP2, and VP3, with the entire sequence of the smallest VP3 contained within VP2 which is in turn contained with VP1; VP1 has a unique N-terminal PLA2 region. VP3, which is only generated from VP2 following genome packaging, forms the majority of the capsid protein content, at ~90%, and contains the receptor recognition site. Significantly, this receptor-recognition site is only created in the assembled capsid with amino acid contributions from icosahedral symmetry related VPs[3].
File:MVMMonoCapsid.jpg

The glycan structures below have been observed to interact with MVM capsids using the CFG glycan array
File:structuresGD3SiaLN.jpg

Biological roles of GBP-ligand interaction

Interaction with cell surface sialic acid, in the context of a glycoprotein, is an essential first step in cellular recognition and tropism by MVM[4][5]. Glycan recognition by members of the Parvoviridae family dictates tissue tropism and is involved in tissue tropism and pathogenicity differences between highly homologous strains for several pathogenic members.

CFG resources used in investigations

The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the CFG database search results for "parvovirus".

Three CFG resources have been used in the characterization of MVM glycan interactions and in vitro tissue tropism.

Glycan profiling

TThe CFG performed glycan profiling of three different cell lines, A9 fibroblasts, EL4T lymphocytes, and NB324K cells used for in vitro studies of MVM, in order to correlate the glycan screening results with the glycans present on the cells that are permissive to the MVM strains (unpublished data).

Glycogene microarray

MVM is not represented on the CFG microarrays, which only contain probes for mouse and human glycogenes.

Knockout mouse lines

N/A

Glycan array

The glycan recognition properties of the two MVM strains (click here), as well as virulent mutants arising from in vivo studies of MVMp, were further defined using the CFG glycan array[11] (and unpublished data). These capsids were the first intact virus capsids to be screened by the CFG. This was done using plate arrays versions 2 and 3[11]. The glycans identified in the array screening were then provided by the CFG for X-ray crystallographic studies to map the receptor binding site on the virus capsids (unpublished data). Mutations of capsid surface amino acids residues at the mapped binding site results in reduced sialic acid affinity[5][11]. CFG PIs have also used the CFG glycan array to screen AAV capsids. To see all glycan array results for MVM, click here.

Related GBPs

Other parvovirus GBPs have been studied by the CFG, including H1 (rat parvovirus) and several AAV serotypes: AAV1 (CFG data), AAV2, AAV4-AAV9[13] (and unpublished data; CFG data: AAV5, AAV6, AAV7, AAV8, AAV9.) Glycan array analyses have been used to identify glycans recognized by the capsids of these viruses, which includes terminal sialic acid containing oligosaccharides as well as those which terminate in galatose [13](and unpublished data).

References

  1. Chapman, M.S. and M. Agbandje-McKenna, Atomic structure if viral particles., in Parvoviruses, J.R. Kerr, et al., Editors. 2006, Edward Aenold Ltd. New York: New York. p. 107-123.
  2. Agbandje-McKenna, M. and M.S. Chapman, Correlating structure with function in the viral capsid, in Parvoviruses, J.R. Kerr, et al., Editors. 2006, Edward Arnold, New York: New York.
  3. 3.0 3.1 Kontou, M., 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. Virol., 79:10931-10943.
  4. 4.0 4.1 4.2 Cotmore, S. F., and P. Tattersall. 1987. The autonomously replicating parvoviruses of vertebrates. Adv. Virus Res. 33:91–174.
  5. 5.0 5.1 5.2 5.3 5.4 López-Bueno, A, M-P. Rubio, N. Bryant, R. McKenna, M. Agbandje-McKenna, J. M. Almendral. 2006. Host-selected amino acid changes at the sialic acid binding pocket of the parvovirus capsid modulate cell binding affinity and determine virulence. J. Virol., 80: 1563-1573.
  6. 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. Lab. Investig. 65:357–363.
  7. Brownstein, D. G., A. L. Smith, E. A. Johnson, D. J. Pintel, L. K. Naeger, and P. Tattersall. 1992. The pathogenesis of infection with minute virus of mice depends on expression of the small nonstructural protein NS2 and on the genotype of the allotropic determinants VP1 and VP2. J. Virol. 66:3118– 3124.
  8. Ramı´rez, J. C., A. Fiaren, 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 cerebral young neurons. J. Virol. 70:8109–8116.
  9. 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). J. Virol. 69:3229–3232.
  10. 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. J. Virol. 73:1774–1784.
  11. 11.0 11.1 11.2 11.3 11.4 Nam, H.-J., B. Gurda-Whitaker, W. Y. Gan, S. Ilaria, R. McKenna, P. Mehta, R. A. Alvarez, M. Agbandje-McKenna. 2006. Identification of the sialic acid structures recognized by minuterole of binding affinity in virulence adaptation. J. Bio. Chem., 281:25670-25677.
  12. Etingov I, R. Itah, M. Mincberg, A. Keren-Naus, H.-J. Nam, M. Agbandje-McKenna, C. Davis C. 2008. An extension of the Minute Virus of Mice tissue tropism. Virology, 379:245-255.
  13. 13.0 13.1 Wu Z, E. Miller E, M. Agbandje-McKenna, R. J. Samulski. 2006. {alpha}2,3 and {alpha}2,6 N Linked Sialic Acids Facilitate Efficient Binding and Transduction by Adeno-Associated Virus Types 1 and 6. J. Virol., 80:9093-9103.

Acknowledgements

The CFG is grateful to the following PIs for their contributions to this wiki page: Mavis Agbandje-McKenna, Thilo Stehle

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