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 (Chapman and Agbandje-McKenna, 2006)Cite error: Invalid <ref> tag; refs with no name must have content. 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 (Agbandje-McKenna and Chapman, 2006)Cite error: Invalid <ref> tag; refs with no name must have content. 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 (Kontou et al., 2005)Cite error: Invalid <ref> tag; refs with no name must have content.

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 (Cotmore and Tattersall, 1987; Lopez-Bueno et al., 2006)Cite error: Invalid <ref> tag; refs with no name must have content[1]. 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 (Brownstein et al., 1991, 1992, Ramı´rez et al., 1996, Segovia et al., 1995, 1999)Cite error: Invalid <ref> tag; refs with no name must have contentCite error: Invalid <ref> tag; refs with no name must have contentCite error: Invalid <ref> tag; refs with no name must have contentCite error: Invalid <ref> tag; refs with no name must have contentCite error: Invalid <ref> tag; refs with no name must have content. 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 (Nam et. al. 2006, Lopez-Bueno et al., 2006)[2]Cite error: Closing </ref> missing for <ref> tag. 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


Cellular expression


Structure


Biological roles of GBP-ligand interaction


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".

Glycan profiling


Glycogene microarray


Knockout mouse lines


Glycan array

Three CFG resources have been used in the characterization of MVM glycan interactions and in vitro tissue tropism. Using CFG core H the glycan recognition properties of the two MVM strains as well as virulent mutants arising from in vivo studies of MVMp were further defined (Nam et. al. 2006)[2] (and unpublished data). These capsids were the first intact virus capsids to be screened by core H. This was done using plate arrays versions 2 and 3[2]. The glycans identified in the array screening were provided by CFG core D 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 (Lopez-Bueno et al., 2006, Nam et al. 2006)[2]Cite error: Invalid <ref> tag; refs with no name must have content. Glycan profiling of three different cell lines used for in vitro studies of MVM (via CFG core C) has been done to correlate the glycan screening results from core H with the glycans present on the cells that are permissive to the MVM strains (unpublished data).

Related GBPs

Other parvovirus GBPs have been studied by the CFG including H1 (hamster parvovirus) and several AAV serotypes: AAV1, AAV2, AAV4-AAV9 (Wu et al., 2006) (and unpublished data). Other CFG PIs who have used the resources of the CFG for AAV capsid studies are Aravind Asokan (resource requests to core D for glycans) and Regine Heilbronn (resource requests to core H for the screening of AAV2 capsids).

References

  1. Cite error: Invalid <ref> tag; no text was provided for refs named Lopez-Bueno_2006
  2. Cite error: Invalid <ref> tag; no text was provided for refs named Nam_2006

Acknowledgements

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

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